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Clinical Trial Results:
An open label, dose escalation followed by dose expansion, safety and tolerability trial of CAN04, a fully humanized monoclonal antibody against IL1RAP, in subjects with solid malignant tumors

Summary
EudraCT number	2017-001111-36
Trial protocol	BE NO DK NL DE AT SE EE ES LT LV
Global end of trial date	14 Mar 2024

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions
Summary report(s)	CAN04CLIN001 Summary Attachment

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

CAN04CLIN001

ISRCTN number

US NCT number

NCT03267316

WHO universal trial number (UTN)

Sponsor organisation name

Cantargia AB

Sponsor organisation address

Scheelevagen 27, Lund, Sweden, 22363

Public contact

Regulatory Affairs , Cantargia AB, +46 (0)46 2756260, regulatory@cantargia.com

Scientific contact

Regulatory Affairs , Cantargia AB, +46 (0)46 2756260, regulatory@cantargia.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Aug 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Mar 2024

Global end of trial reached?

Yes

Global end of trial date

14 Mar 2024

Was the trial ended prematurely?

Main objective of the trial

Part I • To define the Maximum Tolerated Dose (MTD) or Recommended Phase 2 dose (RP2D) of CAN04, given weekly (Q1W) in subjects with relapsed or refractory non small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), triple negative breast cancer (TNBC) or colorectal cancer (CRC). Part II • To determine the safety and tolerability of CAN04 in subjects with squamous or non-squamous NSCLC or PDAC tumors, when given as monotherapy or in combination with standard of care (SoC) chemotherapy regimen and to identify the RP2D of CAN04 in combination with SoC chemotherapy.

Protection of trial subjects

Priming dose of CAN04 in combination with pre-medication with corticosteroids, paracetamol and antihistamines was introduced during Part I and used to reduce the risk of infusion related reactions. The priming dose was for PDEXx and NCP arms replaced with a ramping infusion of CAN04 for patients being able to start treatment with CAN04 and chemotherapy on the same day.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Aug 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

36 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 22

Country: Number of subjects enrolled

Norway: 6

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

Sweden: 5

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 40

Country: Number of subjects enrolled

Denmark: 28

Country: Number of subjects enrolled

Estonia: 2

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Latvia: 14

Country: Number of subjects enrolled

Lithuania: 30

Worldwide total number of subjects

167

EEA total number of subjects

167

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Overall recruitment period for the study was between 26-Aug-2017 to 12-Apr-2023 and subjects were recruited among 26 centres in Belgium, the Netherlands, Denmark, Norway, Austria, Sweden, Germany, Spain, Estonia, Latvia, Lithuania.

Screening details

Subjects should have a measurable disease in accordance with irRC (enrolled prior to protocol version 7) or iRECIST (enrolled from protocol version 7) by CT or MR scan. If received any previous treatment with chemo-, biologic/targeted- or radiation therapy a wash-out period of 4 weeks applied (6 weeks for treatments known having delayed toxicity).

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part I - Dose escalation

Arm description

Phase 1 dose-escalation arm (3+3 design) to assess the safety of CAN04 monotherapy administered at 1, 1.5, 3, 6, and 10 mg/kg in patients with unresectable NSCLC, PDAC, CRC, or TNBC that were refractory to standard therapy or for whom no standard therapy existed. The primary aim was to assess safety and to define the MTD or RP2D of CAN04 administered once weekly.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 monotherapy was administered at 1, 1.5, 3, 6, or 10 mg/kg depending on cohort once weekly. For cohort 2 and 3 a priming dose of 1.0 mg/kg was used and from cohort 4 and onwards a priming dose of 0.5 mg/kg was used. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only from second part of cohort 4 onwards. From cohort 2 onwards premedication with corticosteroids, antihistamine and paracetamol was given before first administration.

Part II Monotherapy Arm A

Arm description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 10 mg/kg (RP2D) once weekly in patients with unresectable squamous or non-squamous NSCLC or PDAC that were refractory to standard therapy or for whom no standard therapy existed.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 monotherapy was administered at 10 mg/kg once weekly. A priming dose of 0.5 mg/kg was given at first administration. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only. Premedication with corticosteroids, antihistamine and paracetamol was given before first administration.

Part II Monotherapy Arm B

Arm description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 10 mg/kg (RP2D) once weekly for first 6 weeks followed by biweekly administration in patients with unresectable squamous or non-squamous NSCLC or PDAC that were refractory to standard therapy or for whom no standard therapy existed.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 monotherapy was administered at 10 mg/kg once weekly for first 6 weeks followed by biweekly administration. A priming dose of 0.5 mg/kg was given at first administration. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only. Premedication with corticosteroids, antihistamine and paracetamol was given before first administration.

Part II Monotheraphy Arm E

Arm description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 15 mg/kg once weekly for first 6 weeks followed by biweekly administration in patients with unresectable, locally advanced or metastatic squamous or non-squamous NSCLC or PDAC that were refractory to standard therapy or for whom no standard therapy existed.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 monotherapy was administered at 15 mg/kg once weekly for first 6 weeks followed by biweekly administration. A priming dose of 0.5 mg/kg was given at first administration. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only. Premedication with corticosteroids, antihistamine and paracetamol was given before first administration.

Part II Combination therapy Arm C

Arm description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with gemcitabine and cisplatin in patients with stage III or IV squamous or non-squamous non-small cell lung cancer (NSCLC) who were candidates for 1st line of standard chemotherapy regimen with cisplatin/gemcitabine or who relapsed after 1st line with pembrolizumab monotherapy and was candidates for 2nd line of standard chemotherapy regimen with cisplatin/gemcitabine. The arm was initially designed with a limited dose escalation phase as a 3+3 design and 3 dose levels: 5, 7.5, and 10 mg/kg (the monotherapy RP2D). After the identification of MTD/RP2D, it was planned to continue the arm with a dose expansion phase but a provisional MTD was reached on 5 mg/kg and dose reduced to 1 mg/kg and re-escaleted to 2.5 mg/kg.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 was administered at assigned dose (5, 1 or 2.5 mg/kg) once weekly for first 6 weeks followed by biweekly administration. A priming dose of 0.5 mg/kg was given at first administration. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only. Before first administration of CAN04 premedication with corticosteroids, antihistamine and paracetamol was given. CAN04 alone or with gemcitabine as maintenance therapy was allowed once the 4-6 cycles in combination with cisplatin was completed.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

L01BC05

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use, Intravenous drip use

Dosage and administration details

Gemcitabine was administered at 1250 mg/m2 on Days 1 and 8 in cycles of 21 days in combination with cisplatin for 4-6 cycles. CAN04 alone or with gemcitabine as maintenance therapy was subsequently allowed. Treatment with gemcitabine started with second administration of CAN04. Administration of gemcitabine followed the recommendations for premedication and administration outlined for the indication and in combination with cisplatin in the SmPC of the marketed product and in alignment with local clinical practice.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

L01XA01

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Cisplatin was administered at 75 to 100 mg/m2 on Day 1 in cycles of 21 days in combination with gemcitabine for 4 - 6 cycles. Treatment with cisplatin started with second administration of CAN04. Administration of cisplatin followed the recommendations for premedication and administration outlined for the indication and in combination with gemcitabine in the SmPC of the marketed product and in alignment with local clinical practice.

Part II Combination therapy Arm NCP

Arm description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with carboplatin and pemetrexed in patients with stage III or IV non-squamous non-small cell lung cancer (NSCLC) who were candidates for 1st line of standard chemotherapy regimen with carboplatin/pemetrexed or who relapsed after 1st line with pembrolizumab monotherapy and was candidates for 2nd line of standard chemotherapy regimen with carboplatin/pemetrexed.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 was administered at 2.5 mg/kg on Day 1 and on Day 8 in cycles of 21 days. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). Assigned full dose was administered at first administration as a 4 hour ramping infusion. Before first administration of CAN04 premedication with corticosteroids, antihistamine and paracetamol was given. CAN04 alone or with pemetrexed as maintenance therapy was subsequently allowed after 4-6 cycles of carboplatin was completed.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

L01XA02

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Carboplatin was administered at AUC 5 mg/ml/min on Day 1 in cycles of 21 days for 4-6 cycles. Administration of carboplatin followed the recommendations for premedication and administration outlined for the indication in the SmPC of the marketed product and in alignment with local clinical practice.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

L01BA04

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Pemetrexed was administered at 500 mg/m2 on Day 1 in cycles of 21 days in combination with carboplatin for 4-6 cycles. CAN04 alone or with pemetrexed as maintenance therapy was subsequently allowed. Administration of pemetrexed followed the recommendations for premedication and administration outlined for the indication in the SmPC of the marketed product and in alignment with local clinical practice.

Part II Combination therapy Arm D

Arm description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who were candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The arm was initially designed with a limited dose escalation phase as a 3+3 design and 3 dose levels: 5, 7.5, and 10 mg/kg (the monotherapy RP2D). After the identification of MTD/RP2D, it was planned to continue the arm with a dose expansion phase. After 7.5 mg/kg was found to be above MTD the expansion phase was done with 5 mg/kg.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use, Intravenous drip use

Dosage and administration details

CAN04 was administered at assigned dose (5, or 7.5 mg/kg) once weekly for first 6 weeks followed by biweekly administration. A priming dose of 0.5 mg/kg was given at first administration. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). A prolonged infusion time (120 minutes) was applied for the priming dose only. Before first administration of CAN04 premedication with corticosteroids, antihistamine and paracetamol was given. CAN04 alone or with gemcitabine or nab-paclitaxel as maintenance therapy was allowed once the investigator discontinued gemcitabine or nab-paclitaxel due to toxicity.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

L01BC05

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Gemcitabine was administered at 1000 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with nab-paclitaxel as maintenance therapy was subsequently allowed if investigator discontinued gemcitabine due to toxicity. Treatment with gemcitabine started with second administration of CAN04. Administration of gemcitabine followed the recommendations for premedication and administration outlined for the indication and in combination with nab-paclitaxel in the SmPC of the marketed product and in alignment with local clinical practice.

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

L01CD01

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Nab-paclitaxel was administered at 125 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with gemcitabine as maintenance therapy was subsequently allowed if investigator discontinued nab-paclitaxel due to toxicity. Treatment with nab-paclitaxel started with second administration of CAN04. Administration of nab-paclitaxel followed the recommendations for premedication and administration outlined for the indication and in combination with gemcitabine in the SmPC of the marketed product and in alignment with local clinical practice.

Part II Combination therapy Arm PDEX1

Arm description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 at 1 mg/kg in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who were candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The starting dose selected in Arm PDEX1 was chosen to explore doses below the MTD (5.0 mg/kg) after the completion of Part II Combination therapy Arm D.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 was administered at 1.0 mg/kg on Day 1 and Day 15 in cycles of 28. During Cycle 1 CAN04 was administered also on Day 8. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). Assigned full dose was administered at first administration as a 4 hour ramping infusion. Before first administration of CAN04 premedication with corticosteroids, antihistamine and paracetamol was given. CAN04 alone or with gemcitabine or nab-paclitaxel as maintenance therapy was allowed once the investigator discontinued gemcitabine or nab-paclitaxel due to toxicity.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

L01BC05

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Gemcitabine was administered at 1000 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with nab-paclitaxel as maintenance therapy was subsequently allowed if investigator discontinued gemcitabine due to toxicity. Administration of gemcitabine followed the recommendations for premedication and administration outlined for the indication and in combination with nab-paclitaxel in the SmPC of the marketed product and in alignment with local clinical practice.

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

L01CD01

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Nab-paclitaxel was administered at 125 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with gemcitabine as maintenance therapy was subsequently allowed if investigator discontinued nab-paclitaxel due to toxicity. Administration of nab-paclitaxel followed the recommendations for premedication and administration outlined for the indication and in combination with gemcitabine in the SmPC of the marketed product and in alignment with local clinical practice.

Part II Combination therapy Arm PDEX2.5

Arm description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 at 2.5 mg/kg in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who were candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The starting dose selected in Arm PDEX2.5 was chosen to explore doses below the MTD (5.0 mg/kg) after the completion of Part II Combination therapy Arm D.

Arm type

Experimental

Investigational medicinal product name

CAN04

Investigational medicinal product code

Other name

Nadunolimab

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

CAN04 was administered at 2.5 mg/kg on Day 1 and Day 15 in cycles of 28. During Cycle 1 CAN04 was administered also on Day 8. CAN04 is a concentrate for infusion diluted to the appropriate concentration in normal saline and was administered via intravenous infusion over a 60-minute period (an infusion period of 55-70 minutes was allowed). Assigned full dose was administered at first administration as a 4 hour ramping infusion. Before first administration of CAN04 premedication with corticosteroids, antihistamine and paracetamol was given. CAN04 alone or with gemcitabine or nab-paclitaxel as maintenance therapy was allowed once the investigator discontinued gemcitabine or nab-paclitaxel due to toxicity.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

L01BC05

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Gemcitabine was administered at 1000 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with nab-paclitaxel as maintenance therapy was subsequently allowed if investigator discontinued gemcitabine due to toxicity. Administration of gemcitabine followed the recommendations for premedication and administration outlined for the indication and in combination with nab-paclitaxel in the SmPC of the marketed product and in alignment with local clinical practice.

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

L01CD01

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous drip use , Intravenous use

Dosage and administration details

Nab-paclitaxel was administered at 125 mg/m2 on Days 1, 8 and 15 in cycles of 28 days. CAN04 alone or with gemcitabine as maintenance therapy was subsequently allowed if investigator discontinued nab-paclitaxel due to toxicity. Administration of nab-paclitaxel followed the recommendations for premedication and administration outlined for the indication and in combination with gemcitabine in the SmPC of the marketed product and in alignment with local clinical practice.

Number of subjects in period 1	Part I - Dose escalation	Part II Monotherapy Arm A	Part II Monotherapy Arm B	Part II Monotheraphy Arm E	Part II Combination therapy Arm C	Part II Combination therapy Arm NCP	Part II Combination therapy Arm D	Part II Combination therapy Arm PDEX1	Part II Combination therapy Arm PDEX2.5
Started	22	10	10	6	33	10	36	20	20
Completed	17	7	10	4	25	5	25	16	10
Not completed	5	3	0	2	8	5	11	4	10
Adverse event, serious fatal	-	-	-	1	-	-	2	-	-
Physician decision	3	-	-	-	-	-	-	-	1
Consent withdrawn by subject	-	-	-	-	2	-	3	1	2
Adverse event, non-fatal	2	2	-	1	1	-	4	1	4
Death	-	1	-	-	3	2	2	2	2
Termination of the study	-	-	-	-	2	2	-	-	1
General health deterioration	-	-	-	-	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part I - Dose escalation

Reporting group description

Reporting group title

Part II Monotherapy Arm A

Reporting group description

Reporting group title

Part II Monotherapy Arm B

Reporting group description

Reporting group title

Part II Monotheraphy Arm E

Reporting group description

Reporting group title

Part II Combination therapy Arm C

Reporting group description

Reporting group title

Part II Combination therapy Arm NCP

Reporting group description

Reporting group title

Part II Combination therapy Arm D

Reporting group description

Reporting group title

Part II Combination therapy Arm PDEX1

Reporting group description

Reporting group title

Part II Combination therapy Arm PDEX2.5

Reporting group description

Reporting group values	Part I - Dose escalation	Part II Monotherapy Arm A	Part II Monotherapy Arm B	Part II Monotheraphy Arm E	Part II Combination therapy Arm C	Part II Combination therapy Arm NCP	Part II Combination therapy Arm D	Part II Combination therapy Arm PDEX1	Part II Combination therapy Arm PDEX2.5	Total
Number of subjects	22	10	10	6	33	10	36	20	20	167
Age categorical
Units: Subjects
Adults (18-64 years)	15	5	6	5	17	3	22	12	11	96
From 65-84 years	7	5	4	1	16	7	13	8	8	69
85 years and over	0	0	0	0	0	0	1	0	1	2
Age continuous
Units: years
median (full range (min-max))	63.0 (39 to 81)	61.0 (49 to 72)	63.5 (40 to 73)	62.0 (58 to 73)	64.0 (39 to 77)	66.5 (55 to 76)	62.0 (46 to 87)	63.0 (43 to 78)	61.5 (43 to 89)	-
Gender categorical
Units: Subjects
Female	8	2	2	3	11	5	17	7	8	63
Male	14	8	8	3	22	5	19	13	12	104
Child-bearing Potential
Units: Subjects
No	7	2	2	3	10	5	16	6	8	59
Yes	1	0	0	0	1	0	1	1	0	4
Not applicable	14	8	8	3	22	5	19	13	12	104
Ethnicity
Units: Subjects
Not Hispanic or Latino	14	2	5	4	32	10	30	19	20	136
Not reported	8	8	5	2	1	0	6	1	0	31
Race
Units: Subjects
White	14	2	5	4	32	10	30	18	20	135
Asian	0	0	0	0	0	0	0	1	0	1
Not reported	8	8	5	2	1	0	6	1	0	31
Primary Disease
Units: Subjects
NSCLC - subtype not defined	4	2	4	3	1	0	0	0	0	14
NSCLC - squamous	0	0	0	0	14	0	0	0	0	14
NSCLC - non-squamous	0	0	0	0	18	10	0	0	0	28
PDAC	6	8	6	3	0	0	36	20	20	99
CRC	12	0	0	0	0	0	0	0	0	12
TNBC	0	0	0	0	0	0	0	0	0	0
Tumour Still Present at Primary Location at Study Entry
Units: Subjects
Yes	9	6	9	5	32	9	33	19	18	140
No	13	4	1	1	1	1	3	1	2	27
Number of prior lines of treatment for metastatic disease
Units: Subjects
No prior lines		0	0	0	17	7	33	18	18	93
1 prior line		4	3	1	16	3	1	2	2	32
2 prior lines		2	3	2	0	0	1	0	0	8
3 prior lines		3	2	2	0	0	1	0	0	8
4 prior lines		1	0	0	0	0	0	0	0	1
5 prior lines		0	2	1	0	0	0	0	0	3
Not recorded	22	0	0	0	0	0	0	0	0	22
ECOG status
Units: Subjects
ECOG = 0	15	3	5	3	14	2	23	7	4	76
ECOG = 1	7	7	5	3	19	8	13	13	16	91
Height
Units: cm
median (full range (min-max))	174.5 (155 to 191)	177.6 (165 to 198)	179.0 (172 to 185)	171.8 (162 to 188)	172.0 (152 to 189)	169.5 (151 to 175)	170.0 (158 to 205)	172.5 (150 to 194)	173.5 (147 to 184)	-
Weight
Units: kg
median (full range (min-max))	79.1 (53 to 124)	72.3 (45 to 126)	75.7 (62 to 107)	77.7 (74 to 99)	68.0 (53 to 108)	69.5 (54 to 88)	73.7 (48 to 107)	66 (50 to 95)	73.7 (42 to 96)	-
Body Mass Index
Units: kg/m2
median (full range (min-max))	25.6 (18 to 44)	23.3 (16 to 34)	24.5 (21 to 32)	27.1 (22 to 34)	25.6 (18 to 34)	26.8 (20 to 29)	24.4 (17 to 36)	23.1 (18 to 31)	25.3 (17 to 33)	-

Subject analysis set title

Part I - Dose escalation 1 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1 (1 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2 (1.5 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 3 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 3 (3 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 6 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 4 (6 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 10 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 5 (10 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 5 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 1 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 2.5 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 5 mg/kg cohort of Arm D. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 7.5 mg/kg cohort of Arm D. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes same subjects as included in the corresponding reporting group (Part I - Dose escalation), i.e., subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part I - Dose escalation 1 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes same subjects as included in the corresponding safety subject analysis set, i.e., subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 3 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

For monotherapy cohorts/arms mITT is the same as reporting groups and any safety analysis sets. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 6 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 10 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Monotherapy Arm A mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes same subjects as included in the corresponding reporting group (Part II Monotheraphy Arm A) , i.e., subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part II Monotherapy Arm B mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes same subjects as included in the corresponding reporting group (Part II Monotheraphy Arm B) , i.e., subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part II Monotherapy Arm E mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes same subjects as included in the corresponding reporting group (Part II Monotheraphy Arm E) , i.e., subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part II Monotherapy mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

This mITT subject analysis set includes subjects from miTT subject analysis sets Part II Monotherapy Arm A mITT, Part II Monotherapy Arm B mITT and Part II Monotherapy Arm E mITT. Subjects have received at least one dose (even partial) of CAN04 (monotherapy).

Subject analysis set title

Part II Combination therapy Arm C mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 1 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 2.5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm NCP mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm NCP, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm D, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm D allocated to the 5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 7.5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm PDEX1 mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm PDEX1, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm PDEX2.5 mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm PDEX2.5, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part I - Dose escalation 1 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 3 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 6 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 10 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm A - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm B - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm E - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm PDEX1 - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm PDEX2.5 - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I: Dose escalation - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis sets values	Part I - Dose escalation 1 mg/kg	Part I - Dose escalation 1.5 mg/kg	Part I - Dose escalation 3 mg/kg	Part I - Dose escalation 6 mg/kg	Part I - Dose escalation 10 mg/kg	Part II Combination therapy Arm C 5 mg/kg	Part II Combination therapy Arm C 1 mg/kg	Part II Combination therapy Arm C 2.5 mg/kg	Part II Combination therapy Arm D 5 mg/kg	Part II Combination therapy Arm D 7.5 mg/kg	Part I - Dose escalation mITT	Part I - Dose escalation 1 mg/kg mITT	Part I - Dose escalation 1.5 mg/kg mITT	Part I - Dose escalation 3 mg/kg mITT	Part I - Dose escalation 6 mg/kg mITT	Part I - Dose escalation 10 mg/kg mITT	Part II Monotherapy Arm A mITT	Part II Monotherapy Arm B mITT	Part II Monotherapy Arm E mITT	Part II Monotherapy mITT	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm D 7.5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population	Part I: Dose escalation - PK population
Number of subjects	3	3	3	7	6	13	17	3	28	8	22	3	3	3	7	6	10	10	6	26	30	11	16	3	10	33	25	8	20	20	3	3	3	7	6	10	10	6	12	15	3	26	8	18	19	22
Age categorical
Units: Subjects
Adults (18-64 years)	2	1	1	6	5	4	11	2	17	5	15	2	1	1	6	5	5	6	5	16	17	4	11	5	3	20	15	5	12	11	2	1	1	6	5	5	6	5	4	10	2	16	5	11	11	15
From 65-84 years	1	2	2	1	1	9	6	1	10	3	7	1	2	2	1	1	5	4	1	10	13	7	5	1	7	12	9	3	8	8	1	2	2	1	1	5	4	1	8	5	1	9	3	7	7	7
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0
Age continuous
Units: years
median (full range (min-max))	62.0 (61 to 71)	68.0 (48 to 74)	71.0 (62 to 77)	62.0 (39 to 81)	63.0 (48 to 66)	66.0 (61 to 77)	64.0 (39 to 77)	63.0 (61 to 75)	62.5 (52 to 87)	60.0 (46 to 79)	63.0 (39 to 81)	62.0 (61 to 71)	68.0 (48 to 74)	71.0 (62 to 77)	62.0 (39 to 81)	63.0 (48 to 66)	61.0 (49 to 72)	63.5 (40 to 73)	62.0 (58 to 73)	63.5 (40 to 73)	64.0 (39 to 77)	66.0 (61 to 77)	62.0 (39 to 77)	63.0 (61 to 75)	66.5 (55 to 76)	62.0 (46 to 87)	63.0 (52 to 87)	60.0 (46 to 79)	63.0 (43 to 78)	61.5 (43 to 89)	62.0 (61 to 71)	68.0 (48 to 74)	71.0 (62 to 77)	62.0 (39 to 81)	63.0 (48 to 66)	61.0 (49 to 72)	63.5 (40 to 73)	62.0 (58 to 73)	66.0 (61 to 77)	64.0 (39 to 77)	63.0 (61 to 75)	62.5 (52 to 87)	60.0 (46 to 79)	63.0 (48 to 78)	60.0 (43 to 89)	63.0 (39 to 81)
Gender categorical
Units: Subjects
Female	1	1	2	1	3	5	5	1	12	5	8	1	1	2	1	3	2	2	3	7	10	4	5	1	5	15	10	5	7	8	1	1	2	1	3	2	2	3	4	4	1	11	5	6	7	8
Male	2	2	1	6	3	8	12	2	16	3	14	2	2	1	6	3	8	8	3	19	20	7	11	2	5	18	15	3	13	12	2	2	1	6	3	8	8	3	8	11	2	15	3	12	12	14
Child-bearing Potential
Units: Subjects
No	1	1	2	1	2	5	4	1	12	4	7	1	1	2	1	2	2	2	3	7	9	4	4	1	5	14	10	4	6	8	1	1	2	1	2	2	2	3	4	3	1	11	4	6	7	7
Yes	0	0	0	0	1	0	1	0	0	1	1	0	0	0	0	1	0	0	0	0	1	0	1	0	0	1	0	1	1	0	0	0	0	0	1	0	0	0	0	1	0	0	1	0	0	1
Not applicable	2	2	1	6	3	8	12	2	16	3	14	2	2	1	6	3	8	8	3	19	20	7	11	2	5	18	15	3	13	12	2	2	1	6	3	8	8	3	8	11	2	15	3	12	12	14
Ethnicity
Units: Subjects
Not Hispanic or Latino	3	2	1	3	5	12	17	3	24	6	14	3	2	1	3	5	2	5	4	11	30	11	16	3	10	27	21	6	19	20	3	2	1	3	5	2	5	4	12	15	3	22	6	17	19	14
Not reported	0	1	2	4	1	1	0	0	4	2	8	0	1	2	4	1	8	5	2	15	0	0	0	0	0	6	4	2	1	0	0	1	2	4	1	8	5	2	0	0	0	4	2	1	0	8
Race
Units: Subjects
White	3	2	1	3	5	12	17	3	24	6	14	3	2	1	3	5	2	5	4	11	30	11	16	3	10	27	21	6	18	20	3	2	1	3	5	2	5	4	12	15	3	22	6	16	19	14
Asian	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Not reported	0	1	2	4	1	1	0	0	4	2	8	0	1	2	4	1	8	5	2	15	0	0	0	0	0	6	4	2	1	0	0	1	2	4	1	8	5	2	0	0	0	4	2	1	0	8
Primary Disease
Units: Subjects
NSCLC - subtype not defined	1	1	1	0	1	1	0	0	0	0	4	1	1	1	0	1	2	4	3	9	1	1	0	0	0	0	0	0	0	0	1	1	1	0	1	2	4	3	1	0	0	0	0	0	0	4
NSCLC - squamous	0	0	0	0	0	5	7	2	0	0	0	0	0	0	0	0	0	0	0	0	13	5	6	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	5	6	2	0	0	0	0	0
NSCLC - non-squamous	0	0	0	0	0	7	10	1	0	0	0	0	0	0	0	0	0	0	0	0	16	5	10	1	10	0	0	0	0	0	0	0	0	0	0	0	0	0	6	9	1	0	0	0	0	0
PDAC	0	0	1	3	2	0	0	0	28	8	6	0	0	1	3	2	8	6	3	17	0	0	0	0	0	33	25	8	20	20	0	0	1	3	2	8	6	3	0	0	0	26	8	18	19	6
CRC	2	2	1	4	3	0	0	0	0	0	12	2	2	1	4	3	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	2	1	4	3	0	0	0	0	0	0	0	0	0	0	12
TNBC	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tumour Still Present at Primary Location at Study Entry
Units: Subjects
Yes	1	1	1	3	3	13	16	3	25	8	9	1	1	1	3	3	6	9	5	20	29	11	15	3	9	30	22	8	19	18	1	1	1	3	3	6	9	5	12	14	3	23	8	17	17	9
No	2	2	2	4	3	0	1	0	3	0	13	2	2	2	4	3	4	1	1	6	1	0	1	0	1	3	3	0	1	2	2	2	2	4	3	4	1	1	0	1	0	3	0	1	2	13
Number of prior lines of treatment for metastatic disease
Units: Subjects
No prior lines	0	0	0	0	0	7	10	0	25	8	0	0	0	0	0	0	0	0	0	0	15	6	9	0	7	30	22	8	18	18	0	0	0	0	0	0	0	0	7	9	0	23	8	16	17	0
1 prior line	0	0	0	0	0	6	7	3	1	0	0	0	0	0	0	0	4	3	1	8	15	5	7	3	3	1	1	0	2	2	0	0	0	0	0	4	3	1	5	6	3	1	0	2	2	0
2 prior lines	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	2	3	2	7	0	0	0	0	0	1	1	0	0	0	0	0	0	0	0	2	3	2	0	0	0	1	0	0	0	0
3 prior lines	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	3	2	2	7	0	0	0	0	0	1	1	0	0	0	0	0	0	0	0	3	2	2	0	0	0	1	0	0	0	0
4 prior lines	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
5 prior lines	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	1	3	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	1	0	0	0	0	0	0	0	0
Not recorded	3	3	3	7	6	0	0	0	0	0	22	3	3	3	7	6	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	3	3	7	6	0	0	0	0	0	0	0	0	0	0	22
ECOG status
Units: Subjects
ECOG = 0	2	2	1	5	5	4	9	1	18	5	15	2	2	1	5	5	3	5	3	11	14	4	9	1	2	22	17	5	7	4	2	2	1	5	5	3	5	3	4	9	1	17	5	6	4	15
ECOG = 1	1	1	2	2	1	9	8	2	10	3	7	1	1	2	2	1	7	5	3	15	16	7	7	2	8	11	8	3	13	16	1	1	2	2	1	7	5	3	8	6	2	9	3	12	15	7
Height
Units: cm
median (full range (min-max))	175.0 (160 to 180)	175.0 (155 to 176)	161.0 (155 to 178)	181.0 (165 to 188)	168.0 (155 to 191)	169.0 (152 to 179)	176.0 (153 to 189)	164.0 (161 to 176)	170.0 (161 to 205)	165.0 (158 to 194)	174.5 (155 to 191)	175.0 (160 to 180)	175.0 (155 to 176)	161.0 (155 to 178)	181.0 (165 to 188)	168.0 (155 to 191)	177.6 (165 to 198)	179.0 (172 to 185)	171.8 (162 to 188)	177.5 (162 to 198)	172.0 (152 to 189)	169.0 (152 to 179)	174.0 (153 to 189)	164.0 (161 to 176)	169.5 (151 to 175)	170.0 (158 to 205)	170.0 (161 to 205)	165.5 (158 to 194)	172.5 (150 to 194)	173.5 (147 to 184)	175.0 (160 to 180)	175.0 (155 to 176)	161.0 (155 to 178)	181.0 (165 to 188)	168.0 (155 to 191)	177.6 (165 to 198)	179.0 (172 to 185)	171.8 (162 to 188)	169.5 (152 to 179)	180.0 (153 to 189)	164.0 (161 to 176)	170.0 (161 to 205)	165.5 (158 to 194)	173.5 (150 to 194)	175.0 (147 to 184)	174.5 (155 to 191)
Weight
Units: kg
median (full range (min-max))	69.6 (66 to 91)	71.0 (61 to 79)	87.6 (68 to 98)	84.5 (53 to 103)	80.7 (53 to 124)	69.0 (57 to 90)	70.0 (53 to 108)	64.9 (60 to 66)	73.7 (48 to 107)	74.1 (51 to 95)	79.1 (53 to 124)	69.6 (66 to 91)	71.0 (61 to 79)	87.6 (68 to 98)	84.5 (53 to 103)	80.7 (53 to 124)	72.3 (45 to 126)	75.7 (62 to 107)	77.7 (74 to 99)	77.1 (45 to 126)	68.0 (53 to 108)	69.0 (57 to 90)	69.0 (53 to 108)	64.9 (60 to 66)	69.5 (54 to 88)	73.8 (48 to 107)	73.8 (48 to 107)	74.1 (51 to 95)	66.0 (50 to 95)	73.7 (42 to 96)	69.6 (66 to 91)	71.0 (61 to 79)	87.6 (68 to 98)	84.5 (53 to 103)	80.7 (53 to 124)	72.3 (45 to 126)	75.7 (62 to 107)	77.7 (74 to 99)	74.0 (57 to 90)	75.0 (53 to 108)	64.9 (60 to 66)	73.7 (48 to 107)	74.1 (51 to 95)	67.3 (50 to 95)	75.0 (51 to 96)	79.1 (53 to 124)
Body Mass Index
Units: kg/m2
median (full range (min-max))	25.6 (23 to 28)	25.6 (23 to 26)	31.0 (28 to 34)	24.9 (18 to 32)	26.3 (20 to 44)	25.8 (19 to 32)	24.4 (18 to 34)	22.3 (21 to 26)	24.7 (17 to 30)	23.9 (19 to 36)	25.6 (18 to 44)	25.6 (23 to 28)	25.6 (23 to 26)	31.0 (28 to 34)	24.9 (18 to 32)	26.3 (20 to 44)	23.3 (16 to 34)	24.5 (21 to 32)	27.1 (22 to 34)	25.2 (16 to 34)	24.4 (18 to 34)	27.4 (19 to 32)	23.4 (18 to 34)	22.3 (21 to 26)	26.8 (20 to 29)	24.3 (17 to 36)	24.4 (17 to 30)	23.9 (19 to 36)	23.1 (18 to 31)	25.3 (17 to 33)	25.6 (23 to 28)	25.6 (23 to 26)	31.0 (28 to 34)	24.9 (18 to 32)	26.3 (20 to 44)	23.3 (16 to 34)	24.5 (21 to 32)	27.1 (22 to 34)	26.6 (19 to 32)	25.7 (18 to 34)	22.3 (21 to 26)	24.7 (17 to 30)	23.9 (19 to 36)	22.8 (18 to 31)	25.9 (19 to 33)	25.6 (18 to 44)

End points

Top of page

Reporting group title

Part I - Dose escalation

Reporting group description

Reporting group title

Part II Monotherapy Arm A

Reporting group description

Reporting group title

Part II Monotherapy Arm B

Reporting group description

Reporting group title

Part II Monotheraphy Arm E

Reporting group description

Reporting group title

Part II Combination therapy Arm C

Reporting group description

Reporting group title

Part II Combination therapy Arm NCP

Reporting group description

Reporting group title

Part II Combination therapy Arm D

Reporting group description

Reporting group title

Part II Combination therapy Arm PDEX1

Reporting group description

Reporting group title

Part II Combination therapy Arm PDEX2.5

Reporting group description

Subject analysis set title

Part I - Dose escalation 1 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 1 (1 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 2 (1.5 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 3 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 3 (3 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 6 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 4 (6 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 10 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Cohort 5 (10 mg/kg) of Part I dose escalation (monotherapy). Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 5 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 1 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 2.5 mg/kg cohort of Arm C. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 5 mg/kg cohort of Arm D. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects allocated to the 7.5 mg/kg cohort of Arm D. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 1 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 3 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

For monotherapy cohorts/arms mITT is the same as reporting groups and any safety analysis sets. Subjects have received at least one dose (even partial) of CAN04.

Subject analysis set title

Part I - Dose escalation 6 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part I - Dose escalation 10 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Monotherapy Arm A mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Monotherapy Arm B mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Monotherapy Arm E mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Monotherapy mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Combination therapy Arm C mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm C allocated to the 1 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Combination therapy Arm NCP mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm NCP, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm D, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm D allocated to the 5 mg/kg cohort, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part II Combination therapy Arm PDEX1 mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm PDEX1, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part II Combination therapy Arm PDEX2.5 mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subjects enrolled in Part II Combination therapy Arm PDEX2.5, who have received at least one dose (even partial) of CAN04 and applicable combination treatment was initiated.

Subject analysis set title

Part I - Dose escalation 1 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 1.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 3 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 6 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I - Dose escalation 10 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm A - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm B - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Monotherapy Arm E - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 1 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm C 2.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm D 5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm D 7.5 mg/kg - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm PDEX1 - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part II Combination therapy Arm PDEX2.5 - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Subject analysis set title

Part I: Dose escalation - PK population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The PK population includes all subjects who have received CAN04 and have provided at least one evaluable pre-dose and post-dose PK blood sample.

Primary: Incidence of Grade ≥3 adverse events related to CAN04 administration

Top of page

End point title

Incidence of Grade ≥3 adverse events related to CAN04 administration ^[1]

End point description

Incidence of Grade 3 and higher Adverse Events related to CAN04 administration and according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).

End point type

Primary

End point timeframe

Adverse events were collected from ICF signature until 28 days after last administration of study drug.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics is presented. Since no comparator arm is included in the study no statistical comparisons have been performed.

Part I - Dose escalation

Part II Monotherapy Arm A

Part II Monotherapy Arm B

Part II Monotheraphy Arm E

Part II Combination therapy Arm C

Part II Combination therapy Arm NCP

Part II Combination therapy Arm D

Part II Combination therapy Arm PDEX1

Part II Combination therapy Arm PDEX2.5

Part I - Dose escalation 1 mg/kg

Part I - Dose escalation 1.5 mg/kg

Part I - Dose escalation 3 mg/kg

Part I - Dose escalation 6 mg/kg

Part I - Dose escalation 10 mg/kg

Part II Combination therapy Arm C 5 mg/kg

Part II Combination therapy Arm C 1 mg/kg

Part II Combination therapy Arm C 2.5 mg/kg

Part II Combination therapy Arm D 5 mg/kg

Part II Combination therapy Arm D 7.5 mg/kg

Number of subjects analysed

Units: percent

number (confidence interval 95%)

9 (1 to 29)

10 (0 to 45)

0 (0 to 31)

17 (0 to 64)

58 (39 to 75)

90 (55 to 100)

61 (43 to 77)

55 (32 to 77)

80 (56 to 94)

0 (0 to 71)

33 (1 to 91)

14 (0 to 58)

0 (0 to 46)

85 (55 to 98)

41 (18 to 67)

33 (1 to 91)

57 (37 to 76)

75 (35 to 97)

No statistical analyses for this end point

Secondary: Pharmacokinetics: Concentration at the end of infusion - Single dose

Top of page

End point title

Pharmacokinetics: Concentration at the end of infusion - Single dose

End point description

Pharmacokinetics: Concentration at the end of infusion (C inf end) - Single dose (Dose 1) Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	0 ^[2]	3	2	6	6
Units: ng/mL
geometric mean (geometric coefficient of variation)	( )	14487 ( 71 )	19801 ( 37 )	5681 ( 30 )	8922 ( 12 )

Notes
[2] - Not evaluable due to concentration below lower limit of quantification.

No statistical analyses for this end point

Secondary: Pharmacokinetics: Maximum concentration - Single dose

Top of page

End point title

Pharmacokinetics: Maximum concentration - Single dose

End point description

Maximum concentration (Cmax) - Single dose (Dose 1) Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	7	6
Units: ng/mL
geometric mean (geometric coefficient of variation)	17581 ( 17 )	20227 ( 61 )	26244 ( 23 )	6927 ( 21 )	10028 ( 15 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Single dose

Top of page

End point title

Pharmacokinetics: Time taken to reach maximum concentration - Single dose

End point description

Time taken to reach maximum concentration (t max) - Single dose (Dose 1). Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	7	6
Units: h
median (full range (min-max))	5.3 (2.6 to 8.0)	3.1 (2.0 to 3.1)	3.1 (2.1 to 4.1)	2.1 (1.3 to 8.0)	4.3 (1.0 to 9.0)

No statistical analyses for this end point

Secondary: Pharmacokinetics: Terminal half-life - Single dose

Top of page

End point title

Pharmacokinetics: Terminal half-life - Single dose

End point description

Pharmacokinetics: Terminal half-life (t½) - Single dose (Dose 1). Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing,.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	7	6
Units: h
geometric mean (geometric coefficient of variation)	57.9 ( 56 )	43.8 ( 11 )	81.0 ( 3 )	31.4 ( 47 )	36.5 ( 33 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Clearance - Single dose

Top of page

End point title

Pharmacokinetics: Clearance - Single dose

End point description

Pharmacokinetics: Clearance (CL) - Single dose. Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	2	4
Units: mL/h
geometric mean (geometric coefficient of variation)	53.1 ( 51 )	51.2 ( 25 )	28.5 ( 25 )	75.6 ( 18 )	61.3 ( 29 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Single dose

Top of page

End point title

Pharmacokinetics: Apparent volume of distribution during the terminal phase - Single dose

End point description

Pharmacokinetics: Apparent volume of distribution during the terminal phase (Vz) - Single dose Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	2	4
Units: L
geometric mean (geometric coefficient of variation)	4.44 ( 4 )	3.23 ( 30 )	3.33 ( 23 )	5.79 ( 7 )	3.82 ( 24 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Single dose

Top of page

End point title

Pharmacokinetics: Area under the curve from time 0 to infinity - Single dose

End point description

Pharmacokinetics: Area under the curve from time 0 to infinity (AUC0-∞) - Single dose Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	2	4
Units: (µg·h/mL)
geometric mean (geometric coefficient of variation)	1392 ( 88 )	1374 ( 23 )	2701 ( 45 )	638 ( 8 )	807 ( 12 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Single dose

Top of page

End point title

Pharmacokinetics: Area under the curve from time 0 to time 24h - Single dose

End point description

Pharmacokinetics: Area under the curve from time 0 to time 24h (AUC0-24) - Single dose (Dose 1) Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	7	6
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	283 ( 34 )	350 ( 37 )	475 ( 34 )	122 ( 25 )	188 ( 12 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Single dose

Top of page

End point title

Pharmacokinetics: Area under the curve from time 0 to time 168 h - Single dose

End point description

Pharmacokinetics: Area under the curve from time 0 to time 168 h (AUC0-168) - Single dose (Dose 1) Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	7	6
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	1178 ( 64 )	1294 ( 22 )	2074 ( 44 )	305 ( 61 )	586 ( 44 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Mean residence time - Single dose

Top of page

End point title

Pharmacokinetics: Mean residence time - Single dose

End point description

Pharmacokinetics: Mean residence time (MRT) - Single dose (Dose 1) Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Subjects were sampled repeatedly at Pre (0) and end of infusion, 2, 4, 8, 24 and 168 h post start of dosing.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	2	2	4
Units: h
arithmetic mean (standard deviation)	73.3 ( 51.3 )	41.6 ( 6.3 )	102.0 ( 2.2 )	57.4 ( 20.4 )	41.0 ( 7.3 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Concentration at the end of infusion - Repeated dose

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End point title

Pharmacokinetics: Concentration at the end of infusion - Repeated dose

End point description

Pharmacokinetics: Concentration at the end of infusion (Cinf end) - Repeated dose Part I: Infusion time was initially 1 hour. For cohorts 2 (1.5 mg/kg) and 3 (3.0 mg/kg), the dose level for the first administration was maintained at 1.0 mg/kg as a priming dose and only subsequent doses were given at escalated doses. From cohort 4 onwards, the initial priming dose was reduced to 0.5 mg/kg given over 2 hours. Doses were given with 7-day (168 hour) intervals.

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 3.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	3	3	3	6	5
Units: ng/mL
geometric mean (geometric coefficient of variation)	28124 ( 8 )	29223 ( 55 )	97890 ( 35 )	127281 ( 20 )	289947 ( 21 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Maximum concentration - Repeated dose

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End point title

Pharmacokinetics: Maximum concentration - Repeated dose

End point description

Pharmacokinetics: Maximum concentration (Cmax) - Repeated dose.

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 3. Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	3	3	3	6	6	5	7	4	10	9	2	21	6	11	11
Units: ng/mL
geometric mean (geometric coefficient of variation)	28560 ( 7 )	34429 ( 33 )	110813 ( 25 )	133944 ( 20 )	275333 ( 31 )	382798 ( 47 )	420840 ( 21 )	637385 ( 20 )	133286 ( 29 )	22450 ( 68 )	49614 ( 75 )	105182 ( 44 )	213576 ( 31 )	16300 ( 69 )	42809 ( 45 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Repeated dose

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End point title

Pharmacokinetics: Time taken to reach maximum concentration - Repeated dose

End point description

Pharmacokinetics: Time taken to reach maximum concentration (tmax) - Repeated dose

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 3. Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6.

Part I - Dose escalation 1 mg/kg - PK population

Part I - Dose escalation 1.5 mg/kg - PK population

Part I - Dose escalation 3 mg/kg - PK population

Part I - Dose escalation 6 mg/kg - PK population

Part I - Dose escalation 10 mg/kg - PK population

Part II Monotherapy Arm A - PK population

Part II Monotherapy Arm B - PK population

Part II Monotherapy Arm E - PK population

Part II Combination therapy Arm C 5 mg/kg - PK population

Part II Combination therapy Arm C 1 mg/kg - PK population

Part II Combination therapy Arm C 2.5 mg/kg - PK population

Part II Combination therapy Arm D 5 mg/kg - PK population

Part II Combination therapy Arm D 7.5 mg/kg - PK population

Part II Combination therapy Arm PDEX1 - PK population

Part II Combination therapy Arm PDEX2.5 - PK population

Number of subjects analysed

Units: h

median (full range (min-max))

2.0 (1.6 to 2.1)

2.0 (1.0 to 2.0)

2.0 (2.0 to 3.0)

2.0 (0.9 to 2.0)

1.8 (1.0 to 24.4)

3.0 (2.0 to 4.1)

2.0 (2.0 to 8.0)

2.3 (2.0 to 4.0)

2.0 (2.0 to 8.0)

4.0 (2.0 to 8.0)

2.0 (2.0 to 2.1)

2.1 (2.0 to 8.0)

1.0 (0.8 to 1.2)

1.1 (0.9 to 1.1)

No statistical analyses for this end point

Secondary: Pharmacokinetics: Terminal half-life - Repeated dose

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End point title

Pharmacokinetics: Terminal half-life - Repeated dose

End point description

Pharmacokinetics: Terminal half-life (t½) - Repeated dose

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 3. Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	2	3	3	4	4	6	7	4	10	9	2	21	6	4	8
Units: h
geometric mean (geometric coefficient of variation)	47.3 ( 7 )	75.7 ( 4 )	54.2 ( 23 )	135.4 ( 65 )	82.6 ( 21 )	214.1 ( 149 )	265.8 ( 43 )	246.3 ( 132 )	225.4 ( 26 )	105.5 ( 109 )	111.6 ( 56 )	201.1 ( 42 )	252.7 ( 20 )	118.3 ( 46 )	189.0 ( 25 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Clearance - Repeated dose

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End point title

Pharmacokinetics: Clearance - Repeated dose

End point description

Pharmacokinetics: Clearance (CL) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 2.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	8	10	6	10	12	3	22	7	13	14
Units: mL/h
geometric mean (geometric coefficient of variation)	25.2 ( 42 )	26.5 ( 27 )	22.4 ( 46 )	26.5 ( 21 )	32.3 ( 47 )	35.5 ( 14 )	27.8 ( 34 )	19.0 ( 39 )	38.0 ( 22 )	32.3 ( 19 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Repeated dose

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End point title

Pharmacokinetics: Apparent volume of distribution during the terminal phase - Repeated dose

End point description

Pharmacokinetics: Apparent volume of distribution during the terminal phase (Vz) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 2.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	8	10	6	10	12	3	22	7	13	14
Units: L
geometric mean (geometric coefficient of variation)	4.7 ( 23 )	4.7 ( 18 )	4.2 ( 36 )	4.3 ( 21 )	4.0 ( 28 )	3.9 ( 11 )	4.3 ( 24 )	4.2 ( 18 )	3.2 ( 23 )	3.9 ( 13 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Repeated dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to infinity - Repeated dose

End point description

Pharmacokinetics: Area under the curve from time 0 to infinity (AUC0-∞) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 2.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	8	10	6	10	12	3	22	7	13	14
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	30279 ( 54 )	29434 ( 34 )	53430 ( 48 )	13601 ( 25 )	2708 ( 82 )	4476 ( 9 )	13493 ( 41 )	28187 ( 52 )	1754 ( 30 )	5463 ( 26 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to time t - Repeated dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to time t - Repeated dose

End point description

Pharmacokinetics: Area under the curve from time 0 to time t (AUC0-t) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6 except for PDEX1 and PDEX2.5 after dose 4.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	6	7	4	10	9	2	21	6	4	9
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	33245 ( 130 )	67402 ( 95 )	89810 ( 103 )	27274 ( 40 )	1367 ( 570 )	3041 ( 111 )	17274 ( 61 )	38778 ( 41 )	2108 ( 55 )	8972 ( 38 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Repeated dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to time 24h - Repeated dose

End point description

Pharmacokinetics: Area under the curve from time 0 to time 24h (AUC0-24) - Repeated dose

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 3.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population
Number of subjects analysed	2	3	3	5	6
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	576 ( 5 )	673 ( 18 )	2303 ( 26 )	3030 ( 14 )	5845 ( 34 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Repeated dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to time 168 h - Repeated dose

End point description

Pharmacokinetics: Area under the curve from time 0 to time 168 h (AUC0-168) - Repeated dose

End point type

Secondary

End point timeframe

Part I: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 2. Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6.

End point values	Part I - Dose escalation 1 mg/kg - PK population	Part I - Dose escalation 1.5 mg/kg - PK population	Part I - Dose escalation 3 mg/kg - PK population	Part I - Dose escalation 6 mg/kg - PK population	Part I - Dose escalation 10 mg/kg - PK population	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	3	3	3	6	6	6	7	4	10	9	2	21	6	4	8
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	2263 ( 24 )	2441 ( 28 )	8947 ( 27 )	9795 ( 28 )	21370 ( 21 )	42871 ( 80 )	48969 ( 26 )	72244 ( 24 )	15693 ( 38 )	2117 ( 123 )	5058 ( 45 )	11396 ( 51 )	24927 ( 38 )	1561 ( 52 )	5671 ( 35 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Mean residence time - Repeated dose

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End point title

Pharmacokinetics: Mean residence time - Repeated dose

End point description

Pharmacokinetics: Mean residence time (MRT) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 2.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	8	10	6	10	12	3	22	7	13	14
Units: h
arithmetic mean (standard deviation)	186 ( 47 )	177 ( 36 )	187 ( 45 )	150 ( 24 )	112 ( 54 )	90 ( 8 )	147 ( 43 )	224 ( 103 )	60 ( 31 )	101 ( 18 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Single dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Single dose

End point description

Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Single dose Arms A, B, E, C (5 mg/kg; 1 mg/kg; 2.5 mg/kg), and D (5 mg/kg; 7.5 mg/kg): Assessment was done at dose 2 due to initial priming dose. Arms PDEX 1 and PDEX 2.5: Assessment was done at dose 1.

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after first full dose.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	8	10	6	11	14	3	24	8	15	17
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	18021 ( 38 )	17557 ( 26 )	31805 ( 46 )	7459 ( 67 )	1636 ( 85 )	3585 ( 6 )	7694 ( 75 )	12551 ( 69 )	1124 ( 116 )	3198 ( 68 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau - Repeated dose

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End point title

Pharmacokinetics: Area under the curve from time 0 to tau - Repeated dose

End point description

Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Repeated dose

End point type

Secondary

End point timeframe

Part II: Subjects were sampled repeatedly at 1, 2 and 24 h after dose 6.

End point values	Part II Monotherapy Arm A - PK population	Part II Monotherapy Arm B - PK population	Part II Monotherapy Arm E - PK population	Part II Combination therapy Arm C 5 mg/kg - PK population	Part II Combination therapy Arm C 1 mg/kg - PK population	Part II Combination therapy Arm C 2.5 mg/kg - PK population	Part II Combination therapy Arm D 5 mg/kg - PK population	Part II Combination therapy Arm D 7.5 mg/kg - PK population	Part II Combination therapy Arm PDEX1 - PK population	Part II Combination therapy Arm PDEX2.5 - PK population
Number of subjects analysed	6	7	4	10	9	2	21	6	4	9
Units: µg·h/mL
geometric mean (geometric coefficient of variation)	33245 ( 130 )	67402 ( 95 )	89810 ( 103 )	27274 ( 40 )	1367 ( 570 )	3041 ( 111 )	17274 ( 61 )	38778 ( 41 )	2108 ( 55 )	8972 ( 38 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Changes in serum concentration of sIL1RAP

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End point title

Pharmacokinetics: Changes in serum concentration of sIL1RAP

End point description

Pharmacokinetics: Changes in sIL1RAP from pre-dose visit 1 to pre-dose visit 3.

End point type

Secondary

End point timeframe

Part I: Samples was collected predose visit 1 and predose visit 3

End point values	Part I: Dose escalation - PK population
Number of subjects analysed	21
Units: ng/mL
arithmetic mean (standard deviation)	277 ( 100 )

No statistical analyses for this end point

Secondary: Efficacy: immune related Overall Response Rate (irORR) by irRC

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End point title

Efficacy: immune related Overall Response Rate (irORR) by irRC

End point description

The immune related Overall Response Rate (irORR) is defined as the proportion of responders, i.e., subjects who achieve a immune related Best Overall Response (irBOR) of immune related Complete Response (irCR) or immune related Partial Response (irPR) assessed by immune related Response Criteria (irRC). A confirmatory scan was required. Not evaluable subjects are considered non-responders.

End point type

Secondary

End point timeframe

At screening followed by 8-week intervals after first CAN04 dose while on trial treatment until confirmed disease progression, start of new line of systemic anti-cancer therapy or death.

End point values	Part I - Dose escalation mITT	Part I - Dose escalation 1 mg/kg mITT	Part I - Dose escalation 1.5 mg/kg mITT	Part I - Dose escalation 3 mg/kg mITT	Part I - Dose escalation 6 mg/kg mITT	Part I - Dose escalation 10 mg/kg mITT	Part II Monotherapy Arm A mITT	Part II Monotherapy Arm B mITT	Part II Monotherapy Arm E mITT	Part II Monotherapy mITT
Number of subjects analysed	22	3	3	3	7	6	10	10	6	26
Units: %
number (confidence interval 95%)	0 (0 to 15)	0 (0 to 71)	0 (0 to 71)	0 (0 to 71)	0 (0 to 41)	0 (0 to 46)	0 (0 to 31)	0 (0 to 31)	0 (0 to 46)	0 (0 to 13)

No statistical analyses for this end point

Secondary: Efficacy: immune Overall Response Rate (iORR) by iRECIST

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End point title

Efficacy: immune Overall Response Rate (iORR) by iRECIST

End point description

The immune Overall Response Rate (iORR) is defined as the proportion of responders, i.e., subjects who achieve a confirmed immune Best Overall Response (iBOR) of immune Complete Response (iCR) or immune Partial Response (iPR) assessed by immune Response Evaluation Criteria in Solid Tumours (iRECIST). A confirmatory scan was required. Not evaluable subjects are considered non-responders.

End point type

Secondary

End point timeframe

At screening followed by 8-week intervals after first CAN04 dose (Arm NCP: 6-week intervals for 36 weeks, thereafter every 9 weeks) while on trial treatment until confirmed disease progression, start of new line of systemic anti-cancer therapy or death.

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm D 7.5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	30	11	16	3	10	33	25	8	20	20
Units: %
number (confidence interval 95%)	53 (34 to 72)	55 (23 to 83)	50 (25 to 75)	67 (9 to 99)	60 (26 to 88)	24 (11 to 42)	20 (7 to 41)	38 (9 to 76)	45 (23 to 69)	30 (12 to 54)

No statistical analyses for this end point

Secondary: Efficacy: Overall Response Rate (ORR) by RECIST 1.1

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End point title

Efficacy: Overall Response Rate (ORR) by RECIST 1.1

End point description

The Overall Response Rate (ORR) is defined as the proportion of confirmed responders, i.e., subjects who achieve a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). A confirmatory scan was required. Not evaluable subjects are considered non-responders.

End point type

Secondary

End point timeframe

Part I - Dose escalation mITT

Part I - Dose escalation 1 mg/kg mITT

Part I - Dose escalation 1.5 mg/kg mITT

Part I - Dose escalation 3 mg/kg mITT

Part I - Dose escalation 6 mg/kg mITT

Part I - Dose escalation 10 mg/kg mITT

Part II Monotherapy Arm A mITT

Part II Monotherapy Arm B mITT

Part II Monotherapy Arm E mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm C 2.5 mg/kg mITT

Part II Combination therapy Arm NCP mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: %

number (confidence interval 95%)

0 (0 to 15)

0 (0 to 71)

0 (0 to 41)

0 (0 to 46)

0 (0 to 31)

0 (0 to 46)

0 (0 to 13)

53 (34 to 72)

55 (23 to 83)

50 (25 to 75)

67 (9 to 99)

60 (26 to 88)

24 (11 to 42)

20 (7 to 41)

38 (9 to 76)

45 (23 to 69)

30 (12 to 54)

No statistical analyses for this end point

Secondary: Efficacy: immune related Duration of Response (irDoR) by irRC

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End point title

Efficacy: immune related Duration of Response (irDoR) by irRC

End point description

Duration of response (irDOR) is defined as the time from first confirmed response (irCR or irPR) to disease progression assessed by immune related Response Criteria (irRC) or death from any cause or censoring.

End point type

Secondary

End point timeframe

At screening followed by 8-week interval after first CAN04 dose while on trial treatment until confirmed disease progression, start of new line of systemic anti-cancer therapy or death.

End point values	Part I - Dose escalation mITT	Part I - Dose escalation 1 mg/kg mITT	Part I - Dose escalation 1.5 mg/kg mITT	Part I - Dose escalation 3 mg/kg mITT	Part I - Dose escalation 6 mg/kg mITT	Part I - Dose escalation 10 mg/kg mITT	Part II Monotherapy Arm A mITT	Part II Monotherapy Arm B mITT	Part II Monotherapy Arm E mITT	Part II Monotherapy mITT
Number of subjects analysed	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )

Notes
[3] - irDoR could not be estimated due to no responders.
[4] - irDoR could not be estimated due to no responders.
[5] - irDoR could not be estimated due to no responders.
[6] - irDoR could not be estimated due to no responders.
[7] - irDoR could not be estimated due to no responders.
[8] - irDoR could not be estimated due to no responders.
[9] - irDoR could not be estimated due to no responders.
[10] - irDoR could not be estimated due to no responders.
[11] - irDoR could not be estimated due to no responders.
[12] - irDoR could not be estimated due to no responders.

No statistical analyses for this end point

Secondary: Efficacy: immune Duration of Response (iDoR) by iRECIST

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End point title

Efficacy: immune Duration of Response (iDoR) by iRECIST

End point description

Duration of immune Response (iDOR) is defined as the time from first time the criteria for confirmed response (iCR or iPR) are met to disease progression assessed by immune Response Evaluation Criteria in Solid Tumours (iRECIST) or death from any cause or censoring.

End point type

Secondary

End point timeframe

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm PDEX1 mITT
Number of subjects analysed	16	8	8	9
Units: months
median (confidence interval 95%)	5.8 (3.7 to 11.2)	4.6 (3.6 to 7.5)	6.1 (3.7 to 13.8)	5.6 (3.6 to 11.8)

No statistical analyses for this end point

Secondary: Efficacy: Duration of Response (DoR) by RECIST 1.1

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End point title

Efficacy: Duration of Response (DoR) by RECIST 1.1

End point description

Duration of response (DOR) is defined as the time from first confirmed response (CR or PR) to disease progression assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) or death from any cause or censoring.

End point type

Secondary

End point timeframe

Part I - Dose escalation mITT

Part I - Dose escalation 1 mg/kg mITT

Part I - Dose escalation 1.5 mg/kg mITT

Part I - Dose escalation 3 mg/kg mITT

Part I - Dose escalation 6 mg/kg mITT

Part I - Dose escalation 10 mg/kg mITT

Part II Monotherapy Arm A mITT

Part II Monotherapy Arm B mITT

Part II Monotherapy Arm E mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm PDEX1 mITT

Number of subjects analysed

0 ^[13]

0 ^[14]

0 ^[15]

0 ^[16]

0 ^[17]

0 ^[18]

0 ^[19]

0 ^[20]

0 ^[21]

0 ^[22]

Units: months

median (confidence interval 95%)

( to )

5.8 (3.7 to 11.2)

4.6 (3.6 to 7.5)

6.1 (3.7 to 13.8)

5.6 (3.6 to 11.8)

Notes
[13] - DoR could not be estimated due to no responders.
[14] - DoR could not be estimated due to no responders.
[15] - DoR could not be estimated due to no responders.
[16] - DoR could not be estimated due to no responders.
[17] - DoR could not be estimated due to no responders.
[18] - DoR could not be estimated due to no responders.
[19] - DoR could not be estimated due to no responders.
[20] - DoR could not be estimated due to no responders.
[21] - DoR could not be estimated due to no responders.
[22] - DoR could not be estimated due to no responders.

No statistical analyses for this end point

Secondary: Efficacy: immune related Progression-Free Survival (irPFS) at 6 months by irRC

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End point title

Efficacy: immune related Progression-Free Survival (irPFS) at 6 months by irRC

End point description

Probability for subjects for immune related Progression Free Survival (irPFS) assessed by immune related Response Criteria (irRC) at 6 month after first CAN04 dose.

End point type

Secondary

End point timeframe

At screening followed by 8-week intervals after first CAN04 dose while on trial treatment until confirmed disease progression, start of new line of systemic anti-cancer therapy or death.

End point values	Part I - Dose escalation mITT	Part I - Dose escalation 1 mg/kg mITT
Number of subjects analysed	22	3
Units: %
number (confidence interval 95%)	6 (0 to 23)	33 (1 to 77)

No statistical analyses for this end point

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 6 months by iRECIST

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End point title

Efficacy: immune Progression-Free Survival (iPFS) at 6 months by iRECIST

End point description

Probability for subjects for immune Progression Free Survival (iPFS) assessed by immune Response Evaluation Criteria in Solid Tumours (iRECIST) at 6 month after first CAN04 dose.

End point type

Secondary

End point timeframe

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm D 7.5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	30	11	16	3	10	33	25	8	20	20
Units: %
number (confidence interval 95%)	57 (37 to 73)	82 (45 to 95)	36 (13 to 59)	67 (5 to 95)	70 (33 to 89)	42 (25 to 59)	48 (27 to 66)	25 (4 to 56)	61 (35 to 79)	63 (35 to 81)

No statistical analyses for this end point

Secondary: Efficacy: Progression-Free Survival (PFS) at 6 months by RECIST 1.1

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End point title

Efficacy: Progression-Free Survival (PFS) at 6 months by RECIST 1.1

End point description

Probability for subjects for Progression Free Survival (PFS) assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) at 6 month after first CAN04 dose.

End point type

Secondary

End point timeframe

Part I - Dose escalation mITT

Part I - Dose escalation 1 mg/kg mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm C 2.5 mg/kg mITT

Part II Combination therapy Arm NCP mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: %

number (confidence interval 95%)

5 (0 to 20)

33 (1 to 77)

57 (37 to 73)

82 (45 to 95)

36 (13 to 59)

67 (5 to 95)

60 (25 to 83)

33 (17 to 49)

35 (17 to 54)

25 (4 to 56)

61 (35 to 79)

56 (30 to 76)

No statistical analyses for this end point

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 12 months by iRECIST

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End point title

Efficacy: immune Progression-Free Survival (iPFS) at 12 months by iRECIST

End point description

Probability for subjects for immune Progression Free Survival (iPFS) assessed by immune Response Evaluation Criteria in Solid Tumours (iRECIST) at 12 months after first CAN04 dose.

End point type

Secondary

End point timeframe

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	30	11	16	3	10	33	25	20	20
Units: %
number (confidence interval 95%)	16 (5 to 32)	22 (4 to 50)	7 (1 to 28)	33 (1 to 77)	25 (4 to 55)	16 (6 to 31)	22 (8 to 40)	17 (4 to 37)	19 (4 to 43)

No statistical analyses for this end point

Secondary: Efficacy: Progression-Free Survival (PFS) at 12 months by RECIST 1.1

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End point title

Efficacy: Progression-Free Survival (PFS) at 12 months by RECIST 1.1

End point description

Probability for subjects for Progression Free Survival (PFS) assessed by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) at 12 months after first CAN04 dose.

End point type

Secondary

End point timeframe

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	30	11	16	3	10	33	25	20	20
Units: %
number (confidence interval 95%)	16 (5 to 32)	22 (4 to 50)	7 (1 to 28)	33 (1 to 77)	25 (4 to 55)	13 (4 to 27)	18 (6 to 35)	17 (4 to 37)	19 (5 to 40)

No statistical analyses for this end point

Secondary: Efficacy: immune related Progression-Free Survival (irPFS) by irRC

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End point title

Efficacy: immune related Progression-Free Survival (irPFS) by irRC

End point description

immune related Progression Free Survival (irPFS) from first CAN04 dose until confirmed disease progression by immune related Response Criteria (irRC), start of new line of systemic anti-cancer therapy or death.

End point type

Secondary

End point timeframe

At screening followed by 8-week intervals after first CAN04 dose while on trial treatment until confirmed disease progression, start of new line of systemic anti-cancer therapy or death.

End point values	Part I - Dose escalation mITT	Part II Monotherapy Arm A mITT	Part II Monotherapy Arm B mITT	Part II Monotherapy mITT
Number of subjects analysed	22	10	10	26
Units: months
median (confidence interval 95%)	1.9 (1.8 to 3.2)	1.7 (0.2 to 2.4)	1.9 (0.8 to 2.8)	1.8 (1.4 to 2.2)

No statistical analyses for this end point

Secondary: Efficacy: immune Progression-Free Survival (iPFS) by iRECIST

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End point title

Efficacy: immune Progression-Free Survival (iPFS) by iRECIST

End point description

immune Progression Free Survival (iPFS) from first CAN04 dose until confirmed disease progression by immune Response Evaluation Criteria in Solid Tumours (iRECIST), start of new line of systemic anticancer therapy or death.

End point type

Secondary

End point timeframe

End point values	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm D 7.5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	30	11	16	33	25	8	20	20
Units: months
median (confidence interval 95%)	7.0 (5.5 to 8.8)	8.8 (5.6 to 13.0)	5.5 (2.7 to 7.4)	5.6 (2.0 to 7.4)	5.6 (2.8 to 9.3)	3.7 (0.6 to 8.5)	7.2 (3.7 to 9.2)	7.4 (5.1 to 11.2)

No statistical analyses for this end point

Secondary: Efficacy: Progression-Free Survival (PFS) by RECIST 1.1

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End point title

Efficacy: Progression-Free Survival (PFS) by RECIST 1.1

End point description

Progression Free Survival (PFS) from first CAN04 dose until confirmed disease progression by Response Evaluation Criteria in Solid Tumours (RECIST version 1.1)

End point type

Secondary

End point timeframe

Part I - Dose escalation mITT

Part II Monotherapy Arm A mITT

Part II Monotherapy Arm B mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: months

median (confidence interval 95%)

1.9 (1.8 to 1.9)

1.7 (0.2 to 1.9)

1.8 (0.8 to 2.2)

1.8 (1.2 to 1.9)

7.0 (5.5 to 8.8)

8.8 (5.6 to 13.0)

5.5 (2.7 to 7.4)

3.7 (1.9 to 5.8)

3.7 (1.9 to 7.1)

3.7 (0.6 to 8.5)

7.2 (2.7 to 9.2)

7.3 (4.9 to 9.3)

No statistical analyses for this end point

Secondary: Efficacy: Overall Survival (OS) at 12 months

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End point title

Efficacy: Overall Survival (OS) at 12 months

End point description

Probability for subjects to be alive 12 months after first CAN04 dose.

End point type

Secondary

End point timeframe

Follow-up for Overall Survival was performed 12, 24 and 36 months after End of Treatment visit.

Part I - Dose escalation mITT

Part I - Dose escalation 1 mg/kg mITT

Part I - Dose escalation 3 mg/kg mITT

Part I - Dose escalation 10 mg/kg mITT

Part II Monotherapy Arm B mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm C 2.5 mg/kg mITT

Part II Combination therapy Arm NCP mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: %

number (confidence interval 95%)

23 (8 to 41)

67 (5 to 95)

17 (1 to 52)

30 (7 to 58)

12 (3 to 27)

57 (37 to 73)

55 (23 to 78)

57 (28 to 78)

67 (5 to 95)

48 (16 to 75)

56 (38 to 71)

54 (33 to 71)

63 (23 to 86)

63 (38 to 81)

56 (31 to 75)

No statistical analyses for this end point

Secondary: Efficacy: Overall Survival (OS) at 24 months

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End point title

Efficacy: Overall Survival (OS) at 24 months

End point description

Probability for subjects to be alive 24 months after first CAN04 dose.

End point type

Secondary

End point timeframe

Follow-up for Overall Survival was performed 12, 24 and 36 months after End of Treatment visit.

Part II Monotherapy Arm B mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm C 2.5 mg/kg mITT

Part II Combination therapy Arm NCP mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: %

number (confidence interval 95%)

10 (1 to 36)

4 (0 to 16)

29 (14 to 46)

36 (11 to 63)

21 (5 to 45)

33 (1 to 77)

24 (2 to 62)

30 (15 to 46)

32 (14 to 51)

25 (4 to 56)

32 (13 to 52)

22 (7 to 43)

No statistical analyses for this end point

Secondary: Efficacy: Overall Survival (OS) at 36 months

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End point title

Efficacy: Overall Survival (OS) at 36 months

End point description

Probability for subjects to be alive 36 months after first CAN04 dose.

End point type

Secondary

End point timeframe

Follow-up for Overall Survival was performed 12, 24 and 36 months after End of Treatment visit.

End point values	Part II Monotherapy Arm B mITT	Part II Monotherapy mITT	Part II Combination therapy Arm C mITT	Part II Combination therapy Arm C 5 mg/kg mITT	Part II Combination therapy Arm C 1 mg/kg mITT	Part II Combination therapy Arm C 2.5 mg/kg mITT	Part II Combination therapy Arm NCP mITT	Part II Combination therapy Arm D mITT	Part II Combination therapy Arm D 5 mg/kg mITT	Part II Combination therapy Arm PDEX1 mITT	Part II Combination therapy Arm PDEX2.5 mITT
Number of subjects analysed	10	26	30	11	16	3	10	33	25	20	20
Units: %
number (confidence interval 95%)	10 (1 to 36)	4 (0 to 16)	16 (5 to 32)	18 (3 to 44)	14 (2 to 37)	33 (1 to 77)	24 (2 to 62)	9 (2 to 23)	12 (2 to 30)	13 (2 to 33)	15 (3 to 36)

No statistical analyses for this end point

Secondary: Efficacy: Overall Survival (OS)

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End point title

Efficacy: Overall Survival (OS)

End point description

Overall Survival (OS) from first CAN04 dose until death of any cause.

End point type

Secondary

End point timeframe

Follow-up for Overall Survival was performed 12, 24 and 36 months after End of Treatment visit.

Part I - Dose escalation mITT

Part I - Dose escalation 6 mg/kg mITT

Part II Monotherapy Arm A mITT

Part II Monotherapy Arm B mITT

Part II Monotherapy mITT

Part II Combination therapy Arm C mITT

Part II Combination therapy Arm C 5 mg/kg mITT

Part II Combination therapy Arm C 1 mg/kg mITT

Part II Combination therapy Arm D mITT

Part II Combination therapy Arm D 5 mg/kg mITT

Part II Combination therapy Arm D 7.5 mg/kg mITT

Part II Combination therapy Arm PDEX1 mITT

Part II Combination therapy Arm PDEX2.5 mITT

Number of subjects analysed

Units: months

median (confidence interval 95%)

6.3 (3.7 to 9.2)

5.1 (1.1 to 9.2)

2.7 (0.2 to 4.9)

5.1 (1.0 to 12.2)

3.8 (2.3 to 5.3)

13.9 (11.1 to 19.4)

13.7 (9.1 to 30.4)

14.9 (6.0 to 22.0)

12.6 (8.0 to 19.2)

12.6 (6.5 to 24.6)

13.0 (0.7 to 25.7)

12.9 (9.9 to 25.7)

14.2 (6.9 to 15.6)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from ICF signature until 28 days after end of treatment with CAN04.

Adverse event reporting additional description

All adverse events reported spontaneoulsy by the subject or observed by the investigator was recorded although reported adverese events below refers to treatment emergent adverse events.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Part I - Dose escalation

Reporting group description

Phase 1 dose-escalation arm (3+3 design) to assess the safety of CAN04 monotherapy administered at 1 (n=3), 1.5 (n=3), 3 (n=3), 6 (n=7), and 10 (n=6) mg/kg in patients with unresectable NSCLC, PDAC, CRC, or TNBC that was refractory to standard therapy or for whom no standard therapy existed. The primary aim was to assess safety and to define the MTD or RP2D of CAN04 administered once weekly.

Reporting group title

Part II Monotherapy Arm A

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 10 mg/kg (RP2D) once weekly in patients with unresectable squamous or non-squamous NSCLC or PDAC that was refractory to standard therapy or for whom no standard therapy existed.

Reporting group title

Part II Monotherapy Arm B

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 10 mg/kg (RP2D) once weekly for first 6 weeks followed by biweekly administration in patients with unresectable squamous or non-squamous NSCLC or PDAC that was refractory to standard therapy or for whom no standard therapy existed.

Reporting group title

Part II Monotheraphy Arm E

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and early signs of efficacy of CAN04 monotherapy administered at 15 mg/kg once weekly for first 6 weeks followed by biweekly administration in patients with unresectable, locally advanced or metastatic squamous or non-squamous NSCLC or PDAC that was refractory to standard therapy or for whom no standard therapy existed.

Reporting group title

Part II Combination therapy Arm C

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with gemcitabine and cisplatin in patients with unresectable, locally advanced or metastatic squamous or non-squamous NSCLC who was candidates for 1st line of standard chemotherapy regimen with cisplatin/gemcitabine or who relapsed after 1st line with pembrolizumab monotherapy and was candidates for 2nd line of standard chemotherapy regimen with cisplatin/gemcitabine. The arm was initially designed with a limited dose escalation phase as a 3+3 design and 3 dose levels: 5, 7.5, and 10 mg/kg (the monotherapy RP2D). After the identification of MTD/RP2D, it was planned to continue the arm with a dose expansion phase but a provisional MTD was reached on 5 mg/kg (n=13) and dose reduced to 1 mg/kg (n=17) and re-escaleted to 2.5 mg/kg (n=3).

Reporting group title

Part II Combination therapy Arm NCP

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with carboplatin and pemetrexed in patients with stage III or IV non-squamous NSCLC who was candidates for 1st line of standard chemotherapy regimen with carboplatin/pemetrexed or who relapsed after 1st line with pembrolizumab monotherapy and was candidates for 2nd line of standard chemotherapy regimen with carboplatin/pemetrexed.

Reporting group title

Part II Combination therapy Arm D

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who was candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The arm was initially designed with a limited dose escalation phase as a 3+3 design and 3 dose levels: 5, 7.5, and 10 mg/kg (the monotherapy RP2D). After the identification of MTD/RP2D, it was planned to continue the arm with a dose expansion phase, and after 7.5 mg/kg (n=8) was found to be above MTD expansion phase was done with 5 mg/kg (n=28).

Reporting group title

Part II Combination therapy Arm PDEX1

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 at 1 mg/kg in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who was candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The starting dose selected in Arm PDEX1 was chosen to explore doses below the MTD (5.0 mg/kg) after the completion of Part II Combination therapy Arm D.

Reporting group title

Part II Combination therapy Arm PDEX2.5

Reporting group description

Part II dose expansion arm to assess safety and tolerability, and preliminary signs of efficacy of CAN04 at 2.5 mg/kg in combination with gemcitabine and nab-paclitaxel in patients with stage III or IV pancreatic ductal adenocarcinoma who was candidates for 1st line of standard chemotherapy regimen with gemcitabine/nab-paclitaxel. The starting dose selected in Arm PDEX2.5 was chosen to explore doses below the MTD (5.0 mg/kg) after the completion of Part II Combination therapy Arm D.

Serious adverse events	Part I - Dose escalation	Part II Monotherapy Arm A	Part II Monotherapy Arm B	Part II Monotheraphy Arm E	Part II Combination therapy Arm C	Part II Combination therapy Arm NCP	Part II Combination therapy Arm D	Part II Combination therapy Arm PDEX1	Part II Combination therapy Arm PDEX2.5
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 22 (40.91%)	7 / 10 (70.00%)	4 / 10 (40.00%)	5 / 6 (83.33%)	22 / 33 (66.67%)	2 / 10 (20.00%)	24 / 36 (66.67%)	9 / 20 (45.00%)	11 / 20 (55.00%)
number of deaths (all causes)	22	10	9	6	25	6	28	16	15
number of deaths resulting from adverse events	2	1	0	1	3	1	2	2	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Elective surgery
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hospitalisation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Fatigue
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	4 / 22 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	5 / 36 (13.89%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	6 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radicular pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	0 / 10 (0.00%)	5 / 36 (13.89%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	5 / 5	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
Additional description: 'White blood cell count decreased' is reported as 'Leukopenia'
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
Additional description: 'Neutrophil count decreased' is reported as 'Neutropenia'
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
Additional description: 'Platelet Count Decreased' is reported as 'Thrombocytopenia'
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	5 / 6	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Intestinal stenosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis membranoproliferative
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Catheter site infection
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis infective
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis bacterial
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	2 / 3	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part I - Dose escalation	Part II Monotherapy Arm A	Part II Monotherapy Arm B	Part II Monotheraphy Arm E	Part II Combination therapy Arm C	Part II Combination therapy Arm NCP	Part II Combination therapy Arm D	Part II Combination therapy Arm PDEX1	Part II Combination therapy Arm PDEX2.5
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 22 (100.00%)	10 / 10 (100.00%)	10 / 10 (100.00%)	6 / 6 (100.00%)	30 / 33 (90.91%)	10 / 10 (100.00%)	35 / 36 (97.22%)	19 / 20 (95.00%)	20 / 20 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Cancer pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	1	0
Haemangioma
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Metastases to central nervous system
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Tumour pain
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	3	2
Deep vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Flushing
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	1 / 10 (10.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	1	1	0	0
Haematoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Hypertension
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	5 / 36 (13.89%)	3 / 20 (15.00%)	2 / 20 (10.00%)
occurrences all number	2	0	0	0	2	0	6	3	4
Hypotension
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	0 / 10 (0.00%)	3 / 36 (8.33%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	3	0	3	3	1
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Peripheral artery occlusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Peripheral coldness
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	2
Phlebitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Subclavian vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Superficial vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Thrombophlebitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Varicose vein
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	6 / 33 (18.18%)	1 / 10 (10.00%)	4 / 36 (11.11%)	4 / 20 (20.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	8	1	4	7	2
Catheter site pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	2 / 22 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	2 / 10 (20.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	3 / 20 (15.00%)
occurrences all number	2	1	0	0	5	2	3	1	4
Chills
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	7 / 36 (19.44%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	1	1	0	11	1	0
Device related thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Disease progression
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Drug intolerance
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Face oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	2 / 10 (20.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Fatigue
subjects affected / exposed	7 / 22 (31.82%)	6 / 10 (60.00%)	6 / 10 (60.00%)	3 / 6 (50.00%)	8 / 33 (24.24%)	1 / 10 (10.00%)	21 / 36 (58.33%)	9 / 20 (45.00%)	11 / 20 (55.00%)
occurrences all number	12	6	6	5	8	1	38	13	16
Feeling hot
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
General physical health deterioration
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	1	0	1	0	2
Inflammation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	3 / 22 (13.64%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	3	0	1	0	2	0	2	1	2
Localised oedema
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0
Malaise
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)
occurrences all number	0	1	0	0	0	0	0	2	2
Medical device site pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	2	1	0
Nodule
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	1	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	5 / 33 (15.15%)	2 / 10 (20.00%)	17 / 36 (47.22%)	10 / 20 (50.00%)	8 / 20 (40.00%)
occurrences all number	0	1	1	1	7	2	25	15	15
Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1	2
Peripheral swelling
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0	0
Pyrexia
subjects affected / exposed	2 / 22 (9.09%)	4 / 10 (40.00%)	2 / 10 (20.00%)	1 / 6 (16.67%)	3 / 33 (9.09%)	0 / 10 (0.00%)	13 / 36 (36.11%)	6 / 20 (30.00%)	7 / 20 (35.00%)
occurrences all number	4	6	2	3	3	0	32	6	12
Secretion discharge
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Swelling face
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Thirst
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Xerosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Cough
subjects affected / exposed	3 / 22 (13.64%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	5 / 33 (15.15%)	1 / 10 (10.00%)	5 / 36 (13.89%)	5 / 20 (25.00%)	4 / 20 (20.00%)
occurrences all number	3	1	0	1	6	1	6	9	6
Dysphonia
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	0	1	1	0	0	0	0	3	1
Dyspnoea
subjects affected / exposed	1 / 22 (4.55%)	4 / 10 (40.00%)	4 / 10 (40.00%)	1 / 6 (16.67%)	3 / 33 (9.09%)	1 / 10 (10.00%)	8 / 36 (22.22%)	6 / 20 (30.00%)	6 / 20 (30.00%)
occurrences all number	1	4	4	1	3	1	10	7	8
Dyspnoea exertional
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 33 (6.06%)	0 / 10 (0.00%)	3 / 36 (8.33%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	2	0	3	0	1
Epistaxis
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	1 / 10 (10.00%)	6 / 36 (16.67%)	5 / 20 (25.00%)	4 / 20 (20.00%)
occurrences all number	1	0	0	0	2	1	9	6	6
Hiccups
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	3
Nasal mucosal disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	1	0	2	2	0
Pleural effusion
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	1	0	2	0	0
Pneumonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	3 / 36 (8.33%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	4	1	1
Productive cough
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	1 / 10 (10.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	3	1	3	0	1
Pulmonary embolism
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	1 / 10 (10.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	1	1	1	0
Rhinorrhoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	1	2	1
Throat irritation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	4
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	0 / 10 (0.00%)	3 / 36 (8.33%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	4	0	3	1	0
Confusional state
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	2	0	0
Depressed mood
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0
Depression
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	1	1	0
Hallucination
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	2 / 36 (5.56%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	2	0	2	5	1
Listless
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Nervousness
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Product issues
Device occlusion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	3 / 10 (30.00%)	3 / 36 (8.33%)	6 / 20 (30.00%)	5 / 20 (25.00%)
occurrences all number	1	1	0	0	7	3	11	10	5
Aspartate aminotransferase increased
subjects affected / exposed	2 / 22 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	3 / 33 (9.09%)	3 / 10 (30.00%)	4 / 36 (11.11%)	4 / 20 (20.00%)	4 / 20 (20.00%)
occurrences all number	2	1	0	1	3	7	11	7	5
Bilirubin conjugated increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 22 (13.64%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	1 / 10 (10.00%)	3 / 36 (8.33%)	3 / 20 (15.00%)	6 / 20 (30.00%)
occurrences all number	3	0	0	1	1	1	3	6	8
Blood bilirubin increased
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	1	1	0	0	0	0	1	1	1
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	4 / 36 (11.11%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	5	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 33 (6.06%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	3	1	0	0	1
Blood uric acid increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	1	0	0	0
C-reactive protein increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	6 / 33 (18.18%)	0 / 10 (0.00%)	3 / 36 (8.33%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	7	0	3	2	1
Cardiac murmur
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 33 (6.06%)	0 / 10 (0.00%)	4 / 36 (11.11%)	4 / 20 (20.00%)	8 / 20 (40.00%)
occurrences all number	1	0	0	1	2	0	4	6	8
International normalised ratio increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	4 / 20 (20.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	4	1
Weight decreased
subjects affected / exposed	3 / 22 (13.64%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	1 / 10 (10.00%)	2 / 36 (5.56%)	3 / 20 (15.00%)	2 / 20 (10.00%)
occurrences all number	3	1	0	1	1	1	3	3	4
Weight increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	5 / 33 (15.15%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	5	0	0	1	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Fall
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	3 / 36 (8.33%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	8	2	0
Incision site haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Inflammation of wound
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Infusion related reaction
subjects affected / exposed	6 / 22 (27.27%)	2 / 10 (20.00%)	1 / 10 (10.00%)	3 / 6 (50.00%)	5 / 33 (15.15%)	2 / 10 (20.00%)	13 / 36 (36.11%)	3 / 20 (15.00%)	3 / 20 (15.00%)
occurrences all number	7	4	1	3	5	2	23	4	3
Rib fracture
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Skin wound
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Wound
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Atrial fibrillation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	1	0	0	1	0	0	0	2
Tachycardia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	2	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Anosmia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Aphasia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0
Ataxia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Balance disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Disturbance in attention
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Dizziness
subjects affected / exposed	0 / 22 (0.00%)	2 / 10 (20.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	3 / 36 (8.33%)	4 / 20 (20.00%)	2 / 20 (10.00%)
occurrences all number	0	3	2	0	2	0	3	5	2
Dysgeusia
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	0 / 10 (0.00%)	6 / 36 (16.67%)	5 / 20 (25.00%)	3 / 20 (15.00%)
occurrences all number	1	1	1	0	5	0	7	6	3
Headache
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	3 / 33 (9.09%)	0 / 10 (0.00%)	7 / 36 (19.44%)	4 / 20 (20.00%)	3 / 20 (15.00%)
occurrences all number	1	0	0	1	5	0	11	7	5
Intracranial pressure increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Neuropathy peripheral
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	2 / 36 (5.56%)	6 / 20 (30.00%)	3 / 20 (15.00%)
occurrences all number	0	0	1	0	2	0	2	6	3
Paraesthesia
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	3 / 36 (8.33%)	3 / 20 (15.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	1	0	3	3	0
Paresis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	7 / 36 (19.44%)	7 / 20 (35.00%)	3 / 20 (15.00%)
occurrences all number	0	1	0	0	0	0	8	7	3
Piriformis syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Polyneuropathy
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	1 / 10 (10.00%)	1 / 36 (2.78%)	2 / 20 (10.00%)	3 / 20 (15.00%)
occurrences all number	0	0	0	0	6	1	1	3	3
Sciatica
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Somnolence
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	4
Syncope
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Taste disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Tremor
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	1	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 22 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	19 / 33 (57.58%)	10 / 10 (100.00%)	15 / 36 (41.67%)	13 / 20 (65.00%)	11 / 20 (55.00%)
occurrences all number	2	1	0	0	28	17	30	22	21
Febrile neutropenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0
Leukocytosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	1	2
Leukopenia
Additional description: 'White blood cell count decreased' is reported as 'Leukopenia'.
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	4 / 10 (40.00%)	13 / 36 (36.11%)	6 / 20 (30.00%)	3 / 20 (15.00%)
occurrences all number	1	1	0	0	4	10	58	7	4
Lymphadenopathy
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Lymphopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	2 / 20 (10.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	1	0	4	2	2
Neutropenia
Additional description: 'Neutrophil count decreased' is reported as 'Neutropenia'.
subjects affected / exposed	2 / 22 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	24 / 33 (72.73%)	9 / 10 (90.00%)	28 / 36 (77.78%)	14 / 20 (70.00%)	16 / 20 (80.00%)
occurrences all number	3	1	0	0	68	32	84	41	31
Neutrophilia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	0
Splenic vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Thrombocytopenia
Additional description: 'Platelet Count Decreased' is reported as 'Thrombocytopenia'.
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	24 / 33 (72.73%)	4 / 10 (40.00%)	14 / 36 (38.89%)	8 / 20 (40.00%)	8 / 20 (40.00%)
occurrences all number	2	0	0	0	64	14	33	14	21
Thrombocytosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	2
Hypoacusis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Vertigo
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Dry eye
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	0
Eye inflammation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Eye pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Eye swelling
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Lacrimation increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Periorbital oedema
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Visual acuity reduced
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	1	3	0	1
Abdominal pain
subjects affected / exposed	1 / 22 (4.55%)	4 / 10 (40.00%)	2 / 10 (20.00%)	2 / 6 (33.33%)	0 / 33 (0.00%)	1 / 10 (10.00%)	13 / 36 (36.11%)	5 / 20 (25.00%)	4 / 20 (20.00%)
occurrences all number	1	5	2	2	0	2	16	8	7
Abdominal pain upper
subjects affected / exposed	4 / 22 (18.18%)	2 / 10 (20.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	2 / 33 (6.06%)	0 / 10 (0.00%)	7 / 36 (19.44%)	6 / 20 (30.00%)	2 / 20 (10.00%)
occurrences all number	5	2	1	1	4	0	7	6	2
Anal haemorrhage
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0
Ascites
subjects affected / exposed	0 / 22 (0.00%)	2 / 10 (20.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	2	2	0	0	0	0	0	3
Constipation
subjects affected / exposed	6 / 22 (27.27%)	5 / 10 (50.00%)	4 / 10 (40.00%)	2 / 6 (33.33%)	5 / 33 (15.15%)	0 / 10 (0.00%)	14 / 36 (38.89%)	7 / 20 (35.00%)	3 / 20 (15.00%)
occurrences all number	7	5	4	2	9	0	19	8	4
Diarrhoea
subjects affected / exposed	6 / 22 (27.27%)	1 / 10 (10.00%)	1 / 10 (10.00%)	2 / 6 (33.33%)	9 / 33 (27.27%)	1 / 10 (10.00%)	15 / 36 (41.67%)	10 / 20 (50.00%)	9 / 20 (45.00%)
occurrences all number	8	1	1	2	18	1	24	14	17
Dry mouth
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	0	1	1	1	1	0	2	2	2
Duodenal ulcer
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Dyspepsia
subjects affected / exposed	2 / 22 (9.09%)	2 / 10 (20.00%)	1 / 10 (10.00%)	2 / 6 (33.33%)	1 / 33 (3.03%)	1 / 10 (10.00%)	6 / 36 (16.67%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	2	2	1	2	3	1	8	1	0
Dysphagia
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	0	0	1	0	0	0	0
Eructation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	2	1
Flatulence
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	3 / 20 (15.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	0	2	3	4
Gastric dilatation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)
occurrences all number	0	0	1	0	0	0	0	3	3
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Hypoaesthesia oral
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Ileus
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Loose tooth
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Mucous stools
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	5 / 22 (22.73%)	5 / 10 (50.00%)	4 / 10 (40.00%)	3 / 6 (50.00%)	9 / 33 (27.27%)	1 / 10 (10.00%)	24 / 36 (66.67%)	12 / 20 (60.00%)	9 / 20 (45.00%)
occurrences all number	8	5	4	5	15	1	65	18	17
Oral mucosal blistering
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	2
Oral pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Salivary hypersecretion
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Steatorrhoea
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	7 / 36 (19.44%)	5 / 20 (25.00%)	4 / 20 (20.00%)
occurrences all number	0	0	0	0	1	0	10	11	4
Terminal ileitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tongue coated
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Toothache
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	0	0	1
Vomiting
subjects affected / exposed	5 / 22 (22.73%)	4 / 10 (40.00%)	4 / 10 (40.00%)	3 / 6 (50.00%)	5 / 33 (15.15%)	0 / 10 (0.00%)	13 / 36 (36.11%)	8 / 20 (40.00%)	6 / 20 (30.00%)
occurrences all number	7	5	4	4	7	0	21	16	17
Hepatobiliary disorders
Bile duct stenosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Biliary obstruction
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Cholecystitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Cholestasis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Hepatic cytolysis
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0
Hepatic pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Hepatotoxicity
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Portal vein thrombosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	6 / 33 (18.18%)	1 / 10 (10.00%)	17 / 36 (47.22%)	10 / 20 (50.00%)	4 / 20 (20.00%)
occurrences all number	0	0	1	0	8	1	18	11	5
Blister
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	0	1	1	2
Dry skin
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	1 / 36 (2.78%)	2 / 20 (10.00%)	2 / 20 (10.00%)
occurrences all number	1	1	0	0	1	2	1	2	2
Eczema
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	2	0	0
Erythema
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	1 / 10 (10.00%)	1 / 36 (2.78%)	2 / 20 (10.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	3	1	1	2	1
Hyperhidrosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	2 / 20 (10.00%)
occurrences all number	0	0	1	0	2	0	2	1	2
Nail discolouration
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Nail disorder
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	0
Nail ridging
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	3	2
Night sweats
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Onycholysis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	3	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Pruritus
subjects affected / exposed	4 / 22 (18.18%)	2 / 10 (20.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	1 / 10 (10.00%)	7 / 36 (19.44%)	5 / 20 (25.00%)	1 / 20 (5.00%)
occurrences all number	4	2	1	0	6	1	8	8	2
Pruritus allergic
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	4 / 33 (12.12%)	1 / 10 (10.00%)	10 / 36 (27.78%)	2 / 20 (10.00%)	3 / 20 (15.00%)
occurrences all number	0	0	0	1	6	1	16	3	6
Rash maculo-papular
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	6 / 36 (16.67%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	6	2	1
Skin exfoliation
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Skin fissures
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Umbilical haematoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	1 / 10 (10.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	3	1	1	1	0
Chronic kidney disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0
Dysuria
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0
Haematuria
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	2	0	0
Incontinence
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Paraneoplastic glomerulonephritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pollakiuria
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0
Proteinuria
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	1	2	1	0	0
Renal failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	1	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	1 / 6 (16.67%)	4 / 33 (12.12%)	2 / 10 (20.00%)	4 / 36 (11.11%)	5 / 20 (25.00%)	3 / 20 (15.00%)
occurrences all number	0	1	2	1	4	2	4	7	3
Back pain
subjects affected / exposed	0 / 22 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	8 / 33 (24.24%)	1 / 10 (10.00%)	8 / 36 (22.22%)	3 / 20 (15.00%)	3 / 20 (15.00%)
occurrences all number	0	2	1	0	10	1	11	6	5
Bone pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	2	0
Bursitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Flank pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	1	2	0	0	0	0	1	0
Joint swelling
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Limb discomfort
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Muscle spasm
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	1 / 10 (10.00%)	1 / 36 (2.78%)	3 / 20 (15.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	1	6	0
Muscular weakness
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	2 / 22 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	0	2	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Myalgia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	4 / 36 (11.11%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	2	0	5	6	1
Neck pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	3	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	6 / 33 (18.18%)	0 / 10 (0.00%)	3 / 36 (8.33%)	3 / 20 (15.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	6	0	3	5	1
Spinal pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tendonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Infections and infestations
Bacterial infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0
Covid-19
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	3 / 10 (30.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	3	2	0	1
Cholangitis infective
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	1	0	1
Conjunctivitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	1	1	0
Cystitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Erysipelas
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	3	0	0
Fungal foot infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Fungal infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	2	1	0
Gastroenteritis Escherichia coli
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Haemophilus infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Herpes zoster
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Hordeolum
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	4 / 36 (11.11%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	2	0	0	4	1	2
Nasopharyngitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	3 / 36 (8.33%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	6	0	2
Onychomycosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	4 / 36 (11.11%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	0	7	0	1
Paronychia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Pharyngitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Pneumonia
subjects affected / exposed	2 / 22 (9.09%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	3 / 33 (9.09%)	2 / 10 (20.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	3	1	1	0	3	3	1	1	0
Prostatic abscess
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	0	1	1
Root canal infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Spontaneous bacterial peritonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Tooth abscess
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	1	1
Tooth infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0	0
Urinary tract infection
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	3 / 33 (9.09%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	1	1	3	0	2	0	0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	5 / 22 (22.73%)	4 / 10 (40.00%)	5 / 10 (50.00%)	3 / 6 (50.00%)	6 / 33 (18.18%)	0 / 10 (0.00%)	13 / 36 (36.11%)	10 / 20 (50.00%)	7 / 20 (35.00%)
occurrences all number	7	4	5	3	8	0	30	15	12
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dyslipidaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	1 / 10 (10.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Food intolerance
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Hypercalcaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	0	0	0	0	1
Hyperkalaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 33 (12.12%)	0 / 10 (0.00%)	1 / 36 (2.78%)	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	10	0	1	0	4
Hypoalbuminaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	2	0	1
Hypocalcaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 33 (6.06%)	0 / 10 (0.00%)	1 / 36 (2.78%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	2	0	1	1	1
Hypoglycaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0	0
Hypokalaemia
subjects affected / exposed	1 / 22 (4.55%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	6 / 33 (18.18%)	2 / 10 (20.00%)	8 / 36 (22.22%)	2 / 20 (10.00%)	3 / 20 (15.00%)
occurrences all number	1	1	1	0	7	2	11	2	3
Hypomagnesaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	12 / 33 (36.36%)	1 / 10 (10.00%)	3 / 36 (8.33%)	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	21	2	9	1	0
Hyponatraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 33 (3.03%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0	0
Hypophosphataemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	2 / 36 (5.56%)	0 / 20 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	2	0	0	0	2	0	0
Iron deficiency
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1	1
Metabolic acidosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 33 (0.00%)	0 / 10 (0.00%)	0 / 36 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

18 Dec 2017

The protocol was amended according to the decisions of the Dose Escalation Committee (DEC) evaluating the first dose cohort with implementation of pre-medication (corticosteroids, antihistamines and paracetamol) at 1st dosing, extended blood sampling to be able to evaluate any infusion related reactions).

29 Mar 2018

The protocol was amended to include: 1) Update of Dose Limiting Toxicity (DLT) criteria list: The DEC will judge if infusion related reactions that appear <24 hours after the first administration of CAN04 are to be considered as a DLT. The DEC has the mandate to decide whether these specific events are to be graded as DLTs or not. 2) Update in procedures for first CAN04 dose: Initial dose of up to 1.0 mg/kg will be given. The dose and infusion rate for this first administration to be decided by the DEC. 3) Addition of treatment options of infusion related reactions.

12 Jul 2018

The protocol was amended to include the final design for Part II, focused on NSCLC and PDAC patients receiving either CAN04 monotherapy or CAN04 in combination with standard of care. Main changes included: 1) Adjustment of the protocol according to the decisions of the Dose Escalation Committe on the initial priming dose to reduce risk for infusion related reactions. 2) Update to include further details of Part II of the study (Arm A, B, C and D). 3) Combination treatment and definition of Arm C (NSCLC) and Arm D (PDAC). 4) Inclusion of quality of life assessment specific for NSCLC. 5) PK and biomarker assessment schedule adjustment.

21 Dec 2018

The protocol was amended to include changes requested by various Competent Authorities and Ethic Committees.

04 Jan 2019

The protocol was amended to remove the note that in Germany only ultrasound-guided procedures to collect new biopsies was allowed.

29 Jul 2019

The protocol was amended to include: 1) Addition of Arm E (up to 12 subjects) to evaluate CAN04 at 15 mg/kg monotherapy and if pre-medication with corticosteroids at priming dose could be reduced without interfering with anticipated incidence and severity of infusion-related reactions. 2) Adjustment of duration of CT/MRI follow-up. 3) Update in dosing procedures for first CAN04 dosing for Part II (0.5 mg/kg over 120 min). 4) Addition of inclusion criterion for Arms C and D (Subjects who underwent (neo)adjuvant treatments was eligible if the (neo)adjuvant treatment ended at least 6 months prior to inclusion). 5) Adjustment of treatment delay instructions. 6) Addition of ADA and PK sampling at FU visit (28 days after last dose of CAN04).

10 Mar 2020

The protocol was amended as follows: 1) Decision to use 5mg/kg CAN04 as pharmacologically active dose (PAD) and discontinuation of Arm E. 2) Updates in the dosage, dose expansion, and dose modification criteria sections in line with the choice of PAD dose. 3) Inclusion of rationale for the choice of PAD dose. 4) Updates the Treatment Limiting Toxicity (TLT) and AE/SAE sections in line with the choice of PAD dose. 5) Change in efficacy endpoint evaluation (from iRC to iRECIST). 6) Updates in the inclusion/exclusion criteria for clarity, to avoid protocol deviations. 7) Update to state that assessment of CA 19-9 in PDAC (Arm D) is mandatory. 8) Updates in statistical considerations to align with the choice of 5.0 mg/kg CAN04 as PAD and discontinuation of Arm E. 9) Inclusion of country-specific changes from V6.1, V6.2, and V6.3 of the protocol.

05 Nov 2020

The protocol was amended to include: 1) Arm C modifications: a) Reduction of assigned dose of CAN04 from 5.0 mg/kg to 1mg/kg. Rationale for the change was safety measures to reduce risk for neutropenia and febrile neutropenia; b) Included the possibility to escalate the CAN04 dose to 2.5 mg/kg if the safety and efficacy observed in subjects newly dosed with 1.0 mg/kg support it; c) Modification of inclusion and exclusion criteria to allow for subjects progressed on all standard of care previous targeted therapies. 2) Addition of 2 new parallel safety expansion cohorts of 20 subjects each with subjects with unresectable locally advanced or metastatic PDAC to be treated with gemcitabine/nab-paclitaxel and 2 lower doses of CAN04: Arm PDEX2.5 with 2.5 mg/kg and Arm PDEX1 with 1.0 mg/kg. a) These new arms test a novel administration schedule for CAN04: (i) removal of the priming dose of 0.5 mg/kg; (ii) schedule modification, with CAN04 being administered on Day 1 and 15 in cycles of 28 days, with exception for Cycle 1 where, in addition, CAN04 also was administered on Day 8; b) Paired tumour biopsies was not required in these new expansion cohorts.

13 Aug 2021

The protocol was amended to include: 1) Addition of a new experimental arm (Arm NCP) to evaluate a new platinum combination with carboplatin and pemetrexed together with CAN04 in subjects with stage III or stage IV non-squamous NSCLC who was candidates for 1st line of standard chemotherapy regimen with carboplatin/pemetrexed or who relapsed after 1st line with pembrolizumab monotherapy. a) The Arm NCP aimed to include in total up to 40 patients and aimed to start with a run-in-phase to identify a safe and potentially efficacious dose to be used in the following expansion phase to evaluate the initial antitumour effect. b) CAN04 to be administered on Day 1 in combination with standard carboplatin and pemetrexed and on Day 8 (CAN04 alone) in cycles of 21 days. Safety Review Committee to decide to de-escalate to 1.0 mg/kg if 2.5 mg/kg was above Maximum Tolerated Dose (MTD). It was also possible to escalate to 5.0 mg/kg if 2.5 mg/kg was not the MTD, based on safety, efficacy and PK data. 2) Addition of exclusion criterion excluding patients with biliary stent placement or cholangitis less than 30 days before the calculated first administration of CAN04 and antibiotic therapy less than 14 days prior to study treatment. 3) Inclusion of country-specific changes from V8.1 of the protocol. 4) Implementation of decisions from Safety Review Committee meeting to implement primary prophylaxis with G-CSF in Arm C and to escalate CAN04 dose in Arm C from 1 to 2.5 mg/kg in remaining patients to be enrolled.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
12 Apr 2023	Early cessation of recruitment in NCP arm. All study arms were recruited and completed according to protocol with the exception of Arm NCP. The decision to prematurely end enrolment into the NCP arm (aimed to enroll 40 subjects but terminated after 10 subjects) was made due to strategic reasons and was not related to any safety or efficacy considerations.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Early cessation of recruitment in NCP arm due to strategic reasons leading to a small number of subjects analyzed for this specific arm.

http://www.ncbi.nlm.nih.gov/pubmed/40680438
http://www.ncbi.nlm.nih.gov/pubmed/34903842
http://www.ncbi.nlm.nih.gov/pubmed/39385434

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Clinical trials

Clinical Trial Results: An open label, dose escalation followed by dose expansion, safety and tolerability trial of CAN04, a fully humanized monoclonal antibody against IL1RAP, in subjects with solid malignant tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of Grade ≥3 adverse events related to CAN04 administration

Primary: Incidence of Grade ≥3 adverse events related to CAN04 administration

Secondary: Pharmacokinetics: Concentration at the end of infusion - Single dose

Secondary: Pharmacokinetics: Concentration at the end of infusion - Single dose

Secondary: Pharmacokinetics: Maximum concentration - Single dose

Secondary: Pharmacokinetics: Maximum concentration - Single dose

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Single dose

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Single dose

Secondary: Pharmacokinetics: Terminal half-life - Single dose

Secondary: Pharmacokinetics: Terminal half-life - Single dose

Secondary: Pharmacokinetics: Clearance - Single dose

Secondary: Pharmacokinetics: Clearance - Single dose

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Single dose

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Single dose

Secondary: Pharmacokinetics: Mean residence time - Single dose

Secondary: Pharmacokinetics: Mean residence time - Single dose

Secondary: Pharmacokinetics: Concentration at the end of infusion - Repeated dose

Secondary: Pharmacokinetics: Concentration at the end of infusion - Repeated dose

Secondary: Pharmacokinetics: Maximum concentration - Repeated dose

Secondary: Pharmacokinetics: Maximum concentration - Repeated dose

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Repeated dose

Secondary: Pharmacokinetics: Time taken to reach maximum concentration - Repeated dose

Secondary: Pharmacokinetics: Terminal half-life - Repeated dose

Secondary: Pharmacokinetics: Terminal half-life - Repeated dose

Secondary: Pharmacokinetics: Clearance - Repeated dose

Secondary: Pharmacokinetics: Clearance - Repeated dose

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Repeated dose

Secondary: Pharmacokinetics: Apparent volume of distribution during the terminal phase - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to infinity - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time t - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time t - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 24h - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to time 168 h - Repeated dose

Secondary: Pharmacokinetics: Mean residence time - Repeated dose

Secondary: Pharmacokinetics: Mean residence time - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau (AUC0-τ) - Single dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau - Repeated dose

Secondary: Pharmacokinetics: Area under the curve from time 0 to tau - Repeated dose

Secondary: Pharmacokinetics: Changes in serum concentration of sIL1RAP

Secondary: Pharmacokinetics: Changes in serum concentration of sIL1RAP

Secondary: Efficacy: immune related Overall Response Rate (irORR) by irRC

Secondary: Efficacy: immune related Overall Response Rate (irORR) by irRC

Secondary: Efficacy: immune Overall Response Rate (iORR) by iRECIST

Secondary: Efficacy: immune Overall Response Rate (iORR) by iRECIST

Secondary: Efficacy: Overall Response Rate (ORR) by RECIST 1.1

Secondary: Efficacy: Overall Response Rate (ORR) by RECIST 1.1

Secondary: Efficacy: immune related Duration of Response (irDoR) by irRC

Secondary: Efficacy: immune related Duration of Response (irDoR) by irRC

Secondary: Efficacy: immune Duration of Response (iDoR) by iRECIST

Secondary: Efficacy: immune Duration of Response (iDoR) by iRECIST

Secondary: Efficacy: Duration of Response (DoR) by RECIST 1.1

Secondary: Efficacy: Duration of Response (DoR) by RECIST 1.1

Secondary: Efficacy: immune related Progression-Free Survival (irPFS) at 6 months by irRC

Secondary: Efficacy: immune related Progression-Free Survival (irPFS) at 6 months by irRC

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 6 months by iRECIST

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 6 months by iRECIST

Secondary: Efficacy: Progression-Free Survival (PFS) at 6 months by RECIST 1.1

Secondary: Efficacy: Progression-Free Survival (PFS) at 6 months by RECIST 1.1

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 12 months by iRECIST

Secondary: Efficacy: immune Progression-Free Survival (iPFS) at 12 months by iRECIST

Clinical Trial Results:
An open label, dose escalation followed by dose expansion, safety and tolerability trial of CAN04, a fully humanized monoclonal antibody against IL1RAP, in subjects with solid malignant tumors