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Clinical Trial Results:
AN OPEN-LABEL, DOSE-FINDING AND PROOF OF CONCEPT STUDY OF THE PD-L1 PROBODY® THERAPEUTIC, CX-072, AS MONOTHERAPY AND IN COMBINATION WITH YERVOY® (IPILIMUMAB) OR WITH ZELBORAF® (VEMURAFENIB) IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS

Summary
EudraCT number	2016-002490-36
Trial protocol	HU ES NL PL GB
Global end of trial date	27 Oct 2020

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 2025
Other versions

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

CTMX-M-072-001

ISRCTN number

US NCT number

NCT03013491

WHO universal trial number (UTN)

Sponsor organisation name

CytomX Therapeutics, Inc

Sponsor organisation address

151 Oyster Point Boulevard, Suite 400, South San Francisco, United States, 94080

Public contact

Head of Clinical Operations, CytomX Therapeutics, Inc, +1 650-515-3185, Clinicaltrials@cytomx.com

Scientific contact

Head of Clinical Operations, CytomX Therapeutics, Inc, +1 650-515-3185, Clinicaltrials@cytomx.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

14 Nov 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Oct 2020

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

Parts A through C: 1. To evaluate the safety and tolerability of multiple doses of CX-072 administered as monotherapy or in combination with ipilimumab or vemurafenib to patients with metastatic or locally advanced unresectable solid tumors or lymphomas; 2. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the following: • CX-072 as a monotherapy administered to programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) naive patients. • CX-072 in combination with ipilimumab administered to PD-1/PD-L1 and CTLA-4 inhibitor naïve patients. • CX-072 in combination with ipilimumab administered to patients who had prior treatment with a PD-1/PD-L1 inhibitor. • CX-072 in combination with vemurafenib administered to PD-1/PD-L1 naive patients Parts D and E: 1. To obtain preliminary and confirmatory evidence of the efficacy of CX-072 monotherapy, respectively, via the objective response rate (ORR) according to the Response Evaluation Criteria

Protection of trial subjects

All considerations regarding the protection of human subjects were carried out in accordance with the protocol, GCP, ICH Guidelines, the ethical principles that have their origin in the Declaration of Helsinki, and all applicable regulatory requirements. The investigator (according to applicable regulatory requirements) or a person designated by the investigator and under the investigator’s responsibility fully informed patients of all pertinent aspects of the clinical trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Jan 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Ethical reason, Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ukraine: 9

Country: Number of subjects enrolled

United States: 100

Country: Number of subjects enrolled

Netherlands: 22

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Spain: 28

Country: Number of subjects enrolled

United Kingdom: 36

Worldwide total number of subjects

196

EEA total number of subjects

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)

136

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a multicenter study with a total of 41 sites in 6 countries (Netherlands, Poland, Spain, Ukraine, UK, and the US). A total of 278 patients were screened for the study, and 196 patients received study treatment.

Screening details

All patients must have had histologically confirmed diagnosis of metastatic or locally advanced unresectable tumors that progressed or were intolerant to standard therapy. Patients who fulfilled the specific inclusion/exclusion criteria for one of the Parts (A, A2, B1, B2, C or D) at the screening visit were eligible for admission into the study.

Period 1 title

Parts A, A2, B1, B2, C and D

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A and Part A2 - CX-072 0.03 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 0.03 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg.

Part A and Part A2 - CX-072 0.1 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 0.1 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg

Part A and Part A2 - CX-072 0.3 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 0.3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg

Part A and Part A2 - CX-072 1 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 1 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg

Part A and Part A2 - CX-072 3 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg.

Part A and Part A2 - CX-072 10 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 10 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg

Part A and Part A2 - CX-072 30 mg/kg

Arm description

Part A and Part A2 - Monotherapy CX-072 30 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg.

Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg

Arm description

Part B1 - Combination CX-072 0.3 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Yervoy (Ipilimumab) is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Participants received escalating doses of CX-072 administered concomitantly with ipilimumab. Ipilimumab was administered intravenously (IV) at the following doses: 3, 6, and 10 mg/kg.

Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg

Arm description

Part B1 - Combination CX-072 1 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg

Arm description

Part B1 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg

Arm description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg

Arm description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 6 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg

Arm description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 10 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 0.3, 1, 3, and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg

Arm description

Part B2 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 3 and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg

Arm description

Part B2 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 3 and 10 mg/kg

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Yervoy

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Part C - CX-072 1 mg/kg + Vemurafenib 960 mg

Arm description

Part C - Combination CX-072 1 mg/kg + Vemurafenib 960 mg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 1, 3 and 10 mg/kg

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Vemurafenib is available as 240 mg tablets for oral use. Tablets are white to off-white and are supplied as 240 mg film-coated tablets with VEM debossed on 1 side. Vemurafenib is administered PO, twice daily (approximately every 12 hours [q12h]) at 960 mg.

Part C - CX-072 3 mg/kg + Vemurafenib 960 mg

Arm description

Part C - Combination CX-072 3 mg/kg + Vemurafenib 960 mg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 1, 3 and 10 mg/kg

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Part C - CX-072 10 mg/kg + Vemurafenib 960 mg

Arm description

Part C - Combination CX-072 10 mg/kg + Vemurafenib 960 mg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 was administered intravenously (IV) at the following doses: 1, 3, and 10 mg/kg

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Vemurafenib is available as 240 mg tablets for oral use. Tablets are white to off-white and are supplied as 240 mg film-coated tablets with VEM debossed on 1 side.

Part D - CX-072 10 mg/kg

Arm description

Part D - Monotherapy CX-072 10 mg/kg

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at 10 mg/kg

Number of subjects in period 1	Part A and Part A2 - CX-072 0.03 mg/kg	Part A and Part A2 - CX-072 0.1 mg/kg	Part A and Part A2 - CX-072 0.3 mg/kg	Part A and Part A2 - CX-072 1 mg/kg	Part A and Part A2 - CX-072 3 mg/kg	Part A and Part A2 - CX-072 10 mg/kg	Part A and Part A2 - CX-072 30 mg/kg	Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg	Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg	Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg	Part C - CX-072 1 mg/kg + Vemurafenib 960 mg	Part C - CX-072 3 mg/kg + Vemurafenib 960 mg	Part C - CX-072 10 mg/kg + Vemurafenib 960 mg	Part D - CX-072 10 mg/kg
Started	2	2	8	9	13	16	3	6	3	3	8	6	1	6	1	3	6	2	98
Completed	0	0	0	1	0	0	0	1	0	0	0	0	0	0	1	0	1	0	11
Not completed	2	2	8	8	13	16	3	5	3	3	8	6	1	6	0	3	5	2	87
Adverse event, serious fatal	2	2	5	3	9	12	3	5	1	2	4	1	1	4	-	3	5	1	47
Consent withdrawn by subject	-	-	-	4	2	1	-	-	-	-	1	2	-	2	-	-	-	-	18
Other	-	-	-	1	-	1	-	-	1	-	2	1	-	-	-	-	-	-	6
Termination of Study by Sponsor	-	-	2	-	1	2	-	-	1	1	1	2	-	-	-	-	-	1	13
Lost to follow-up	-	-	1	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	3

Period 2 title

Long-Term extension

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Long-Term extension

Arm description

Participants from Study CTMX-M-072-001 were eligible to enroll in the LTE if they were actively receiving CX-072 monotherapy and would continue to benefit from treatment with CX-072 monotherapy as determined by the Investigator. Patients continued the same dose of CX-072 that they last received in the previous cohort (Parts A-D) of the study that they were enrolled in. No dose increase or decrease of CX-072 was permitted in long-term extension.

Arm type

Experimental

Investigational medicinal product name

CX-072

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

CX-072 monotherapy was administered intravenously (IV) at the following doses: 0.03, 0.1, 0.3, 1, 3, 10, and 30 mg/kg

Number of subjects in period 2	Long-Term extension
Started	15
Completed	10
Not completed	5
Adverse event, serious fatal	1
Consent withdrawn by subject	1
Adverse event, non-fatal	1
Disease Progression	2

Baseline characteristics

Top of page

Reporting group title

Part A and Part A2 - CX-072 0.03 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.03 mg/kg

Reporting group title

Part A and Part A2 - CX-072 0.1 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.1 mg/kg

Reporting group title

Part A and Part A2 - CX-072 0.3 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.3 mg/kg

Reporting group title

Part A and Part A2 - CX-072 1 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 1 mg/kg

Reporting group title

Part A and Part A2 - CX-072 3 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 3 mg/kg

Reporting group title

Part A and Part A2 - CX-072 10 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 10 mg/kg

Reporting group title

Part A and Part A2 - CX-072 30 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 30 mg/kg

Reporting group title

Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 0.3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 1 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 6 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 10 mg/kg

Reporting group title

Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group description

Part B2 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group description

Part B2 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part C - CX-072 1 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 1 mg/kg + Vemurafenib 960 mg

Reporting group title

Part C - CX-072 3 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 3 mg/kg + Vemurafenib 960 mg

Reporting group title

Part C - CX-072 10 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 10 mg/kg + Vemurafenib 960 mg

Reporting group title

Part D - CX-072 10 mg/kg

Reporting group description

Part D - Monotherapy CX-072 10 mg/kg

Reporting group values	Part A and Part A2 - CX-072 0.03 mg/kg	Part A and Part A2 - CX-072 0.1 mg/kg	Part A and Part A2 - CX-072 0.3 mg/kg	Part A and Part A2 - CX-072 1 mg/kg	Part A and Part A2 - CX-072 3 mg/kg	Part A and Part A2 - CX-072 10 mg/kg	Part A and Part A2 - CX-072 30 mg/kg	Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg	Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg	Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg	Part C - CX-072 1 mg/kg + Vemurafenib 960 mg	Part C - CX-072 3 mg/kg + Vemurafenib 960 mg	Part C - CX-072 10 mg/kg + Vemurafenib 960 mg	Part D - CX-072 10 mg/kg	Total
Number of subjects	2	2	8	9	13	16	3	6	3	3	8	6	1	6	1	3	6	2	98	196
Age categorical
Units: Subjects
Adults (18-64 years)	0	0	4	6	6	13	3	3	3	3	8	6	0	5	1	2	5	2	66	136
From 65-84 years	2	2	4	3	7	3	0	3	0	0	0	0	1	1	0	1	1	0	32	60
Age continuous
Units: years
arithmetic mean (standard deviation)	69.5 ( 2.12 )	72.0 ( 2.83 )	60.8 ( 9.88 )	59.2 ( 9.43 )	63.3 ( 15.12 )	55.3 ( 13.11 )	58.0 ( 10.44 )	56.5 ( 16.94 )	38.0 ( 1.73 )	53.0 ( 8.72 )	53.9 ( 9.14 )	51.8 ( 10.19 )	67.0 ( 0.0 )	56.7 ( 8.38 )	40 ( 0.0 )	47.3 ( 17.24 )	46.3 ( 20.88 )	53.5 ( 9.19 )	59.9 ( 12.28 )	-
Gender categorical
Units: Subjects
Female	1	2	4	3	8	9	1	2	1	3	6	3	1	4	1	2	4	1	60	116
Male	1	0	4	6	5	7	2	4	2	0	2	3	0	2	0	1	2	1	38	80

End points

Top of page

Reporting group title

Part A and Part A2 - CX-072 0.03 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.03 mg/kg

Reporting group title

Part A and Part A2 - CX-072 0.1 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.1 mg/kg

Reporting group title

Part A and Part A2 - CX-072 0.3 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 0.3 mg/kg

Reporting group title

Part A and Part A2 - CX-072 1 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 1 mg/kg

Reporting group title

Part A and Part A2 - CX-072 3 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 3 mg/kg

Reporting group title

Part A and Part A2 - CX-072 10 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 10 mg/kg

Reporting group title

Part A and Part A2 - CX-072 30 mg/kg

Reporting group description

Part A and Part A2 - Monotherapy CX-072 30 mg/kg

Reporting group title

Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 0.3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 1 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 6 mg/kg

Reporting group title

Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg

Reporting group description

Part B1 - Combination CX-072 10 mg/kg + ipilimumab 10 mg/kg

Reporting group title

Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group description

Part B2 - Combination CX-072 3 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group description

Part B2 - Combination CX-072 10 mg/kg + ipilimumab 3 mg/kg

Reporting group title

Part C - CX-072 1 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 1 mg/kg + Vemurafenib 960 mg

Reporting group title

Part C - CX-072 3 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 3 mg/kg + Vemurafenib 960 mg

Reporting group title

Part C - CX-072 10 mg/kg + Vemurafenib 960 mg

Reporting group description

Part C - Combination CX-072 10 mg/kg + Vemurafenib 960 mg

Reporting group title

Part D - CX-072 10 mg/kg

Reporting group description

Part D - Monotherapy CX-072 10 mg/kg

Reporting group title

Long-Term extension

Reporting group description

Primary: The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib

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End point title

The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib ^[1] ^[2]

End point description

Adverse events (AEs) that were considered DLTs: • Grade 5 AEs • Grade 4 AEs judged by the Investigator to be treatment-related or judged by the Sponsor as a DLT, regardless of Investigator-attribution (with some exceptions) • Any Grade 4 endocrinopathy. • Grade 3 AEs judged by the Investigator to be treatment-related or by the Sponsor, regardless of Investigator attribution (with some exceptions) • Any Grade 3 central nervous system event, regardless of duration or reversibility. • Grade 2 pneumonitis necessitating CX-072 discontinuation • Grade 2 ocular toxicity necessitating CX-072 discontinuation The analysis was performed on the safety analysis population which including all enrolled subjects who received at least one dose of study drug. The baseline population and safety analysis populations are the same.

End point type

Primary

End point timeframe

28 days (dose limiting toxicity period)

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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested. A summary of the results has been added in the Endpoint description.
[2] - 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: This endpoint was assessed only in Parts A, B and C.

End point values	Part A and Part A2 - CX-072 0.03 mg/kg	Part A and Part A2 - CX-072 0.1 mg/kg	Part A and Part A2 - CX-072 0.3 mg/kg	Part A and Part A2 - CX-072 1 mg/kg	Part A and Part A2 - CX-072 3 mg/kg	Part A and Part A2 - CX-072 10 mg/kg	Part A and Part A2 - CX-072 30 mg/kg	Part B1 – CX-072 0.3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 1 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 3 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 3 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 6 mg/kg	Part B1 – CX-072 10 mg/kg + Ipilimumab 10 mg/kg	Part B2 – CX-072 3 mg/kg + ipilimumab 3 mg/kg	Part B2 – CX-072 10 mg/kg + ipilimumab 3 mg/kg	Part C - CX-072 1 mg/kg + Vemurafenib 960 mg	Part C - CX-072 3 mg/kg + Vemurafenib 960 mg	Part C - CX-072 10 mg/kg + Vemurafenib 960 mg
Number of subjects analysed	2	2	8	9	13	16	3	6	3	3	8	6	1	6	1	3	6	2
Units: patients	0	0	0	1	1	0	0	1	0	0	0	2	1	0	0	0	0	0

No statistical analyses for this end point

Secondary: The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy

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End point title

The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy ^[3]

End point description

The primary efficacy endpoint, ORR, was defined as the proportion of subjects with complete response (CR) or partial response (PR) on two consecutive tumor assessments according to RECIST v1.1. Per CX-072-001 Statistical Analysis Plan, efficacy analyses will be limited to subjects who received 10 mg/kg CX-072 monotherapy during the study. This efficacy subset includes subjects from Parts A, A2 and D. Efficacy summaries will have parts A and A2 combined.

End point type

Secondary

End point timeframe

2 years

Notes
[3] - 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: The analysis for this endpoint is presented for patients who received the dose of 10 mg/kg of CX-072 in Parts A, A2, and D.

End point values	Part A and Part A2 - CX-072 10 mg/kg	Part D - CX-072 10 mg/kg
Number of subjects analysed	16	98
Units: patients	1	13

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 2 years. Adverse event monitoring starts from the time the patient consents to the study until they complete the trial.

Adverse event reporting additional description

AEs are presented for the treatment-emergent adverse event (TEAE) population. On-study deaths reported as SAEs due to progressive disease and considered unrelated to study drug were excluded from TEAE analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Safety Population- Part A-A2

Reporting group description

CX-072 as Monotherapy.

Reporting group title

Safety Population- Part B1

Reporting group description

CX-072 in combination with Ipilimumab.

Reporting group title

Safety Population- Part B2

Reporting group description

CX-072 in combination with Ipilimumab.

Reporting group title

Safety Population- Part C

Reporting group description

CX-072 in combination with Vemurafenib

Reporting group title

Safety Population- Part D

Reporting group description

CX-072 10 mg/kg as monotherapy. Dose expansion in patients with specific cancer tumor types.

Serious adverse events	Safety Population- Part A-A2	Safety Population- Part B1	Safety Population- Part B2	Safety Population- Part C	Safety Population- Part D
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 53 (39.62%)	13 / 27 (48.15%)	3 / 7 (42.86%)	8 / 11 (72.73%)	33 / 98 (33.67%)
number of deaths (all causes)	38	15	4	9	50
number of deaths resulting from adverse events	0	0	0	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour obstruction
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Testicular pain
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Cough
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Haemoptysis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
immune-mediated pneumonitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Respiratory failure
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	2 / 53 (3.77%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Clavicle fracture
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Humerus fracture
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Cardiopulmonary failure
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Nervous system disorders
Guillain-Barre syndrome
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Seizure
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Spinal cord compression
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	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
Blood loss anaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node haemorrhage
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 53 (3.77%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocutaneous fistula
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 53 (0.00%)	6 / 27 (22.22%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 9	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemobilia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Renal failure
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypophysitis
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	2 / 53 (3.77%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	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
Abdominal wall abscess
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 98 (4.08%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	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
COVID-19
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Hypercalcaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Hyperkalaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	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
Hyponatraemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Safety Population- Part A-A2	Safety Population- Part B1	Safety Population- Part B2	Safety Population- Part C	Safety Population- Part D
Total subjects affected by non serious adverse events
subjects affected / exposed	53 / 53 (100.00%)	26 / 27 (96.30%)	7 / 7 (100.00%)	11 / 11 (100.00%)	94 / 98 (95.92%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	0	0	1	0	5
Infected neoplasm
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Skin papilloma
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 98 (0.00%)
occurrences all number	0	0	0	3	0
Metastases to meninges
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Papilloma
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Vascular disorders
Hypotension
subjects affected / exposed	3 / 53 (5.66%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	3	1	0	0	0
Embolism
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	2	0	0	0
Hypertension
subjects affected / exposed	2 / 53 (3.77%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	8 / 98 (8.16%)
occurrences all number	2	2	0	0	10
Lymphostasis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	16 / 53 (30.19%)	8 / 27 (29.63%)	2 / 7 (28.57%)	3 / 11 (27.27%)	33 / 98 (33.67%)
occurrences all number	21	14	6	7	45
Pyrexia
subjects affected / exposed	7 / 53 (13.21%)	3 / 27 (11.11%)	1 / 7 (14.29%)	1 / 11 (9.09%)	11 / 98 (11.22%)
occurrences all number	10	3	2	1	12
Asthenia
subjects affected / exposed	4 / 53 (7.55%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	4	3	0	0	3
Non-cardiac chest pain
subjects affected / exposed	4 / 53 (7.55%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	7	0	0	0	3
Oedema peripheral
subjects affected / exposed	5 / 53 (9.43%)	3 / 27 (11.11%)	1 / 7 (14.29%)	1 / 11 (9.09%)	9 / 98 (9.18%)
occurrences all number	9	5	1	1	11
Malaise
subjects affected / exposed	1 / 53 (1.89%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	1	2	0	0	1
Influenza like illness
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	7	0	1	0	6
Localised oedema
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	0	1	1	0	1
Oedema
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	1	0	1	0	5
Peripheral swelling
subjects affected / exposed	2 / 53 (3.77%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	2	0	1	0	2
Chest pain
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	1	0	1	0
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	0	0	1	0	1
Vaginal discharge
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	1	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	13 / 53 (24.53%)	4 / 27 (14.81%)	1 / 7 (14.29%)	1 / 11 (9.09%)	16 / 98 (16.33%)
occurrences all number	14	6	1	1	18
Dyspnoea
subjects affected / exposed	9 / 53 (16.98%)	4 / 27 (14.81%)	0 / 7 (0.00%)	0 / 11 (0.00%)	15 / 98 (15.31%)
occurrences all number	11	7	0	0	18
Epistaxis
subjects affected / exposed	3 / 53 (5.66%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	4	0	0	0	2
Productive cough
subjects affected / exposed	1 / 53 (1.89%)	4 / 27 (14.81%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	3	4	0	0	2
Oropharyngeal pain
subjects affected / exposed	1 / 53 (1.89%)	3 / 27 (11.11%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	1	3	1	0	1
Dysphonia
subjects affected / exposed	2 / 53 (3.77%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	2	3	0	0	3
Haemoptysis
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	0	2	0	0	1
Pleural effusion
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	0	2	0	0	2
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 53 (5.66%)	3 / 27 (11.11%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 98 (4.08%)
occurrences all number	3	3	0	0	5
Depression
subjects affected / exposed	1 / 53 (1.89%)	3 / 27 (11.11%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	1	4	0	0	2
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	6 / 53 (11.32%)	4 / 27 (14.81%)	1 / 7 (14.29%)	2 / 11 (18.18%)	9 / 98 (9.18%)
occurrences all number	7	4	1	2	11
Alanine aminotransferase increased
subjects affected / exposed	2 / 53 (3.77%)	5 / 27 (18.52%)	1 / 7 (14.29%)	1 / 11 (9.09%)	14 / 98 (14.29%)
occurrences all number	3	9	2	1	15
Aspartate aminotransferase increased
subjects affected / exposed	1 / 53 (1.89%)	6 / 27 (22.22%)	1 / 7 (14.29%)	2 / 11 (18.18%)	23 / 98 (23.47%)
occurrences all number	2	9	3	2	35
Amylase increased
subjects affected / exposed	1 / 53 (1.89%)	4 / 27 (14.81%)	0 / 7 (0.00%)	2 / 11 (18.18%)	6 / 98 (6.12%)
occurrences all number	3	8	0	2	9
Blood creatinine increased
subjects affected / exposed	0 / 53 (0.00%)	3 / 27 (11.11%)	0 / 7 (0.00%)	1 / 11 (9.09%)	10 / 98 (10.20%)
occurrences all number	0	3	0	1	20
Lipase increased
subjects affected / exposed	0 / 53 (0.00%)	3 / 27 (11.11%)	0 / 7 (0.00%)	4 / 11 (36.36%)	8 / 98 (8.16%)
occurrences all number	0	5	0	9	13
Gamma-glutamyltransferase increased
subjects affected / exposed	2 / 53 (3.77%)	2 / 27 (7.41%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	2	2	2	0	3
Blood bilirubin increased
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	1 / 7 (14.29%)	5 / 11 (45.45%)	1 / 98 (1.02%)
occurrences all number	0	1	5	10	1
Blood thyroid stimulating hormone decreased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Transaminases increased
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	2	1	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 98 (0.00%)
occurrences all number	1	0	0	2	0
Body temperature increased
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	1	0	1	0
Creatinine renal clearance decreased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Heart rate increased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Protein total decreased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Weight decreased
subjects affected / exposed	3 / 53 (5.66%)	1 / 27 (3.70%)	2 / 7 (28.57%)	2 / 11 (18.18%)	12 / 98 (12.24%)
occurrences all number	5	1	3	2	18
Blood albumin decreased
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	10 / 53 (18.87%)	4 / 27 (14.81%)	0 / 7 (0.00%)	4 / 11 (36.36%)	6 / 98 (6.12%)
occurrences all number	26	5	0	14	13
Ligament sprain
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Skin laceration
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	1	1	0	0
Poisoning
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Sunburn
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Cardiac disorders
Coronary artery disease
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	7 / 53 (13.21%)	6 / 27 (22.22%)	2 / 7 (28.57%)	0 / 11 (0.00%)	12 / 98 (12.24%)
occurrences all number	8	13	2	0	13
Dizziness
subjects affected / exposed	6 / 53 (11.32%)	2 / 27 (7.41%)	1 / 7 (14.29%)	0 / 11 (0.00%)	6 / 98 (6.12%)
occurrences all number	6	2	1	0	6
Neuropathy peripheral
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	3	2	0	0	4
Paraesthesia
subjects affected / exposed	2 / 53 (3.77%)	1 / 27 (3.70%)	1 / 7 (14.29%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	3	1	1	0	3
Autonomic nervous system imbalance
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Complex regional pain syndrome
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Facial paresis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Metabolic encephalopathy
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	1	0	0	1	0
Syncope
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	1	0	0	1	0
Taste disorder
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Vascular encephalopathy
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 53 (22.64%)	6 / 27 (22.22%)	2 / 7 (28.57%)	5 / 11 (45.45%)	24 / 98 (24.49%)
occurrences all number	15	6	2	9	40
Lymph node pain
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 98 (0.00%)
occurrences all number	0	0	0	3	0
Neutropenia
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	2 / 11 (18.18%)	2 / 98 (2.04%)
occurrences all number	0	1	0	6	5
Blood loss anaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	0	0	1	1
Eosinophilia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Leukopenia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	2 / 98 (2.04%)
occurrences all number	0	0	0	1	6
Lymph node haemorrhage
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	4	0
Lymphocytosis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Lymphopenia
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	2	0	1	1
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Deafness neurosensory
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	1	0	0	1	0
Keratitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	0	0	1	5
Gastrointestinal disorders
Nausea
subjects affected / exposed	14 / 53 (26.42%)	13 / 27 (48.15%)	4 / 7 (57.14%)	0 / 11 (0.00%)	22 / 98 (22.45%)
occurrences all number	19	21	4	0	28
Constipation
subjects affected / exposed	12 / 53 (22.64%)	5 / 27 (18.52%)	0 / 7 (0.00%)	0 / 11 (0.00%)	14 / 98 (14.29%)
occurrences all number	12	5	0	0	17
Diarrhoea
subjects affected / exposed	6 / 53 (11.32%)	7 / 27 (25.93%)	2 / 7 (28.57%)	2 / 11 (18.18%)	26 / 98 (26.53%)
occurrences all number	11	8	4	2	38
Vomiting
subjects affected / exposed	4 / 53 (7.55%)	7 / 27 (25.93%)	3 / 7 (42.86%)	2 / 11 (18.18%)	17 / 98 (17.35%)
occurrences all number	7	7	3	4	22
Abdominal pain
subjects affected / exposed	4 / 53 (7.55%)	6 / 27 (22.22%)	2 / 7 (28.57%)	1 / 11 (9.09%)	7 / 98 (7.14%)
occurrences all number	7	7	3	1	9
Dyspepsia
subjects affected / exposed	4 / 53 (7.55%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	4	1	0	0	2
Abdominal distension
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	1 / 7 (14.29%)	0 / 11 (0.00%)	4 / 98 (4.08%)
occurrences all number	4	2	1	0	4
Dysphagia
subjects affected / exposed	3 / 53 (5.66%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	3	0	0	0	2
Abdominal pain upper
subjects affected / exposed	1 / 53 (1.89%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	8 / 98 (8.16%)
occurrences all number	1	2	0	0	9
Colitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Dry mouth
subjects affected / exposed	2 / 53 (3.77%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 98 (4.08%)
occurrences all number	3	2	0	0	5
Abdominal tenderness
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Haemorrhoids
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	1	0	1	0	1
Abdominal pain lower
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Oral pain
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Stomatitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	5 / 98 (5.10%)
occurrences all number	2	0	0	1	5
Abdominal discomfort
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	0	0	0	0	2
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Hepatomegaly
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	0	0	1	1
Hyperbilirubinaemia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	0	0	1	1
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	6 / 53 (11.32%)	10 / 27 (37.04%)	1 / 7 (14.29%)	3 / 11 (27.27%)	7 / 98 (7.14%)
occurrences all number	13	22	1	3	7
Night sweats
subjects affected / exposed	3 / 53 (5.66%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	3 / 98 (3.06%)
occurrences all number	3	0	0	0	3
Rash
subjects affected / exposed	1 / 53 (1.89%)	5 / 27 (18.52%)	1 / 7 (14.29%)	7 / 11 (63.64%)	14 / 98 (14.29%)
occurrences all number	1	11	1	14	18
Rash maculo-papular
subjects affected / exposed	1 / 53 (1.89%)	4 / 27 (14.81%)	0 / 7 (0.00%)	1 / 11 (9.09%)	3 / 98 (3.06%)
occurrences all number	1	5	0	2	6
Dry skin
subjects affected / exposed	1 / 53 (1.89%)	3 / 27 (11.11%)	0 / 7 (0.00%)	3 / 11 (27.27%)	0 / 98 (0.00%)
occurrences all number	1	3	0	3	0
Erythema ab igne
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Photosensitivity reaction
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	3 / 11 (27.27%)	0 / 98 (0.00%)
occurrences all number	0	1	0	3	0
Alopecia
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	2 / 98 (2.04%)
occurrences all number	1	1	0	1	2
Drug eruption
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	1	0	0	1	0
Hyperkeratosis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	3 / 53 (5.66%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	3	2	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	0 / 7 (0.00%)	1 / 11 (9.09%)	4 / 98 (4.08%)
occurrences all number	3	3	0	1	4
Hyperthyroidism
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	2 / 98 (2.04%)
occurrences all number	0	2	0	0	2
Empty sella syndrome
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	10 / 53 (18.87%)	4 / 27 (14.81%)	1 / 7 (14.29%)	0 / 11 (0.00%)	11 / 98 (11.22%)
occurrences all number	10	4	2	0	13
Arthralgia
subjects affected / exposed	8 / 53 (15.09%)	3 / 27 (11.11%)	2 / 7 (28.57%)	3 / 11 (27.27%)	12 / 98 (12.24%)
occurrences all number	10	3	2	6	15
Pain in extremity
subjects affected / exposed	6 / 53 (11.32%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	4 / 98 (4.08%)
occurrences all number	8	4	0	0	9
Myalgia
subjects affected / exposed	5 / 53 (9.43%)	3 / 27 (11.11%)	1 / 7 (14.29%)	0 / 11 (0.00%)	8 / 98 (8.16%)
occurrences all number	6	4	1	0	12
Muscular weakness
subjects affected / exposed	3 / 53 (5.66%)	3 / 27 (11.11%)	0 / 7 (0.00%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	3	3	0	0	5
Musculoskeletal pain
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	8 / 98 (8.16%)
occurrences all number	3	2	0	0	9
Neck pain
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	3	2	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	2 / 53 (3.77%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	2	0	0	0	7
Muscle spasms
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	4	1	0	0	5
Infections and infestations
Urinary tract infection
subjects affected / exposed	3 / 53 (5.66%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	11 / 98 (11.22%)
occurrences all number	4	2	0	0	12
Upper respiratory tract infection
subjects affected / exposed	3 / 53 (5.66%)	4 / 27 (14.81%)	0 / 7 (0.00%)	0 / 11 (0.00%)	10 / 98 (10.20%)
occurrences all number	3	5	0	0	16
Nasopharyngitis
subjects affected / exposed	0 / 53 (0.00%)	2 / 27 (7.41%)	0 / 7 (0.00%)	1 / 11 (9.09%)	2 / 98 (2.04%)
occurrences all number	0	2	0	1	2
Pneumonia
subjects affected / exposed	1 / 53 (1.89%)	0 / 27 (0.00%)	2 / 7 (28.57%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	1	0	2	0	8
Candida infection
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	1 / 98 (1.02%)
occurrences all number	0	0	1	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	2 / 11 (18.18%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Conjunctivitis bacterial
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	2	0
Ear infection
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Genital candidiasis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Mastoiditis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Petrositis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Pyelonephritis acute
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	1 / 98 (1.02%)
occurrences all number	0	0	0	1	1
Vestibular neuronitis
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Lower respiratory tract infection
subjects affected / exposed	2 / 53 (3.77%)	0 / 27 (0.00%)	0 / 7 (0.00%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	4	0	0	0	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	15 / 53 (28.30%)	8 / 27 (29.63%)	1 / 7 (14.29%)	4 / 11 (36.36%)	23 / 98 (23.47%)
occurrences all number	19	8	3	5	25
Hyponatraemia
subjects affected / exposed	6 / 53 (11.32%)	2 / 27 (7.41%)	0 / 7 (0.00%)	0 / 11 (0.00%)	7 / 98 (7.14%)
occurrences all number	8	2	0	0	9
Dehydration
subjects affected / exposed	4 / 53 (7.55%)	3 / 27 (11.11%)	1 / 7 (14.29%)	0 / 11 (0.00%)	6 / 98 (6.12%)
occurrences all number	4	4	1	0	7
Hypoalbuminaemia
subjects affected / exposed	5 / 53 (9.43%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	7 / 98 (7.14%)
occurrences all number	5	1	0	1	7
Hypokalaemia
subjects affected / exposed	5 / 53 (9.43%)	3 / 27 (11.11%)	0 / 7 (0.00%)	1 / 11 (9.09%)	3 / 98 (3.06%)
occurrences all number	8	6	0	1	4
Hypercalcaemia
subjects affected / exposed	3 / 53 (5.66%)	1 / 27 (3.70%)	0 / 7 (0.00%)	0 / 11 (0.00%)	5 / 98 (5.10%)
occurrences all number	3	2	0	0	5
Hypomagnesaemia
subjects affected / exposed	2 / 53 (3.77%)	4 / 27 (14.81%)	0 / 7 (0.00%)	0 / 11 (0.00%)	6 / 98 (6.12%)
occurrences all number	4	6	0	0	8
Cachexia
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	0	0	1	0	0
Hypophosphataemia
subjects affected / exposed	2 / 53 (3.77%)	0 / 27 (0.00%)	1 / 7 (14.29%)	0 / 11 (0.00%)	0 / 98 (0.00%)
occurrences all number	3	0	2	0	0
Hyperglycaemia
subjects affected / exposed	0 / 53 (0.00%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	6 / 98 (6.12%)
occurrences all number	0	3	0	1	10
Hyperkalaemia
subjects affected / exposed	1 / 53 (1.89%)	1 / 27 (3.70%)	0 / 7 (0.00%)	1 / 11 (9.09%)	2 / 98 (2.04%)
occurrences all number	1	1	0	1	2
Increased appetite
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0
Tumour lysis syndrome
subjects affected / exposed	0 / 53 (0.00%)	0 / 27 (0.00%)	0 / 7 (0.00%)	1 / 11 (9.09%)	0 / 98 (0.00%)
occurrences all number	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

30 Aug 2016

Module Amendment 1 (Global) (30 August 2016). For Part B1 of the trial, an additional dosing cohort was added, lowering the initial dose for CX-072 to 0.3 mg/kg. The 30 mg/kg CX-072 dosage was changed from an IV infusion duration of over 1 hour to ≥ 90 minutes. The Part B2 population for enrollment text was modified to remove patients with Hodgkin lymphoma with measurable disease. The Part C population for enrollment text was modified to include nonmeasurable BRAF V600E mutation–positive advanced melanoma. The Part D population for enrollment text was modified to clarify the diseases indicated must be measurable. Screening laboratory values were updated to clarify criteria for patients with HCC or pancreatic cancer for AST, ALT, and bilirubin, and to include criteria for amylase and lipase. An exclusion criterion was added for CAR T-cell containing regimens and AMD. Dose proportionality analysis was added. Reticulocyte counts were removed from the hematology assessment. Follow-up procedures for addressing events were added.

14 Nov 2016

Module Amendment 2 (Global) (14 November 2016) • The primary objective was modified to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of CX-072 as monotherapy and in combination in predefined patient populations. • The secondary objectives were expanded to obtain preliminary evidence of anticancer activity on the basis of objective responses in patients treated with CX-072 as monotherapy in advanced or metastatic gastric and gastroesophageal junction (GEJ) tumors. • The study design was modified. • The DLT definitions were updated such that any Grade 5 adverse event, Grade 4 endocrinopathy, and Grade 2 pneumonitis or ocular toxicity necessitating discontinuation of CX-072 were designated as DLTs; the provision to exempt any Grade 3 toxicities (including immune-related) that resolve within 7 days as a DLT was removed; and Grade 3 adverse events of nausea, diarrhea, asthenia, constipation, pyrexia, and vomiting that resolve within 48 hours with appropriate treatment were specified as not considered a DLT. • The DLT evaluation period was increased from 21 days to 28 days for Parts A, B1, B2, and C. • A section was added specifying late stopping rules to be applied when ≥ 2 patients experience Grade ≥ 4 CX‑072–related adverse events beyond the DLT evaluation period. • A Safety Review Committee was added to monitor adverse event data and to provide recommendations related to dose escalation for the subsequent cohort. • The sample size was reduced for the study from approximately 300 patients to ≤ 149 patients and include further justification for the planned sample size. • The inclusion and exclusion criteria were modified to reflect the patient eligibility requirements specified in the updated study design; to remove barrier method as a highly effective method of contraception; and to exclude patients with prior history of myocarditis and prohibit the use of cytochrome P450 1A2 (CYP1A2) substrates, rather than CYP1B1 substrates.

19 Jan 2017

Module Amendment 3 (Global) (19 January 2017) • Nonclinical safety data were updated. • Secondary objectives were updated. • The length of treatment cycles was added for Parts A, B1, B2, C, and D. • Part B2 treatment regimen was updated from 3 doses to 4 doses of CX-072. • Language was added to indicate that a maximum of 4 doses of ipilimumab may be administered in Part B2. • The laboratory values for white blood cells, aspartate aminotransferase for patients in Part C, and total bilirubin in inclusion criterion 8 were updated. • Contraception requirements were updated to include acceptable contraceptive methods. • Exclusion criteria 2 and 14 were updated. • Guidelines for the management of allergic reactions were updated. • Statistical analysis of pharmacokinetic (PK) assessments was updated. • Details of the immunogenicity assessments were updated. • Biopsy collection in Parts B1 and B2 was clarified. • Optional serial collection of blood samples for measurement of exploratory biomarker for patients in Parts A, B1, and D was included. • The definition of adverse event was clarified. • Monitoring of adverse event data was updated to include the completion of an electronic serious adverse event (SAE) form for SAEs and added that the type of follow-up visit will be left to the discretion of the Investigator. • SAE reporting requirements were updated to include SAEs up to and including 30 days after administration of last dose of study drug and to include additional reporting instructions. • Reporting criteria of suspected and unexpected suspected adverse events were updated to include instructions for reporting to the Food and Drug Administration and applicable competent authorities in the European Union Member States concerned, and the Central Institutional Review Board/Ethics Committee.

13 Jul 2017

Module Amendment 4 (Global) (13 July 2017) • A cohort (Part A2) was added to the study to refine the selection of the MTD/maximum achieved dose. • The use of prior immunotherapies was clarified. • An additional exploratory objective was added to examine the relationship between dose/exposure and pharmacodynamics, safety, and efficacy for CX-072 monotherapy. • The late stopping rules were updated. • The patient’s tumor type in Part D was modified to undifferentiated pleomorphic sarcoma. • The sample size and statistical analyses was updated. • The inclusion/exclusion criteria were updated. • The packaging requirements and administration timing for vemurafenib was updated. • The management of allergic reactions was clarified. • A prior/concomitant medication exception was added allowing patients with prostate cancer to receive androgen deprivation therapy.

18 Apr 2018

Module Amendment 5 (Global) (18 April 2018). • The secondary and exploratory objectives were updated. • The 30 mg/kg dose of CX-072 was removed from Parts B1 and B2. • A 6 mg/kg dose of ipilimumab was added. • Language was added to indicated that a monotherapy dose expansion imaging substudy was to be performed in the Netherlands. • Tumor types in Part D were modified to include small bowel adenocarcinoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, thymic carcinoma, anal squamous cell carcinoma, triple-negative breast cancer, and high tumor mutational burden. • The language to allow for cohort over enrollment so enough evaluable patients for DLT evaluation was removed. • The sample size and statistical analyses were updated to reflect changes to CX-072 dose, ipilimumab dose, and Part D tumor type additions. • The inclusion and exclusion criteria were updated. • The use of concomitant medications for patients with triple-negative breast cancer was specified. • A blood sample for tumor mutation burden (Part D) and blood sample for thymoma safety monitoring (Parts A and A2) was added. • The exact dose for each infusion was specified to be calculated based on the patient’s body weight from the specific dosing visit. • A 3-hour postdose (vemurafenib) PK sample on Cycle 1 Day 1 was added for Part C. • Adverse event language was clarified. • Appendix 2 was added to include information on thymic carcinoma classification and staging.

02 Nov 2018

Module Amendment 6 (Global) (02 November 2018) • The introduction and study rationale for dose escalation and dose expansion was updated. • Part E (Response Evaluation of CX-072 Monotherapy with Fixed Dosing) was added because encouraging safety and antitumor activity was observed in patients treated with at least 1 dose of CX-072 monotherapy at ≥ 3 mg/kg. These data warranted planning for confirming antitumor activity that might be observed in Part D by implementing an appropriately designed Part E with clear criteria for advancement from Part D to Part E, based on objective response rates. • The language of the primary, secondary, and exploratory objectives was updated for Parts A to D and defined for Part E. • The 10 mg/kg ipilimumab dose was removed from Parts B1 and B2 due to the increased toxicity according to published ipilimumab safety data. • Intra-patient dose escalation was added for patients in Cohorts 3A2, 4A2, and 5A2. • Language was added to discourage further enrollment of patients in Part B2 receiving CX-072 run-in phased dosing of CX-072 in combination with ipilimumab. Future patients enrolling in Part B2 were to receive CX072 administered in a concomitant combination schedule with ipilimumab. • Language was updated to clarify that TET encompasses thymic epithelial tumors, which includes thymoma and thymic carcinoma. • Assessment of dose-limiting toxicities was clarified for vemurafenib. • The sample size determination and statistical analyses was updated to reflect the addition of Part E and define the criteria for cohort expansion in Part D and assumptions and criteria for Simon’s 2-stage design in Part E. • The inclusion criteria were updated to clarify Part D criteria and define Part E criteria to limit prior lines of therapy to target patient populations that are more likely to benefit from participation in the trial. • Inclusion criterion 8 was updated to define acceptable contraception methods and introduce Appendix 5.

20 Feb 2020

Module Amendment 7 (Global) (03 April 2020) Not Submitted

04 Jun 2020

Module Amendment 8 (Global) (04 June 2020) Updates were made to reflect the addition of a long-term extension to the study.

19 Aug 2020

Module Amendment 9 (Global) (19 August 2020) Updates were made to reflect the commitments made to the UK MHRA for changes to the long-term extension study safety assessment and to clarify the purpose of the long-term extension study.

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

http://www.ncbi.nlm.nih.gov/pubmed/34253583
http://www.ncbi.nlm.nih.gov/pubmed/34301809
http://www.ncbi.nlm.nih.gov/pubmed/34301808
http://www.ncbi.nlm.nih.gov/pubmed/32681519

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Clinical trials

Clinical Trial Results:
AN OPEN-LABEL, DOSE-FINDING AND PROOF OF CONCEPT STUDY OF THE PD-L1 PROBODY® THERAPEUTIC, CX-072, AS MONOTHERAPY AND IN COMBINATION WITH YERVOY® (IPILIMUMAB) OR WITH ZELBORAF® (VEMURAFENIB) IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS

Trial information

Trial information

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib

Primary: The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib

Secondary: The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy

Secondary: The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy

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Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: AN OPEN-LABEL, DOSE-FINDING AND PROOF OF CONCEPT STUDY OF THE PD-L1 PROBODY® THERAPEUTIC, CX-072, AS MONOTHERAPY AND IN COMBINATION WITH YERVOY® (IPILIMUMAB) OR WITH ZELBORAF® (VEMURAFENIB) IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib

Primary: The Number of Subjects Experiencing a Dose Limiting Toxicity (DLT) at Various Dose Levels When Given Multiple Doses of CX-072 as a Monotherapy or in Combination With Ipilimumab or Vemurafenib

Secondary: The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy

Secondary: The Percentage of Subjects Experiencing Anti-cancer Activity (ORR) When Given 10 mg/kg CX-072 as Monotherapy

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
AN OPEN-LABEL, DOSE-FINDING AND PROOF OF CONCEPT STUDY OF THE PD-L1 PROBODY® THERAPEUTIC, CX-072, AS MONOTHERAPY AND IN COMBINATION WITH YERVOY® (IPILIMUMAB) OR WITH ZELBORAF® (VEMURAFENIB) IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS OR LYMPHOMAS