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Clinical Trial Results:
An Open-label, Randomized, Phase I/II Trial Investigating the Safety and Efficacy of IO102 in Combination with Pembrolizumab, with or without Chemotherapy, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer

Summary
EudraCT number	2018-000139-28
Trial protocol	ES GB DE NL
Global end of trial date	12 Apr 2022

Results information
Results version number	v1(current)
This version publication date	04 Apr 2024
First version publication date	04 Apr 2024
Other versions
Summary report(s)	iCTR synopsis CTR Addendum synopsis

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

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Trial information

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Sponsor protocol code

IO102-012

ISRCTN number

US NCT number

NCT03562871

WHO universal trial number (UTN)

Sponsor organisation name

IO Biotech ApS

Sponsor organisation address

Ole Maaløes Vej 3, Copenhagen N, Denmark, DK-2200

Public contact

Qasim Ahmad, Chief Medical Officer, IO Biotech ApS, +1 9084005672, qah@iobiotech.com

Scientific contact

Qasim Ahmad, Chief Medical Officer, IO Biotech ApS, +1 9084005672, qah@iobiotech.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

19 May 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Apr 2022

Global end of trial reached?

Yes

Global end of trial date

12 Apr 2022

Was the trial ended prematurely?

Main objective of the trial

Primary objective: a) Phase I (Safety Run-in): to investigate the safety of IO102 in combination with either pembrolizumab (pembro) alone or pembro + chemotherapy (carboplatin and pemetrexed) in patients with metastatic non-small cell lung cancer (NSCLC), that were eligible for pembro treatment as first-line therapy for stage IV disease. b) Phase II part: to assess the efficacy of IO102 in combination with either pembro alone or pembro + chemotherapy versus either pembro alone or pembro + chemotherapy as measured by objective response rate (ORR) per investigator assessment in patients with metastatic NSCLC, that were eligible for pembro treatment as first-line therapy. Secondary objective: To investigate the safety profile and the secondary measures of efficacy including disease control rate (DCR), time to event parameters including duration of response (DOR), progression free survival (PFS), overall survival (OS), and tumor shrinkage.

Protection of trial subjects

As per attached synopsis

Background therapy

Pembrolizumab (Keytruda®), with or without chemotherapy doublet (carboplatin + pemetrexed)

Evidence for comparator

Actual start date of recruitment

19 Sep 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Spain: 92

Country: Number of subjects enrolled

United Kingdom: 9

Worldwide total number of subjects

110

EEA total number of subjects

101

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

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Recruitment details

First patient on trial: 19 September 2018 Last patient last visit: 12 April 2022 This was a multicentre study that involved 17 participating sites: nine centres in Spain, six centres in Germany, one centre in the United Kingdom, and one centre in The Netherlands.

Screening details

Male or female, aged ≥18 years, diagnosis of metastatic NSCLC (Cohort A) or non-squamous NSCLC (Cohort B) with no prior systemic treatment for their metastatic disease, had PD-L1 tumor expression ≥50% (Cohort A) or <50% (Cohort B), measurable disease, adequate organ function, and an ECOG performance status of 0 or 1.

Period 1 title

Phase I and Phase II (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This was an open-label study. No blinding of the patients or investigators was necessary. N.B.: Phase II patients were randomized to the experimental treatment (A1 and B1) or the control treatment (A2 and B2) on a 2:1 ratio, depending on the level of tumor PD-L1 expression.

Are arms mutually exclusive

Yes

Arm A1 (Phase II)

Arm description

PD-L1 expression ≥50%, Phase II Cohort A treatment A1 (IO102 + Pembrolizumab)

Arm type

Experimental

Investigational medicinal product name

IO102

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

100 μg SC Q3W, administered on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Arm A2 (Phase II)

Arm description

PD-L1 expression ≥50%, Phase II Cohort A treatment A2 (Pembrolizumab)

Arm type

Active comparator

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Arm B1 (Phase II)

Arm description

PD-L1 expression <50%, Phase II Cohort B treatment B1 (IO102 + Pembrolizumab + Chemotherapy)

Arm type

Experimental

Investigational medicinal product name

IO102

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

100 μg SC Q3W, administered on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500mg/m2 IV Q3W administered as 10min infusion at least one hour after administration of pembrolizumab, on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

5mg/mL/min IV Q3W administered as 15-60min infusion immediately after administration of pemetrexed, on Day 1 of each 3-week cycle for a maximum of 4 cycles.

Arm B2 (Phase II)

Arm description

PD-L1 expression <50%, Phase II Cohort B treatment B2 (Pembrolizumab + Chemotherapy)

Arm type

Active comparator

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500mg/m2 IV Q3W administered as 10min infusion at least one hour after administration of pembrolizumab, on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

5mg/mL/min IV Q3W administered as 15-60min infusion immediately after administration of pemetrexed, on Day 1 of each 3-week cycle for a maximum of 4 cycles.

Arm A (Phase I)

Arm description

PD-L1 expression ≥50%, Phase I Cohort A (IO102 + Pembrolizumab)

Arm type

Experimental

Investigational medicinal product name

IO102

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

100 μg SC Q3W, administered on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Arm B (Phase I)

Arm description

PD-L1 expression <50%, Phase I Cohort B (IO102 + Pembrolizumab + Chemotherapy)

Arm type

Active comparator

Investigational medicinal product name

IO102

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

100 μg SC Q3W, administered on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

200mg IV Q3W, administered as a 30-minute infusion on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

500mg/m2 IV Q3W administered as 10min infusion at least one hour after administration of pembrolizumab, on Day 1 of each 3-week cycle for a maximum of 35 cycles.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

5mg/mL/min IV Q3W administered as 15-60min infusion immediately after administration of pemetrexed, on Day 1 of each 3-week cycle for a maximum of 4 cycles.

Number of subjects in period 1	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Started	32	16	33	17	6	6
Patients who discontinued from treatment	32	16	33	17	6	6
Patients not attending safety follow-up	12	4	11	4	1	1
Patients who discontinued from trial	32	16	33	17	6	6
Completed	0	0	0	0	0	0
Not completed	32	16	33	17	6	6
Physician decision	1	1	-	-	-	-
Disease progression	23	8	22	10	2	5
Adverse event, non-fatal	1	5	4	2	3	-
Other	7	2	4	2	1	-
Death	-	-	3	-	-	1
Need for prohibited concomitant medication	-	-	-	1	-	-
Patient non-compliance	-	-	-	1	-	-
Withdrawal of study treatment by patient	-	-	-	1	-	-

Baseline characteristics

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Reporting group title

Arm A1 (Phase II)

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A1 (IO102 + Pembrolizumab)

Reporting group title

Arm A2 (Phase II)

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A2 (Pembrolizumab)

Reporting group title

Arm B1 (Phase II)

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B1 (IO102 + Pembrolizumab + Chemotherapy)

Reporting group title

Arm B2 (Phase II)

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B2 (Pembrolizumab + Chemotherapy)

Reporting group title

Arm A (Phase I)

Reporting group description

PD-L1 expression ≥50%, Phase I Cohort A (IO102 + Pembrolizumab)

Reporting group title

Arm B (Phase I)

Reporting group description

PD-L1 expression <50%, Phase I Cohort B (IO102 + Pembrolizumab + Chemotherapy)

Reporting group values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)	Total
Number of subjects	32	16	33	17	6	6	110
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	65.4 ± 7.94	63.7 ± 6.71	65.4 ± 9.60	62.2 ± 9.85	67.7 ± 8.38	51.7 ± 17.34	-
Gender categorical
Units: Subjects
Female	7	5	15	6	1	4	38
Male	25	11	18	11	5	2	72
PD-L1 category
Units: Subjects
<1%	0	0	17	6	0	3	26
1-49%	0	0	16	11	0	3	30
≥50%	32	16	0	0	6	0	54
ECOG performance status
Units: Subjects
PS 0	11	8	13	5	2	2	41
PS 1	21	8	20	12	4	4	69
Race
Units: Subjects
White	31	16	32	17	6	6	108
Black or African American	1	0	1	0	0	0	2
Ethnicity
Units: Subjects
Hispanic or Latino	2	1	0	0	0	0	3
Not Hispanic or Latino	30	15	33	17	6	6	107
PD-L1 TPS
Units: per cent
arithmetic mean (standard deviation)	72.3 ± 19.92	73.8 ± 16.74	5.5 ± 10.43	7.5 ± 10.67	82.5 ± 18.91	0.7 ± 0.82	-

End points

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Reporting group title

Arm A1 (Phase II)

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A1 (IO102 + Pembrolizumab)

Reporting group title

Arm A2 (Phase II)

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A2 (Pembrolizumab)

Reporting group title

Arm B1 (Phase II)

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B1 (IO102 + Pembrolizumab + Chemotherapy)

Reporting group title

Arm B2 (Phase II)

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B2 (Pembrolizumab + Chemotherapy)

Reporting group title

Arm A (Phase I)

Reporting group description

PD-L1 expression ≥50%, Phase I Cohort A (IO102 + Pembrolizumab)

Reporting group title

Arm B (Phase I)

Reporting group description

PD-L1 expression <50%, Phase I Cohort B (IO102 + Pembrolizumab + Chemotherapy)

Subject analysis set title

Phase I - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

Equivalent to the safety population (patients who received any trial treatment [IO102 and/or pembrolizumab]).

Subject analysis set title

Phase I - per protocol

Subject analysis set type

Per protocol

Subject analysis set description

All patients with measurable disease per RECIST v1.1 who received at least four cycles of IO102 treatment and had at least two post-baseline planned radiographic assessments of response. The per protocol population serves as the secondary analysis population for efficacy endpoints.

Subject analysis set title

Phase II - ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized patients, regardless of whether trial medication was administered or not. The ITT population serves as the primary analysis population for efficacy endpoints.

Subject analysis set title

Phase II - per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Phase I/II - Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

Combined Phase I and Phase II Safety Population, comprises all patients who received any trial treatment (IO102 and/or pembrolizumab).

Subject analysis set title

Phase I/II - ITT Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

Combined Phase I and Phase II ITT Population

Subject analysis set title

Phase I/II - per protocol

Subject analysis set type

Per protocol

Subject analysis set description

Combined Phase I and Phase II per protocol Population

Primary: Safety Endpoint - Summary of adverse events (AEs)

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End point title

Safety Endpoint - Summary of adverse events (AEs) ^[1]

End point description

The primary endpoint of Phase I of the trial included the occurrence of dose limiting toxicities (DLTs) and the incidence and severity of AEs and serious adverse events (SAEs), including events of clinical interest (ECIs), Eastern Cooperative Oncology Group (ECOG) performance status, physical examination, vital signs, electrocardiogram (ECG), and changes in laboratory values (clinical chemistry and hematology). National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used for grading of events. AEs are further described in the "Adverse events" section.

End point type

Primary

End point timeframe

AEs and ECIs were reported from the time of treatment allocation/randomization and through 30 days following cessation of trial treatment. Abbreviation: TEAE = treatment-emergent adverse event.

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: Safety variables were summarised descriptively.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	16	6	6
Units: Subjects
With at least one TEAE	32	16	33	16	6	6
Related TEAE (any study treatment)	26	13	32	16	3	6
TEAE related to IO102	22	0	22	0	3	5
TEAE related to Pembrolizumab	25	13	25	15	3	6
TEAE related to Carboplatin	0	0	30	15	0	6
TEAE related to Pemetrexed	0	0	31	16	0	6
Serious TEAE	13	5	14	9	3	2
Serious related TEAE (any study treatment)	2	0	6	6	0	1
Grade 3 or 4 TEAE	17	10	24	15	4	4
TEAE leading to discont. of any study treatment	2	2	12	4	3	2
TEAE leading to discontinuation of IO102	2	0	7	0	3	1
TEAE leading to discontinuation of Pembrolizumab	2	2	7	4	3	1
TEAE leading to discontinuation of Carboplatin	0	0	1	1	0	0
TEAE leading to discontinuation of Pemetrexed	0	0	11	2	0	2
TEAE leading to dose interruption of Pembrolizumab	12	10	22	9	3	3
Fatal TEAE	1	1	4	0	0	1
COVID-19 Infection	1	1	2	3	0	0
DLTs	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population

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End point title

Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population ^[2]

End point description

The primary endpoint of Phase II of the trial was the ORR evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR was defined as the rate of partial response (PR) plus complete response (CR).

End point type

Primary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 urgent safety measure [USM]) for the first 12 months, and Q12W thereafter.

Notes
[2] - 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: The study was not formally statistically powered and no statistical hypotheses were tested. Data were summarised descriptively.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	17	6	6
Units: Subjects
Complete response (CR)	1	1	0	0	0	0
Partial response (PR)	14	6	13	9	3	1
Stable disease (SD)	10	7	18	3	1	4
Progressive disease (PD)	6	0	1	2	2	1
Not evaluable (NE)	0	0	0	1	0	0
Missing (screen failure+died prior 1st assessment)	1	2	1	2	0	0

No statistical analyses for this end point

Primary: Efficacy endpoint: ORR - Phase II, ITT population

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End point title

Efficacy endpoint: ORR - Phase II, ITT population ^[3] ^[4]

End point description

The primary endpoint of Phase II of the trial was the ORR evaluated by RECIST 1.1. ORR was defined as the rate of PR + CR. ORR by baseline PD-L1 expression was a secondary endpoint and the corresponding data are provided for cohorts B and B1 combined in an attached document.

End point type

Primary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

Notes
[3] - 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: The study was not formally statistically powered and no statistical hypotheses were tested. Data were summarised descriptively.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only ORR data for the four Phase II arms are provided under this section. ORR data for the two Phase I arms are provided separately. This is so that 95% confidence interval data can be entered when available (i.e., for Phase II arms but not for Phase I arms).

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)
Number of subjects analysed	32	16	33	17
Units: Ratio
number (confidence interval 95%)
ORR	0.469 (0.309 to 0.636)	0.438 (0.231 to 0.668)	0.394 (0.247 to 0.563)	0.529 (0.310 to 0.738)

Attachments

ORR by baseline PD-L1 expression

No statistical analyses for this end point

Primary: Efficacy endpoint: ORR - Phase I, ITT Population

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End point title

Efficacy endpoint: ORR - Phase I, ITT Population ^[5] ^[6]

End point description

The ORR was evaluated by RECIST 1.1. ORR was defined as the rate of PR + CR. Although ORR was the primary endpoint for Phase II, it was a secondary endpoint for Phase I. ORR by baseline PD-L1 expression was a secondary endpoint for both phases and the corresponding data are provided for cohorts B and B1 combined in an attached document.

End point type

Primary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

Notes
[5] - 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: The study was not formally statistically powered and no statistical hypotheses were tested. Data were summarised descriptively.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only ORR data for the two Phase I arms are provided under this section. ORR data for the four Phase II arms are provided separately. This is so that 95% confidence interval data can be entered when available (i.e., for Phase II arms but not for Phase I arms).

End point values	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	6	6
Units: Ratio
number (not applicable)
ORR	0.500	0.167

No statistical analyses for this end point

Secondary: Efficacy endpoint: DCR - Phase II, ITT population

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End point title

Efficacy endpoint: DCR - Phase II, ITT population ^[7]

End point description

DCR was defined as the ratio of CR + PR + stable disease (SD) (for 24 weeks or more).

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only DCR data for the four Phase II arms are provided under this section. DCR data for the two Phase I arms are provided separately. This is so that 95% confidence interval data can be entered when available (i.e., for Phase II arms but not for Phase I arms).

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)
Number of subjects analysed	32	16	33	17
Units: Ratio
number (confidence interval 95%)
DCR	0.563 (0.393 to 0.718)	0.500 (0.280 to 0.720)	0.727 (0.558 to 0.849)	0.706 (0.469 to 0.867)

No statistical analyses for this end point

Secondary: Efficacy endpoint: DCR - Phase I, ITT population

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End point title

Efficacy endpoint: DCR - Phase I, ITT population ^[8]

End point description

DCR was defined as the ratio of CR + PR + SD (for 24 weeks or more).

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only DCR data for the two Phase I arms are provided under this section. DCR data for the four Phase II arms are provided separately. This is so that 95% confidence interval data can be entered when available (i.e., for Phase II arms but not for Phase I arms).

End point values	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	6	6
Units: Ratio
number (not applicable)
DCR	0.500	0.500

No statistical analyses for this end point

Secondary: Efficacy endpoint: Time to response (TTR)

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End point title

Efficacy endpoint: Time to response (TTR) ^[9]

End point description

The TTR was defined as the time from first study treatment administration until confirmed CR or confirmed PR. This occurrence of confirmed CR or PR was defined as TTR event. For patients with no report of confirmed CR or PR, observation was censored on the date of their last disease assessment. TTR cumulative incidence curves for Cohort A (both phases) and Cohort B (both phases) are provided in Attachment 2.

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: TTR results are provided in an attachment.

End point values	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	6	6
Units: Months
arithmetic mean (standard deviation)
Time to response (months)	3.32 ± 2.00	5.82 ± 5.75

Attachments

TTR

No statistical analyses for this end point

Secondary: Efficacy endpoint: DOR

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End point title

Efficacy endpoint: DOR

End point description

The DOR was defined as the time from first observation of a confirmed CR or a confirmed PR to Progressive Disease (PD) or death. In case an assessment of PD or a death record did not exist, the DOR was censored at the time of the last tumor assessment. DOR for cohort A (both phases) and cohort B (both phases) is provided in Attachment 3. DOR by PD-L1 score TPS <1% and TPS >1-49% for cohort B (both phases) is also included in Attachment 3.

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	17	6	6
Units: Subjects
Number of patients with objective response	15	7	13	9	3	1
Number of DOR events	8	2	10	8	3	1

Attachments

DOR

No statistical analyses for this end point

Secondary: Efficacy endpoint: PFS

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End point title

Efficacy endpoint: PFS

End point description

The PFS was defined as the time from first study treatment administration until the first occurrence of PD or death. Patients who had not progressed or died were censored on the date of their last disease assessment. PFS for cohort A (both phases) and cohort B (both phases) is provided in Attachment 4. PFS by PD-L1 score TPS <1% and TPS >1-49% for cohort B (both phases) is also included in Attachment 4.

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	17	6	6
Units: Subjects
Number of PFS events	25	11	30	15	6	6

Attachments

PFS

No statistical analyses for this end point

Secondary: Efficacy endpoint: OS

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End point title

Efficacy endpoint: OS

End point description

The OS was defined as the time from first study treatment administration until death of any cause. Patients for whom no death was captured in the clinical database were censored at the most recent date they were known to be alive. The OS for cohort A (both phases) and cohort B (both phases) is provided in Attachment 5. OS by PD-L1 score TPS <1% and TPS >1-49% for cohort B (both phases) is also included in Attachment 5.

End point type

Secondary

End point timeframe

Patients had their disease assessed Q9W (or Q12W as part of the COVID-19 USM) for the first 12 months, and Q12W thereafter.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	17	6	6
Units: Subjects
Number of OS events (deaths)	20	8	24	11	4	4

Attachments

No statistical analyses for this end point

Secondary: Efficacy endpoint: Time to First Subsequent Treatment or Death (TFST)

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End point title

Efficacy endpoint: Time to First Subsequent Treatment or Death (TFST)

End point description

The TFST was defined as the time from first study treatment administration until the commencement of first subsequent treatment or death, whichever occurred first. This occurrence of a first Subsequent Treatment or death was defined as TFST event. For patients with no report of first subsequent treatment or death, observation was censored on the most recent date the patients were known to be alive. TFST for cohort A (both phases) and cohort B (both phases) is provided in Attachment 6.

End point type

Secondary

End point timeframe

Time from first study treatment administration until the commencement of first subsequent treatment or death.

End point values	Arm A1 (Phase II)	Arm A2 (Phase II)	Arm B1 (Phase II)	Arm B2 (Phase II)	Arm A (Phase I)	Arm B (Phase I)
Number of subjects analysed	32	16	33	17	6	6
Units: Number of TFST events
Number of TFST events	24	11	28	14	4	5

Attachments

TFST

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were monitored from the time patients provided written informed consent and throughout the trial duration, until 30 days after the last dose of trial treatment.

Adverse event reporting additional description

AEs were graded and recorded throughout the trial and during the follow-up period according to NCI CTCAE (Version 4.03).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Phase I cohort A

Reporting group description

PD-L1 expression ≥50%, Phase I Cohort A (IO102 + Pembrolizumab)

Reporting group title

Phase I cohort B

Reporting group description

PD-L1 expression <50%, Phase I Cohort B (IO102 + Pembrolizumab + Chemotherapy)

Reporting group title

Phase II cohort A treatment A1

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A1 (IO102 + Pembrolizumab)

Reporting group title

Phase II cohort A treatment A2

Reporting group description

PD-L1 expression ≥50%, Phase II Cohort A treatment A2 (Pembrolizumab)

Reporting group title

Phase II cohort B treatment B1

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B1 (IO102 + Pembrolizumab + Chemotherapy)

Reporting group title

Phase II cohort B treatment B2

Reporting group description

PD-L1 expression <50%, Phase II Cohort B treatment B2 (Pembrolizumab + Chemotherapy)

Reporting group title

Overall trial population

Reporting group description

All patients who received any trial treatment (IO102 and/or pembrolizumab), regardless of the duration of treatment.

Serious adverse events	Phase I cohort A	Phase I cohort B	Phase II cohort A treatment A1	Phase II cohort A treatment A2	Phase II cohort B treatment B1	Phase II cohort B treatment B2	Overall trial population
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	13 / 32 (40.63%)	5 / 16 (31.25%)	14 / 33 (42.42%)	9 / 16 (56.25%)	46 / 109 (42.20%)
number of deaths (all causes)	4	4	20	8	24	11	71
number of deaths resulting from adverse events	0	1	1	1	4	0	7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the tongue
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Transitional cell carcinoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	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
Pneumonitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dysarthria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
Additional description: SAE of anaemia (phase I cohort B ) was not related to IO102, not related to pembrolizumab but was definitely related to carboplatin and definitely related to pemetrexed.
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	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
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	2 / 16 (12.50%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	3 / 3	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Immune-mediated enterocolitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	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
Renal and urinary disorders
Anuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Chronic kidney disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	1 / 16 (6.25%)	1 / 33 (3.03%)	2 / 16 (12.50%)	5 / 109 (4.59%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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
COVID-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Endocarditis bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	2 / 33 (6.06%)	1 / 16 (6.25%)	7 / 109 (6.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 1	2 / 2	0 / 2	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	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
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	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
Submandibular abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetic ketoacidosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	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	Phase I cohort A	Phase I cohort B	Phase II cohort A treatment A1	Phase II cohort A treatment A2	Phase II cohort B treatment B1	Phase II cohort B treatment B2	Overall trial population
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	32 / 32 (100.00%)	16 / 16 (100.00%)	32 / 33 (96.97%)	16 / 16 (100.00%)	108 / 109 (99.08%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	2	0	0	0	2
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	2 / 33 (6.06%)	0 / 16 (0.00%)	6 / 109 (5.50%)
occurrences all number	0	0	4	1	2	0	7
Intermittent claudication
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Phlebitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Subclavian vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
General disorders and administration site conditions
Administration site erythema
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Asthenia
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	8 / 32 (25.00%)	4 / 16 (25.00%)	18 / 33 (54.55%)	10 / 16 (62.50%)	45 / 109 (41.28%)
occurrences all number	2	6	11	4	22	18	63
Fatigue
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	5 / 32 (15.63%)	1 / 16 (6.25%)	10 / 33 (30.30%)	3 / 16 (18.75%)	21 / 109 (19.27%)
occurrences all number	1	1	5	1	11	4	23
Injection site induration
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 32 (3.13%)	0 / 16 (0.00%)	4 / 33 (12.12%)	0 / 16 (0.00%)	6 / 109 (5.50%)
occurrences all number	0	2	1	0	5	0	8
Oedema peripheral
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 32 (9.38%)	0 / 16 (0.00%)	4 / 33 (12.12%)	4 / 16 (25.00%)	13 / 109 (11.93%)
occurrences all number	1	1	3	0	7	6	18
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	9 / 32 (28.13%)	3 / 16 (18.75%)	8 / 33 (24.24%)	3 / 16 (18.75%)	26 / 109 (23.85%)
occurrences all number	1	3	10	4	10	4	32
Chest discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	1	0	0	1	2
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	6 / 32 (18.75%)	0 / 16 (0.00%)	4 / 33 (12.12%)	2 / 16 (12.50%)	12 / 109 (11.01%)
occurrences all number	0	0	8	0	4	2	14
Feeling hot
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	2	0	0	2
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	3 / 33 (9.09%)	2 / 16 (12.50%)	5 / 109 (4.59%)
occurrences all number	0	0	0	0	3	2	5
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	1	0	0	1	2
Injection site reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	4 / 33 (12.12%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	0	0	0	0	4	0	4
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	1 / 16 (6.25%)	2 / 33 (6.06%)	4 / 16 (25.00%)	9 / 109 (8.26%)
occurrences all number	0	0	2	1	4	6	13
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	2 / 16 (12.50%)	0 / 33 (0.00%)	2 / 16 (12.50%)	5 / 109 (4.59%)
occurrences all number	0	0	1	2	0	2	5
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	2	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	7 / 32 (21.88%)	3 / 16 (18.75%)	7 / 33 (21.21%)	3 / 16 (18.75%)	21 / 109 (19.27%)
occurrences all number	0	2	8	3	7	3	23
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	15 / 32 (46.88%)	4 / 16 (25.00%)	8 / 33 (24.24%)	4 / 16 (25.00%)	34 / 109 (31.19%)
occurrences all number	1	3	17	4	11	5	41
Haemoptysis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 32 (9.38%)	2 / 16 (12.50%)	3 / 33 (9.09%)	1 / 16 (6.25%)	10 / 109 (9.17%)
occurrences all number	2	0	3	5	3	1	14
Pleural effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	1	0	2	0	1	0	4
Productive cough
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	2 / 33 (6.06%)	2 / 16 (12.50%)	9 / 109 (8.26%)
occurrences all number	4	0	3	1	2	2	12
Pulmonary embolism
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	1	1	0	0	1	0	3
Rhinorrhoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	3 / 109 (2.75%)
occurrences all number	1	0	0	0	1	1	3
Catarrh
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	1	1	2
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	1 / 33 (3.03%)	1 / 16 (6.25%)	6 / 109 (5.50%)
occurrences all number	0	0	3	1	1	1	6
Hiccups
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	2	0	2
Pneumonitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	5 / 32 (15.63%)	2 / 16 (12.50%)	0 / 33 (0.00%)	1 / 16 (6.25%)	8 / 109 (7.34%)
occurrences all number	0	0	5	2	0	1	8
Tachypnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	1	0	0	1	2
Psychiatric disorders
Disorientation
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	2	0	0	0	0	2
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	1 / 33 (3.03%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	0	1	1	2	4
Apathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	1 / 33 (3.03%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	0	1	1	1	1	4
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	6 / 32 (18.75%)	2 / 16 (12.50%)	4 / 33 (12.12%)	6 / 16 (37.50%)	19 / 109 (17.43%)
occurrences all number	1	0	6	2	7	9	25
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	5 / 33 (15.15%)	4 / 16 (25.00%)	14 / 109 (12.84%)
occurrences all number	1	0	3	1	8	8	21
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	1	0	1	0	1	0	3
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	5 / 32 (15.63%)	2 / 16 (12.50%)	8 / 33 (24.24%)	3 / 16 (18.75%)	20 / 109 (18.35%)
occurrences all number	0	3	7	2	13	3	28
Blood potassium increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	1	0	0	0	0	1
Blood urea increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	2	0	0	2	1	5
Blood uric acid increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	1	2	0	0	1	0	4
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	4 / 33 (12.12%)	2 / 16 (12.50%)	11 / 109 (10.09%)
occurrences all number	1	0	3	1	4	3	12
International normalised ratio increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	1	0	0	3	0	4
Blood alkaline phosphatase
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	1 / 16 (6.25%)	3 / 33 (9.09%)	4 / 16 (25.00%)	10 / 109 (9.17%)
occurrences all number	0	0	2	1	4	4	11
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	1 / 16 (6.25%)	1 / 33 (3.03%)	1 / 16 (6.25%)	5 / 109 (4.59%)
occurrences all number	0	0	2	2	1	1	6
Blood calcium increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Blood cholesterol increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Blood phosphorus decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	2	0	0	0	2
C-reactive protein increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Glomerular filtration rate
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	1	0	4	0	5
Sputum abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	4 / 33 (12.12%)	1 / 16 (6.25%)	7 / 109 (6.42%)
occurrences all number	0	0	1	1	4	1	7
White blood cells urine
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Injury, poisoning and procedural complications
Anaemia postoperative
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Post procedural haematuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Limb injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Skin wound
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Cardiac disorders
Pericardial effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	1	0	1	0	0	0	2
Arrhythmia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Supraventricular tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Nervous system disorders
Neuropathy peripheral
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	3	0	0	0	0	0	3
Neurotoxicity
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	2	0	0	0	0	2
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	1	0	0	3	1	5
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	3 / 109 (2.75%)
occurrences all number	0	1	0	0	1	1	3
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	2 / 33 (6.06%)	3 / 16 (18.75%)	6 / 109 (5.50%)
occurrences all number	0	0	0	2	3	3	8
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	5 / 33 (15.15%)	1 / 16 (6.25%)	7 / 109 (6.42%)
occurrences all number	0	0	1	0	5	1	7
Head discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	5 / 33 (15.15%)	3 / 16 (18.75%)	10 / 109 (9.17%)
occurrences all number	0	0	2	0	6	4	12
Paresis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Syncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	1	0	2	0	3
Taste disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	3 / 33 (9.09%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	0	0	3	0	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	5 / 6 (83.33%)	8 / 32 (25.00%)	2 / 16 (12.50%)	23 / 33 (69.70%)	11 / 16 (68.75%)	49 / 109 (44.95%)
occurrences all number	0	6	8	3	34	16	67
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	9 / 33 (27.27%)	7 / 16 (43.75%)	20 / 109 (18.35%)
occurrences all number	0	6	0	1	12	10	29
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	3 / 32 (9.38%)	0 / 16 (0.00%)	8 / 33 (24.24%)	5 / 16 (31.25%)	18 / 109 (16.51%)
occurrences all number	0	2	4	0	11	5	22
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	0	2	2
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	0	0	3	2	5
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	4 / 33 (12.12%)	0 / 16 (0.00%)	6 / 109 (5.50%)
occurrences all number	0	0	2	0	9	0	11
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Ear discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	2	0	2
Excessive cerumen production
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Hypoacusis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Eye disorders
Eye pruritus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Eyelid oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	1 / 16 (6.25%)	3 / 33 (9.09%)	1 / 16 (6.25%)	6 / 109 (5.50%)
occurrences all number	0	1	0	1	3	1	6
Retinal vein occlusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Conjunctival cyst
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	3 / 33 (9.09%)	1 / 16 (6.25%)	6 / 109 (5.50%)
occurrences all number	0	0	2	0	3	1	6
Erythema of eyelid
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Eye disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Lacrimation increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	4 / 33 (12.12%)	3 / 16 (18.75%)	8 / 109 (7.34%)
occurrences all number	0	0	1	0	4	4	9
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	2	0	0	0	2
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	6 / 32 (18.75%)	1 / 16 (6.25%)	12 / 33 (36.36%)	4 / 16 (25.00%)	28 / 109 (25.69%)
occurrences all number	2	3	9	1	14	8	37
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	3 / 6 (50.00%)	9 / 32 (28.13%)	5 / 16 (31.25%)	7 / 33 (21.21%)	4 / 16 (25.00%)	28 / 109 (25.69%)
occurrences all number	0	4	10	7	10	7	38
Dry mouth
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 32 (3.13%)	2 / 16 (12.50%)	2 / 33 (6.06%)	1 / 16 (6.25%)	8 / 109 (7.34%)
occurrences all number	1	1	1	2	2	1	8
Nausea
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	3 / 32 (9.38%)	1 / 16 (6.25%)	12 / 33 (36.36%)	5 / 16 (31.25%)	25 / 109 (22.94%)
occurrences all number	1	3	3	1	14	9	31
Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 32 (0.00%)	0 / 16 (0.00%)	3 / 33 (9.09%)	1 / 16 (6.25%)	7 / 109 (6.42%)
occurrences all number	1	2	0	0	3	1	7
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 32 (6.25%)	1 / 16 (6.25%)	4 / 33 (12.12%)	2 / 16 (12.50%)	11 / 109 (10.09%)
occurrences all number	0	3	3	1	6	4	17
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	0	0	4	0	2	0	6
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	0	2	0	1	1	4
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	3 / 109 (2.75%)
occurrences all number	0	0	1	0	2	1	4
Leukoplakia oral
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Oesophagitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Salivary hypersecretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 32 (9.38%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	1	0	3	0	0	0	4
Steatohepatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	1	0	0	0	1	0	2
Hyperbilirubinaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	1	1	0	0	2
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	1	0	0	1	0	2
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	1	1	0	0	2	4
Erythema multiforme
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Pruritus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	8 / 32 (25.00%)	2 / 16 (12.50%)	6 / 33 (18.18%)	4 / 16 (25.00%)	21 / 109 (19.27%)
occurrences all number	1	0	13	3	7	6	30
Rash
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	6 / 32 (18.75%)	0 / 16 (0.00%)	6 / 33 (18.18%)	4 / 16 (25.00%)	18 / 109 (16.51%)
occurrences all number	1	1	8	0	7	5	22
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	0	0	2	2	4
Dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	0 / 33 (0.00%)	1 / 16 (6.25%)	3 / 109 (2.75%)
occurrences all number	0	0	1	1	0	1	3
Dermatitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	2 / 33 (6.06%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	0	0	1	1	2	0	4
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	1 / 33 (3.03%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	1	2	1	0	4
Intertrigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Onycholysis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Palmar erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Parapsoriasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Psoriasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	1	1	2
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	0	1	0	1	2
Rash pruritic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	3 / 33 (9.09%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	0	0	0	1	3	0	4
Skin hyperpigmentation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	1	0	0	0	0	1
Renal impairment
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	1	1	0	0	0	0	2
Urinary tract disorder
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Chronic kidney disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	3 / 33 (9.09%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	0	0	0	1	3	0	4
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	2	0	0	3	5
Nocturia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	1	1	2
Renal failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	2 / 109 (1.83%)
occurrences all number	0	0	1	0	0	1	2
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	1 / 33 (3.03%)	0 / 16 (0.00%)	4 / 109 (3.67%)
occurrences all number	1	0	2	0	1	0	4
Hypothyroidism
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 32 (0.00%)	4 / 16 (25.00%)	1 / 33 (3.03%)	5 / 16 (31.25%)	13 / 109 (11.93%)
occurrences all number	2	1	0	4	1	5	13
Adrenal insufficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	1 / 33 (3.03%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	1	2	0	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	9 / 32 (28.13%)	3 / 16 (18.75%)	13 / 33 (39.39%)	6 / 16 (37.50%)	35 / 109 (32.11%)
occurrences all number	4	2	12	4	15	11	48
Back pain
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	5 / 32 (15.63%)	1 / 16 (6.25%)	4 / 33 (12.12%)	1 / 16 (6.25%)	14 / 109 (12.84%)
occurrences all number	2	1	7	1	4	1	16
Musculoskeletal chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	6 / 33 (18.18%)	2 / 16 (12.50%)	11 / 109 (10.09%)
occurrences all number	1	0	2	0	7	3	13
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 32 (3.13%)	0 / 16 (0.00%)	3 / 33 (9.09%)	0 / 16 (0.00%)	5 / 109 (4.59%)
occurrences all number	0	1	1	0	3	0	5
Pain in extremity
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	3 / 32 (9.38%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	8 / 109 (7.34%)
occurrences all number	2	0	5	0	2	1	10
Sjogren's syndrome
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Systemic lupus erythematosus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Arthritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	2 / 16 (12.50%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	2	0	0	2
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	3 / 109 (2.75%)
occurrences all number	0	0	0	0	2	1	3
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Joint swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	1 / 33 (3.03%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	1	1	0	2
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	2 / 16 (12.50%)	1 / 33 (3.03%)	0 / 16 (0.00%)	5 / 109 (4.59%)
occurrences all number	0	0	2	2	1	0	5
Musculoskeletal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	1 / 16 (6.25%)	2 / 33 (6.06%)	0 / 16 (0.00%)	5 / 109 (4.59%)
occurrences all number	0	0	2	1	2	0	5
Polymyalgia rheumatica
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	2	2
Infections and infestations
Diverticulitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Escherichia infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Localised infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	1	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 32 (6.25%)	0 / 16 (0.00%)	4 / 33 (12.12%)	1 / 16 (6.25%)	8 / 109 (7.34%)
occurrences all number	0	1	2	0	4	1	8
Respiratory tract infection
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	8 / 32 (25.00%)	2 / 16 (12.50%)	6 / 33 (18.18%)	5 / 16 (31.25%)	24 / 109 (22.02%)
occurrences all number	2	3	13	2	7	5	32
Rhinitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	1	0	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	0 / 33 (0.00%)	2 / 16 (12.50%)	3 / 109 (2.75%)
occurrences all number	0	0	1	0	0	2	3
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	0	1	0	2	1	4
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	0	0	2	2	4
Fungal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	0	0	0	0	2	0	2
Gingivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	2	2
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	1 / 33 (3.03%)	2 / 16 (12.50%)	3 / 109 (2.75%)
occurrences all number	0	0	0	0	1	3	4
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	2 / 16 (12.50%)	0 / 33 (0.00%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	1	2	0	0	3
Paronychia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Pharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	1 / 16 (6.25%)	2 / 33 (6.06%)	1 / 16 (6.25%)	5 / 109 (4.59%)
occurrences all number	0	0	1	1	2	1	5
Tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	0 / 33 (0.00%)	1 / 16 (6.25%)	1 / 109 (0.92%)
occurrences all number	0	0	0	0	0	1	1
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	3 / 33 (9.09%)	1 / 16 (6.25%)	5 / 109 (4.59%)
occurrences all number	0	0	1	0	3	1	5
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	4 / 33 (12.12%)	1 / 16 (6.25%)	6 / 109 (5.50%)
occurrences all number	0	0	3	0	4	1	8
Lymphangitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	4 / 32 (12.50%)	2 / 16 (12.50%)	8 / 33 (24.24%)	4 / 16 (25.00%)	21 / 109 (19.27%)
occurrences all number	1	3	4	3	8	8	27
Hyperuricaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	2 / 109 (1.83%)
occurrences all number	1	0	0	1	0	0	2
Hypoalbuminaemia
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	5 / 32 (15.63%)	3 / 16 (18.75%)	8 / 33 (24.24%)	2 / 16 (12.50%)	21 / 109 (19.27%)
occurrences all number	3	0	7	4	14	3	31
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 32 (6.25%)	0 / 16 (0.00%)	3 / 33 (9.09%)	2 / 16 (12.50%)	9 / 109 (8.26%)
occurrences all number	0	3	2	0	6	2	13
Hypomagnesaemia
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	5 / 109 (4.59%)
occurrences all number	1	2	0	0	2	0	5
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 32 (6.25%)	0 / 16 (0.00%)	2 / 33 (6.06%)	1 / 16 (6.25%)	6 / 109 (5.50%)
occurrences all number	0	2	3	0	2	1	8
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	2 / 33 (6.06%)	2 / 16 (12.50%)	6 / 109 (5.50%)
occurrences all number	0	0	2	0	2	2	6
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	0 / 16 (0.00%)	2 / 33 (6.06%)	2 / 16 (12.50%)	4 / 109 (3.67%)
occurrences all number	0	0	0	0	6	2	8
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	2 / 16 (12.50%)	1 / 33 (3.03%)	1 / 16 (6.25%)	5 / 109 (4.59%)
occurrences all number	0	0	2	3	2	1	8
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 32 (3.13%)	0 / 16 (0.00%)	2 / 33 (6.06%)	0 / 16 (0.00%)	3 / 109 (2.75%)
occurrences all number	0	0	1	0	6	0	7
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 32 (6.25%)	0 / 16 (0.00%)	1 / 33 (3.03%)	1 / 16 (6.25%)	4 / 109 (3.67%)
occurrences all number	0	0	2	0	1	1	4
Malnutrition
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 32 (0.00%)	1 / 16 (6.25%)	0 / 33 (0.00%)	0 / 16 (0.00%)	1 / 109 (0.92%)
occurrences all number	0	0	0	1	0	0	1

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Were there any global substantial amendments to the protocol? Yes

17 Sep 2018

Global amendment 1, Protocol v2.0, dated 17-Sep-2018 Changes in the Conduct of the Trial: - Eligibility criteria updated to clarify: a) permissible genomic tumor aberrations in line with KEYNOTE-024 and KEYNOTE-189. b) the permissible prior anti-cancer therapy and to align with KEYNOTE-042 to ensure the patient population was comparable. c) the location and timeframes of prior radiotherapy which would exclude patients from the trial to ensure no added toxicity after curatively intended radiotherapy and to align with KEYNOTE-189 and KEYNOTE-021. d) the permissible participation in a trial of an investigational agent or device (and related timeframes) prior to inclusion in the trial. - Addition of exclusion criterion of prior allogeneic tissue/solid organ transplant in line with standard text from Merck. - Secondary endpoints in the Trial Summary section updated for consistency with protocol Section 4. - Schedule of assessments updated to clarify the use of archival tissue for screening, the requirements for biopsies, and to introduce a nadir period to ensure all lab values were known prior to biopsy. - Trial design updated to clarify: a) the decision process by the SMC for expansion of the cohort, recruitment into Phase II and Cohort B. b) the process for sequential patient enrolment and clarify the trial pause criteria. - DLT definition updated to clarify the decision process by the SMC. - Therapeutic background updated to clarify IO102 mode of action. - Trial diagram updated to clarify AE and ECI reporting requirements and End of Trial definition. - Trial treatment section updated to clarify IO102 dose and duration of treatments. - Contraception guidance updated to include use of highly effective contraception methods and requirements for female contraception. - Blood sampling for biomarkers mandated to ensure enough material for the analysis. Clarification re. number of samples. - General administrative changes and corrections were also made.

03 Apr 2020

Global amendment 2, Protocol v3.0, dated 03-Apr-2020 Changes in the Conduct of the Trial: - Urgent Safety Measures were implemented in response to the COVID-19 pandemic to allow Investigators to minimize or eliminate the immediate hazard of COVID-19 by reducing the number of hospital visits associated with this clinical trial. Pembrolizumab and IO102 could be administered on a Q6W basis, rather than Q3W, and radiological tumor assessments for patients in the first 12 months of the trial could be carried out Q12W rather than Q9W to coincide with the new dosing schedule. Investigators could also discontinue pemetrexed maintenance and combination chemotherapy given to Cohort B1 and B2 patients. Furthermore, patients suspected of having COVID-19 could be given a COVID-19 polymerase chain reaction test. - IO102 preparation updated per regulatory request regarding the preparation of IO102 in a laminar flow cabinet. Timing of IO102 preparation also updated. - General administrative changes and corrections were also made throughout the protocol. Changes in the Planned Analyses: - Statistical methods section was updated to clarify how the statistical analysis plan was being updated as a result of the COVID-19 pandemic.

Were there any global interruptions to the trial? No

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

None reported

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Clinical Trial Results:
An Open-label, Randomized, Phase I/II Trial Investigating the Safety and Efficacy of IO102 in Combination with Pembrolizumab, with or without Chemotherapy, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer

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Subject disposition

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Baseline characteristics

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End points

Primary: Safety Endpoint - Summary of adverse events (AEs)

Primary: Safety Endpoint - Summary of adverse events (AEs)

Primary: Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population

Primary: Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population

Primary: Efficacy endpoint: ORR - Phase II, ITT population

Primary: Efficacy endpoint: ORR - Phase II, ITT population

Primary: Efficacy endpoint: ORR - Phase I, ITT Population

Primary: Efficacy endpoint: ORR - Phase I, ITT Population

Secondary: Efficacy endpoint: DCR - Phase II, ITT population

Secondary: Efficacy endpoint: DCR - Phase II, ITT population

Secondary: Efficacy endpoint: DCR - Phase I, ITT population

Secondary: Efficacy endpoint: DCR - Phase I, ITT population

Secondary: Efficacy endpoint: Time to response (TTR)

Secondary: Efficacy endpoint: Time to response (TTR)

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Secondary: Efficacy endpoint: DOR

Secondary: Efficacy endpoint: PFS

Secondary: Efficacy endpoint: PFS

Secondary: Efficacy endpoint: OS

Secondary: Efficacy endpoint: OS

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Secondary: Efficacy endpoint: Time to First Subsequent Treatment or Death (TFST)

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Clinical trials

Clinical Trial Results: An Open-label, Randomized, Phase I/II Trial Investigating the Safety and Efficacy of IO102 in Combination with Pembrolizumab, with or without Chemotherapy, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety Endpoint - Summary of adverse events (AEs)

Primary: Safety Endpoint - Summary of adverse events (AEs)

Primary: Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population

Primary: Efficacy endpoint: Best Overall Response (BOR) - Phase I/II, ITT Population

Primary: Efficacy endpoint: ORR - Phase II, ITT population

Primary: Efficacy endpoint: ORR - Phase II, ITT population

Primary: Efficacy endpoint: ORR - Phase I, ITT Population

Primary: Efficacy endpoint: ORR - Phase I, ITT Population

Secondary: Efficacy endpoint: DCR - Phase II, ITT population

Secondary: Efficacy endpoint: DCR - Phase II, ITT population

Secondary: Efficacy endpoint: DCR - Phase I, ITT population

Secondary: Efficacy endpoint: DCR - Phase I, ITT population

Secondary: Efficacy endpoint: Time to response (TTR)

Secondary: Efficacy endpoint: Time to response (TTR)

Secondary: Efficacy endpoint: DOR

Secondary: Efficacy endpoint: DOR

Secondary: Efficacy endpoint: PFS

Secondary: Efficacy endpoint: PFS

Secondary: Efficacy endpoint: OS

Secondary: Efficacy endpoint: OS

Secondary: Efficacy endpoint: Time to First Subsequent Treatment or Death (TFST)

Secondary: Efficacy endpoint: Time to First Subsequent Treatment or Death (TFST)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-label, Randomized, Phase I/II Trial Investigating the Safety and Efficacy of IO102 in Combination with Pembrolizumab, with or without Chemotherapy, as First-line Treatment for Patients with Metastatic Non-Small Cell Lung Cancer