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Clinical Trial Results:
A Phase 1/2 Study of ALKS 4230 Administered Intravenously as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors –ARTISTRY-1

Summary
EudraCT number	2019-001998-90
Trial protocol	HU ES
Global end of trial date	02 Aug 2023

Results information
Results version number	v1(current)
This version publication date	09 Apr 2025
First version publication date	09 Apr 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

ALK4230-A101

ISRCTN number

US NCT number

NCT02799095

WHO universal trial number (UTN)

Other trial identifiers

IND: 128,159

Sponsor organisation name

Mural Oncology, Inc.

Sponsor organisation address

852 Winter Street, Waltham, United States, MA 02451

Public contact

Study Director, Mural Oncology, Inc., +1 (781) 614-0100, clinicaltrials@muraloncology.com

Scientific contact

Study Director, Mural Oncology, Inc., +1 (781) 614-0100, clinicaltrials@muraloncology.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

02 Aug 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Aug 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objectives were to: • Investigate the safety and tolerability of nemvaleukin alfa and to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of nemvaleukin alfa in subjects with advanced solid tumors who were refractory or intolerant to therapies known to provide clinical benefit (Part A) • Assess the safety profile and characterize antitumor activity by overall response rate (ORR) of nemvaleukin alfa at the RP2D in subjects with melanoma or renal cell carcinoma (RCC) (Part B) • Characterize the safety profile and antitumor activity by ORR of nemvaleukin alfa administered intravenously (IV) in combination with pembrolizumab in subjects with advanced solid tumors (Part C) • Describe the dose-limiting toxicity (DLT) of nemvaleukin alfa (Part A)

Protection of trial subjects

This study was conducted in accordance with the ethical principles of Good Clinical Practice (GCP), according to the International Council on Harmonisation (ICH) Harmonised Tripartite Guideline, and in accordance with 21 CFR 312.120.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 50

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

United States: 159

Country: Number of subjects enrolled

Australia: 6

Worldwide total number of subjects

286

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)

154

From 65 to 84 years

131

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 47 investigative sites in the United States, Spain, Canada, South Korea, Australia, Belgium, and Poland. A total of 243 subjects were enrolled in this 3-part study (Parts A, B and C) to receive nemvaleukin alfa (ALKS 4230) either as monotherapy or in combination with pembrolizumab.

Screening details

Selected subjects (43) enrolled in Monotherapy Parts A and B, and who did not demonstrate clinical benefit were eligible to rollover to Combination Therapy Part C and were rolled over in Part C, Cohort 4.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 0.1 microgram per kilogram (mcg/kg) intravenous (IV) infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 0.3 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 1 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 8 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Arm description

Subjects with advanced solid tumors received nemvaleukin alfa 10 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Arm description

Subjects with melanoma received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Arm description

Subjects with renal cell carcinoma (RCC) received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Arm description

Subjects with any tumor type received nemvaleukin alfa 1 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Arm description

Subjects with programmed death receptor-1/programmed death ligand-1 (PD-1/L1) unapproved tumor types (PD-1/L1 treatment naive) received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation. The Safety Run-in for nemvaleukin alfa 3 mcg/kg was combined with Cohort 1 of Part C due to same dosing level and regimen.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Arm description

Subjects with PD-1/L1 approved tumor types (PD-1/L1 treatment pretreated) received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Arm description

Subjects with PD-1/L1 approved tumor types (PD-1/L1 treatment naive) received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Arm description

Subjects rolled over from Parts A or B received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Arm description

Subjects with melanoma received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Arm description

Subjects with non-small-cell lung cancer (NSCLC) received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Arm description

Subjects with squamous cell carcinoma of the head and neck (SCCHN) received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Arm type

Experimental

Investigational medicinal product name

Nemvaleukin Alfa

Investigational medicinal product code

Other name

ALKS 4230

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nemvaleukin alfa administration via IV infusion.

Investigational medicinal product name

Pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Pembrolizumab administration via IV infusion.

Number of subjects in period 1	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Started	5	4	7	8	12	3	7	47	27	3	42	26	26	43	3	21	2
Completed	0	0	0	0	0	0	0	3	1	0	1	0	4	8	2	1	0
Not completed	5	4	7	8	12	3	7	44	26	3	41	26	22	35	1	20	2
Consent withdrawn by subject	-	-	-	-	-	1	1	10	7	-	13	15	13	21	-	12	1
Physician decision	-	-	-	-	-	-	-	-	-	-	1	-	-	-	-	-	-
Adverse Event	1	-	1	4	1	-	-	-	-	-	3	1	-	1	-	-	-
Death	-	-	-	-	-	-	3	7	7	-	7	5	6	8	1	8	1
Lost to Follow-up	-	-	-	-	-	-	1	-	-	-	1	1	1	3	-	-	-
Other	-	-	-	-	-	-	-	-	-	-	-	2	2	-	-	-	-
Progressive Disease	3	3	3	2	2	-	-	1	-	2	13	2	-	1	-	-	-
Rollover from Part A or B to Part C, Cohort 4	-	-	-	-	1	2	2	26	12	-	-	-	-	-	-	-	-
Withdrawal by Subject	-	-	-	1	3	-	-	-	-	-	-	-	-	-	-	-	-
Lost to follow-up	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Clinical Progression	1	-	2	1	5	-	-	-	-	1	3	-	-	1	-	-	-
Protocol deviation	-	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Reporting group description

Reporting group title

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Total
Number of subjects	5	4	7	8	12	3	7	47	27	3	42	26	26	43	3	21	2	286
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	5	3	5	4	4	3	4	20	10	0	30	20	15	18	1	7	1	150
From 65-84 years	0	1	2	4	8	0	3	27	17	3	12	6	11	25	2	14	1	136
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	1	1	0	4	7	2	4	22	3	1	28	12	13	18	1	7	1	125
Male	4	3	7	4	5	1	3	25	24	2	14	14	13	25	2	14	1	161
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	0	0	0	0	0	1	0	1	0	1	1	2	1	0	1	0	9
Not Hispanic or Latino	4	4	7	8	12	3	6	47	26	3	40	25	24	42	3	20	2	276
Unknown or Not Reported	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0	5	1	0	0	1	0	1	0	1	0	9
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	1	0	2	1	0	0	1	0	7	3	3	1	0	1	0	20
White	5	4	6	8	10	2	6	42	25	3	34	20	22	40	3	18	2	250
More than one race	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	1	0	0	0	1	2	1	1	0	1	0	7

End points

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Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Reporting group description

Reporting group title

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Reporting group description

Reporting group title

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Subject analysis set title

Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with PD-1/L1 unapproved tumor types (PD-1/L1 treatment naive) received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subject could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Subject analysis set title

Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with PD-1/L1 unapproved tumor types (PD-1/L1 treatment naive) received nemvaleukin alfa 3 mcg/kg infusion IV administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Primary: Part A: Number of Subjects With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE)

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End point title

Part A: Number of Subjects With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE) ^[1] ^[2]

End point description

DLT defined by any of following events possibly, probably, or definitely related to ALKS 4230: Grade 4 neutrophil count decreased (neutropenia); Febrile neutropenia; CTCAE Grade 4 thrombocytopenia; Thrombocytopenia; Any Grade 3 cardiac or central nervous system toxicity; Liver transaminase elevation higher than 8*upper limit of normal (ULN) or total bilirubin higher than 6*ULN; Grade 4 hypoalbuminemia; Fever more than (>) 40 degree Celsius (°C) sustained for >24 hours; Hypotension required the use of pressors or prolonged hospitalization (>48 hours) for hypotension requiring medical intervention; Grade 3 or higher electrolyte abnormalities; Increase in amylase or lipase; Grade 3 or higher nausea, vomiting, or diarrhea; Any other Grade 4 nonhematologic toxicity or any other Grade 3 non-hematologic toxicity; Any other toxicity or adverse event (AE) not defined above that resulted in subject removal from the study or discontinuation of dosing by the Investigator. Safety population.

End point type

Primary

End point timeframe

Cycle 1 Day 1 through Cycle 2 Day 15 (Cycle 1 length = 14 days; Cycle 2 length= 21 days)

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: Only descriptive data was planned.
[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: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg
Number of subjects analysed	5	4	7	8	12	3	7
Units: Subjects	0	0	0	2	3	0	1

No statistical analyses for this end point

Primary: Parts A, B, and C: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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End point title

Parts A, B, and C: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) ^[3]

End point description

TEAEs were defined as AEs that were newly occurring or worsening from the time of the first dose of study drug. An AE was any untoward medical occurrence in a subjects or clinical investigation subject administered a pharmaceutical product. Safety population included all subjects who received at least 1 dose of nemvaleukin alfa or pembrolizumab.

End point type

Primary

End point timeframe

From first dose of study drug until 30 days after last dose (up to 10 months for Part A; up to 41.3 months for Part B; up to 51.5 months for Part C)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	7	8	12	3	7	47	27	3	42	26	26	43	3	21	2
Units: Subjects	5	4	7	8	12	3	7	46	27	3	42	26	26	39	3	21	2

No statistical analyses for this end point

Primary: Parts A, B, and C: Number of Subjects With TEAEs by Severity Grading

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End point title

Parts A, B, and C: Number of Subjects With TEAEs by Severity Grading ^[4]

End point description

TEAEs were defined as AEs that were newly occurring or worsening from the time of the first dose of study drug. Severity was graded according to the National Cancer Institute (NCI) CTCAE (version 4.03) where, Grade 1: Mild- asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate- minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. As planned, Grades 1 and 2 were combined for reporting. Safety population included all subjects who received at least 1 dose of nemvaleukin alfa or pembrolizumab.

End point type

Primary

End point timeframe

From first dose of study drug until 30 days after last dose (up to 10 months for Part A; up to 41.3 months for Part B; up to 51.5 months for Part C)

Notes
[4] - 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: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	7	8	12	3	7	47	27	3	42	26	26	43	3	21	2
Units: Subjects
Grade 1 and 2 TEAEs	2	3	4	2	3	1	1	6	5	3	16	7	6	13	1	4	0
Grade 3 TEAEs	3	1	3	6	8	2	3	28	16	0	19	14	15	21	1	16	1
Grade 4 TEAEs	0	0	0	0	0	0	2	12	5	0	4	5	5	4	1	1	1
Grade 5 TEAEs	0	0	0	0	1	0	1	0	1	0	3	0	0	1	0	0	0

No statistical analyses for this end point

Primary: Parts B and C: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

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End point title

Parts B and C: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 ^[5] ^[6]

End point description

ORR rate was defined as the percentage of subjects with objective evidence of CR or PR based on RECIST v1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). Partial Response (PR): At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The antitumor evaluable population consisted of subjects who complete 2 cycles of therapy and had at least one follow-up scan.

End point type

Primary

End point timeframe

From first dose of study drug up to 40.3 months for Part B and up to 50.5 months for Part C

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	46	22	3	36	22	21	39	3	18	2
Units: Percentage of subjects
number (confidence interval 95%)	8.7 (2.4 to 20.8)	13.6 (2.9 to 34.9)	0.0 (0.0 to 70.8)	13.9 (4.7 to 29.5)	0.0 (0.0 to 15.4)	28.6 (11.3 to 52.2)	7.7 (1.6 to 20.9)	66.7 (9.4 to 99.2)	11.1 (1.4 to 34.7)	50.0 (1.3 to 98.7)

No statistical analyses for this end point

Secondary: Parts A and B: Serum Concentrations of Nemvaleukin Alfa

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End point title

Parts A and B: Serum Concentrations of Nemvaleukin Alfa ^[7]

End point description

Cycle 1 length = 14 days for Part A and 21 days for Part B; Cycle 2 length= 21 days for Parts A and B. The PK population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least 1 measurable serum concentration of nemvaleukin alfa at any scheduled PK time point. Here, "number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at specified timepoints. Here, "99999" means data could not be calculated due to less subject.

End point type

Secondary

End point timeframe

Cycle (C) 1 and 2 Day (D) 1: 0, 0.5, 1, 2, 4, 8, 16, and 24 hours (h) post-dose; Cycle 1 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, and 72 hours post-dose; Cycle 2 Day 5: 0, 0.5, 1, 2, 4, 8, 16, 24, 72, and 240 hours post-dose

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg
Number of subjects analysed	5	4	7	8	12	3	7	45	27
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
C1D1:0 h (n=5,4,7,8,11,3,7,45,27)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.0137 ( 0.0917 )	0.0329 ( 0.171 )
C1D1: 0.5 h (n=5,3,5,6,9,3,5,41,26)	2.24 ( 1.06 )	6.13 ( 0.653 )	20.1 ( 5.32 )	77.9 ( 15.5 )	109 ( 29.6 )	157 ( 56.8 )	148 ( 18.2 )	102 ( 36.1 )	131 ( 51.3 )
C1D1: 1 h (n=3,4,7,8,12,3,5,43,26)	1.61 ( 0.265 )	5.67 ( 1.61 )	16.6 ( 3.84 )	58.8 ( 25.3 )	112 ( 24.5 )	132 ( 33.0 )	135 ( 33.9 )	101 ( 32.3 )	117 ( 19.9 )
C1D1: 2 h (n=3,4,7,8,12,3,5,45,27)	0.965 ( 0.0894 )	3.83 ( 1.01 )	12.3 ( 2.80 )	44.0 ( 18.5 )	83.0 ( 19.6 )	98.9 ( 21.8 )	100 ( 27.1 )	77.4 ( 21.5 )	97.6 ( 21.7 )
C1D1: 4 h (n=5,3,7,8,12,3,6,45,27)	0.142 ( 0.318 )	1.87 ( 0.710 )	6.97 ( 2.25 )	25.2 ( 11.7 )	51.4 ( 15.9 )	57.4 ( 11.9 )	62.1 ( 26.5 )	50.1 ( 16.2 )	66.4 ( 15.9 )
C1D1: 8 h (n=5,4,6,8,11,3,6,43,26)	0.00 ( 0.00 )	0.453 ( 0.314 )	2.55 ( 1.27 )	10.0 ( 4.85 )	21.6 ( 7.61 )	24.9 ( 9.77 )	31.2 ( 16.9 )	31.8 ( 28.9 )	32.5 ( 7.83 )
C1D1: 16 h (n=5,4,5,4,4,0,6,0,0)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.522 ( 0.641 )	1.50 ( 1.20 )	7.27 ( 4.49 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C1D1: 24 h (n=5,4,7,8,11,2,7,44,26)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.106 ( 0.280 )	1.19 ( 0.633 )	2.95 ( 1.61 )	3.21 ( 0.253 )	5.18 ( 4.20 )	3.64 ( 1.90 )	3.53 ( 1.25 )
C1D5: 0 h (n=5,4,7,7,10,3,4,37,20)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.104 ( 0.276 )	0.619 ( 0.462 )	2.36 ( 2.29 )	1.59 ( 0.692 )	1.67 ( 0.531 )	1.51 ( 0.654 )	1.96 ( 0.987 )
C1D5: 0.5 h (n=4,3,6,5,8,3,4,32,16)	2.00 ( 0.238 )	6.00 ( 1.45 )	20.1 ( 8.08 )	71.3 ( 14.0 )	111 ( 26.0 )	112 ( 14.6 )	104 ( 13.0 )	85.1 ( 28.1 )	101 ( 29.2 )
C1D5: 1 h (n=3,3,7,6,8,3,3,35,15)	1.55 ( 0.245 )	5.28 ( 1.07 )	13.8 ( 7.79 )	48.9 ( 26.6 )	87.6 ( 14.7 )	98.4 ( 10.5 )	70.3 ( 9.27 )	78.0 ( 29.5 )	83.8 ( 14.8 )
C1D5: 2 h (n=3,3,7,7,9,3,4,33,14)	0.909 ( 0.164 )	3.53 ( 1.10 )	9.26 ( 5.76 )	30.1 ( 18.1 )	65.2 ( 22.1 )	66.4 ( 6.97 )	66.2 ( 15.1 )	57.8 ( 20.2 )	61.0 ( 14.3 )
C1D5: 4 h (n=5,3,7,7,9,2,4,36,14)	0.00 ( 0.00 )	1.17 ( 0.450 )	4.17 ( 3.72 )	12.9 ( 7.19 )	32.0 ( 14.0 )	29.1 ( 7.92 )	28.0 ( 14.0 )	39.4 ( 43.2 )	30.3 ( 6.20 )
C1D5: 8 h (n=5,4,7,7,8,2,4,28,14)	0.00 ( 0.00 )	0.00 ( 0.00 )	1.16 ( 1.31 )	3.25 ( 1.84 )	6.67 ( 2.74 )	6.68 ( 1.85 )	5.06 ( 1.68 )	6.78 ( 3.25 )	6.33 ( 2.04 )
C1D5: 16 h (n=5,4,4,3,3,0,0,0,0)	0.00 ( 0.00 )	0.158 ( 0.316 )	0.244 ( 0.488 )	0.625 ( 0.586 )	1.65 ( 0.707 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C1D5: 24 h (n=5,4,4,3,3,0,0,0,0)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.147 ( 0.294 )	0.221 ( 0.382 )	1.38 ( 0.631 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C1D5: 72 h (n=5,4,4,6,8,3,7,8,7)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.498 ( 0.596 )	0.824 ( 0.333 )	0.664 ( 0.597 )	0.623 ( 0.973 )	0.538 ( 0.383 )
C2D1: 0 h (n=4,4,6,7,9,3,4,42,23)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	8.24 ( 24.7 )	0.00 ( 0.00 )	0.00 ( 0.00 )	2.11 ( 13.7 )	0.120 ( 0.410 )
C2D1: 0.5 h (n=4,1,6,5,4,3,3,36,22)	1.80 ( 0.590 )	5.42 ( 99999 )	20.7 ( 6.83 )	72.2 ( 13.0 )	105 ( 23.9 )	113 ( 15.1 )	121 ( 40.4 )	174 ( 372 )	123 ( 31.7 )
C2D1: 1 h (n=2,4,6,5,6,3,3,39,21)	1.36 ( 0.646 )	4.84 ( 0.806 )	17.3 ( 5.46 )	58.3 ( 11.8 )	94.6 ( 14.3 )	105 ( 27.7 )	102 ( 33.2 )	93.3 ( 34.9 )	106 ( 30.3 )
C2D1: 2 h (n=3,4,6,6,7,3,3,2,22)	0.889 ( 0.174 )	3.43 ( 0.797 )	12.6 ( 4.40 )	44.9 ( 14.5 )	74.5 ( 18.2 )	76.9 ( 23.3 )	85.9 ( 26.8 )	76.7 ( 26.5 )	87.9 ( 23.5 )
C2D1: 4 h (n=4,4,6,6,7,3,3,39,22)	0.00 ( 0.00 )	1.31 ( 0.422 )	7.16 ( 3.53 )	27.8 ( 10.6 )	45.1 ( 14.0 )	50.5 ( 16.2 )	52.5 ( 15.8 )	46.8 ( 16.5 )	57.1 ( 14.9 )
C2D1: 8 h (n=4,4,5,6,7,3,3,40,21)	0.00 ( 0.00 )	0.00 ( 0.00 )	2.32 ( 1.45 )	9.29 ( 4.62 )	16.5 ( 7.44 )	18.7 ( 9.48 )	24.9 ( 13.1 )	26.8 ( 35.4 )	24.1 ( 8.09 )
C2D1: 16 h (n=4,4,3,3,2,0,0,0,0)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.405 ( 0.701 )	2.47 ( 2.14 )	4.24 ( 3.60 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D1: 24 h (n=4,4,6,6,7,3,3,40,22)	0.00 ( 0.00 )	0.205 ( 0.410 )	0.219 ( 0.342 )	0.940 ( 0.561 )	2.11 ( 1.45 )	1.81 ( 1.30 )	2.51 ( 1.19 )	2.03 ( 1.69 )	1.95 ( 0.854 )
C2D5: 0 h (n=3,4,6,5,10,2,3,40,21)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.0868 ( 0.213 )	0.914 ( 0.614 )	1.36 ( 0.589 )	2.24 ( 1.46 )	2.36 ( 1.11 )	1.58 ( 0.653 )	1.72 ( 0.599 )
C2D5: 0.5 h (n=2,3,4,2,6,2,3,34,19)	1.92 ( 0.296 )	6.06 ( 0.454 )	17.2 ( 3.44 )	69.1 ( 16.8 )	93.9 ( 22.2 )	98.8 ( 34.7 )	91.2 ( 40.2 )	153 ( 300 )	101 ( 18.6 )
C2D5: 1 h (n=2,4,6,3,7,2,3,33,19)	1.44 ( 0.260 )	4.82 ( 0.794 )	14.7 ( 3.80 )	44.9 ( 18.3 )	84.8 ( 23.7 )	90.5 ( 16.3 )	78.4 ( 39.9 )	94.8 ( 104 )	83.4 ( 19.4 )
C2D5: 2 h (n=2,4,6,4,7,2,3,34,19)	0.988 ( 0.0219 )	2.84 ( 0.751 )	9.09 ( 3.13 )	29.9 ( 12.3 )	58.4 ( 19.3 )	59.0 ( 6.87 )	49.9 ( 15.2 )	55.3 ( 20.9 )	62.0 ( 17.8 )
C2D5: 4 h (n=3,4,6,4,7,2,3,35,19)	0.00 ( 0.00 )	1.13 ( 0.471 )	4.18 ( 1.98 )	14.9 ( 6.75 )	27.1 ( 10.4 )	24.2 ( 2.26 )	24.3 ( 11.6 )	27.6 ( 8.71 )	29.1 ( 10.4 )
C2D5: 8 h (n=3,4,6,5,7,2,2,29,18)	0.00 ( 0.00 )	0.00 ( 0.00 )	1.27 ( 0.509 )	3.89 ( 1.58 )	6.93 ( 3.91 )	5.74 ( 0.0933 )	7.51 ( 3.23 )	7.94 ( 6.53 )	6.49 ( 2.96 )
C2D5: 16 h (n=3,4,3,3,3,0,0,0,0)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.218 ( 0.378 )	1.15 ( 0.687 )	1.64 ( 0.597 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D5: 24 h (n=3,4,3,3,3,0,0,0,0)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.631 ( 0.630 )	1.38 ( 0.697 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D5: 72 h (n=3,3,2,3,7,3,2,6,11)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.200 ( 0.347 )	0.488 ( 0.376 )	0.611 ( 0.625 )	1.57 ( 0.584 )	0.578 ( 0.475 )	0.396 ( 0.450 )
C2D5: 240 h (n=3,2,3,5,6,3,3,10,12)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )

No statistical analyses for this end point

Secondary: Parts C: Serum Concentrations of Nemvaleukin Alfa

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End point title

Parts C: Serum Concentrations of Nemvaleukin Alfa ^[8]

End point description

End point type

Secondary

End point timeframe

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	3	25	26	43	3	20	2	6	35
Units: ng/mL
arithmetic mean (standard deviation)
C1D1:0 h (n=3,25,26,43,3,19,2,6,35)	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.0151 ( 0.0988 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )
C1D1: 0.5h (n=3,23,25,33,2,15,2,6,29)	18.6 ( 3.94 )	71.5 ( 51.7 )	62.5 ( 20.2 )	48.9 ( 19.8 )	120 ( 6.24 )	131 ( 52.7 )	89.3 ( 2.71 )	67.1 ( 14.9 )	61.7 ( 13.4 )
C1D1: 1 h (n=2,23,24,36,3,20,1,6,33)	17.4 ( 5.33 )	61.6 ( 25.5 )	57.5 ( 17.9 )	49.9 ( 37.0 )	120 ( 22.0 )	121 ( 32.2 )	86.3 ( 99999 )	50.0 ( 22.3 )	56.3 ( 11.2 )
C1D1: 2 h (n=3,24,24,35,3,20,2,6,34)	14.0 ( 2.74 )	43.6 ( 11.5 )	42.6 ( 13.8 )	34.0 ( 18.8 )	94.9 ( 19.7 )	93.5 ( 30.7 )	70.7 ( 5.51 )	38.7 ( 17.4 )	42.5 ( 9.20 )
C1D1: 4 h (n=3,24,26,37,3,20,2,6,35)	8.74 ( 1.50 )	27.6 ( 7.91 )	26.4 ( 8.67 )	22.5 ( 13.6 )	63.8 ( 12.3 )	59.7 ( 15.5 )	48.9 ( 12.6 )	21.9 ( 7.94 )	25.6 ( 5.22 )
C1D1: 8 h (n=2,25,25,32,3,20,2,6,32)	4.49 ( 1.26 )	10.8 ( 4.41 )	10.8 ( 4.29 )	11.8 ( 11.9 )	27.7 ( 6.94 )	30.2 ( 8.92 )	18.7 ( 99999 )	9.63 ( 4.37 )	10.2 ( 2.88 )
C1D1: 16 h (n=0,0,1,0,0,0,0,1,0)	99999 ( 99999 )	99999 ( 99999 )	4.95 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.00 ( 99999 )	99999 ( 99999 )
C1D1: 24 h (n=2,25,25,37,3,20,2,5,31)	0.498 ( 0.704 )	1.64 ( 1.42 )	1.29 ( 0.749 )	2.94 ( 6.88 )	4.49 ( 2.06 )	13.8 ( 43.0 )	3.45 ( 1.59 )	1.46 ( 0.803 )	1.64 ( 1.44 )
C1D5: 0 h (n=3,20,22,37,3,17,2,6,33)	0.209 ( 0.361 )	2.16 ( 3.95 )	0.933 ( 0.529 )	3.90 ( 9.89 )	2.03 ( 0.979 )	2.67 ( 2.06 )	1.92 ( 0.336 )	0.416 ( 0.538 )	1.10 ( 0.965 )
C1D5: 0.5 h (n=3,17,20,31,2,16,2,5,30)	19.5 ( 3.90 )	63.6 ( 41.8 )	61.1 ( 30.1 )	51.8 ( 29.6 )	118 ( 2.15 )	111 ( 42.4 )	104 ( 1.86 )	49.5 ( 19.7 )	58.3 ( 25.3 )
C1D5: 1 h (n=2,19,21,31,2,16,2,5,31)	18.9 ( 2.50 )	47.3 ( 12.2 )	41.9 ( 11.7 )	45.0 ( 28.2 )	105 ( 14.3 )	102 ( 29.5 )	89.8 ( 99999 )	45.6 ( 22.3 )	47.2 ( 12.7 )
C1D5: 2 h (n= 2,19,22,32,2,16,2,5,31)	13.1 ( 0.626 )	31.8 ( 9.39 )	27.4 ( 9.80 )	39.6 ( 38.3 )	65.1 ( 0.651 )	71.1 ( 23.8 )	66.5 ( 4.01 )	31.8 ( 17.0 )	30.6 ( 9.57 )
C1D5: 4 h (n=3,19,22,32,2,16,2,5,33)	6.18 ( 0.687 )	17.2 ( 18.5 )	13.0 ( 7.01 )	17.7 ( 16.2 )	28.4 ( 1.42 )	32.4 ( 13.5 )	33.4 ( 7.99 )	13.1 ( 11.7 )	13.2 ( 5.51 )
C1D5: 8 h (n=3,17,19,26,2,17,2,5,32)	1.86 ( 0.257 )	4.85 ( 3.63 )	3.26 ( 1.32 )	7.80 ( 12.3 )	20.2 ( 18.7 )	8.60 ( 5.71 )	7.22 ( 0.698 )	3.39 ( 3.39 )	3.41 ( 1.66 )
C1D5: 16 h (n=0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C1D5: 24 h (n=0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C1D5: 72 h (n=0,4,26,5,0,2,1,0,0)	99999 ( 99999 )	0.210 ( 0.419 )	0.103 ( 0.273 )	0.00 ( 0.00 )	99999 ( 99999 )	0.610 ( 0.00778 )	0.989 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D1: 0 h (n=3,23,20,38,3,17,2,5,31)	0.00 ( 0.00 )	0.00 ( 0.00 )	2.10 ( 9.24 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.372 ( 1.36 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.0170 ( 0.0945 )
C2D1: 0.5 h (n=2,22,19,34,3,16,0,5,26)	15.8 ( 2.82 )	79.6 ( 93.1 )	55.7 ( 22.7 )	51.1 ( 28.0 )	113 ( 16.8 )	137 ( 47.3 )	99999 ( 99999 )	56.3 ( 9.99 )	57.8 ( 15.4 )
C2D1: 1 h (n=1,22,20,34,3,17,2,6,29)	13.7 ( 99999 )	54.2 ( 14.2 )	47.8 ( 13.0 )	43.0 ( 27.4 )	117 ( 17.2 )	114 ( 29.2 )	120 ( 5.86 )	48.2 ( 13.7 )	51.5 ( 10.0 )
C2D1: 2 h (n=2,23,20,34,3,17,2,6,30)	11.3 ( 1.39 )	38.3 ( 11.1 )	37.1 ( 10.5 )	35.6 ( 30.6 )	92.6 ( 16.1 )	84.4 ( 24.6 )	89.7 ( 5.33 )	35.6 ( 8.32 )	38.8 ( 9.33 )
C2D1: 4 h (n=2,23,20,34,3,17,2,6,30)	7.00 ( 0.412 )	24.0 ( 7.15 )	21.4 ( 8.75 )	24.1 ( 19.1 )	54.9 ( 6.38 )	54.7 ( 16.7 )	58.0 ( 8.50 )	19.5 ( 4.90 )	25.1 ( 12.7 )
C2D1: 8 h (n=1,20,16,32,3,17,2,5,30)	2.51 ( 99999 )	8.85 ( 3.92 )	7.40 ( 3.67 )	12.8 ( 18.3 )	24.3 ( 3.79 )	24.0 ( 11.5 )	26.4 ( 6.55 )	8.66 ( 4.83 )	7.91 ( 3.47 )
C2D1: 16 h (n=0,0,1,1,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	1.97 ( 99999 )	1.69 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D1: 24 h (n=2,20,19,35,3,15,2,6,28)	0.00 ( 0.00 )	1.16 ( 0.777 )	1.15 ( 1.40 )	4.96 ( 11.7 )	3.16 ( 1.58 )	2.98 ( 1.51 )	3.19 ( 1.10 )	0.737 ( 0.518 )	1.06 ( 0.802 )
C2D5: 0 h (n=3,22,18,37,2,16,2,6,27)	0.180 ( 0.312 )	0.922 ( 0.670 )	1.01 ( 1.71 )	4.17 ( 8.72 )	1.45 ( 0.417 )	2.17 ( 1.46 )	1.86 ( 0.354 )	0.756 ( 0.786 )	2.14 ( 6.54 )
C2D5: 0.5 h (n=2,20,19,33,2,15,1,5,23)	13.4 ( 3.07 )	58.8 ( 38.5 )	52.7 ( 14.4 )	56.7 ( 31.1 )	100 ( 20.0 )	100 ( 28.8 )	103 ( 99999 )	44.3 ( 9.53 )	64.2 ( 60.1 )
C2D5: 1 h (n=2,20,19,31,2,14,2,6,22)	16.8 ( 5.53 )	42.7 ( 12.9 )	42.3 ( 15.5 )	48.1 ( 28.2 )	86.3 ( 15.0 )	90.9 ( 24.6 )	89.7 ( 4.66 )	33.8 ( 7.91 )	69.8 ( 124 )
C2D5: 2 h (n=2,20,19,29,2,14,2,6,22)	10.3 ( 4.44 )	29.9 ( 9.94 )	28.5 ( 9.68 )	36.7 ( 27.9 )	57.6 ( 10.5 )	59.9 ( 19.7 )	67.3 ( 4.50 )	21.3 ( 4.81 )	28.6 ( 9.10 )
C2D5: 4 h (n=3,21,19,34,2,15,2,6,25)	6.40 ( 2.13 )	14.8 ( 6.00 )	13.3 ( 5.22 )	25.2 ( 32.6 )	29.8 ( 2.81 )	30.8 ( 12.5 )	34.7 ( 8.12 )	8.11 ( 2.77 )	12.0 ( 4.47 )
C2D5: 8 h (n=3,17,16,27,2,15,2,6,25)	1.47 ( 0.445 )	3.99 ( 1.69 )	3.94 ( 1.97 )	12.2 ( 19.7 )	4.98 ( 1.92 )	9.78 ( 5.22 )	8.47 ( 3.87 )	28.2 ( 64.5 )	3.33 ( 1.87 )
C2D5: 16 h (n=0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D5: 24 h (n=0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D5: 72 h (n=0,1,6,4,0,2,1,0,0)	99999 ( 99999 )	0.00 ( 99999 )	0.00 ( 0.00 )	0.00 ( 0.00 )	99999 ( 99999 )	1.17 ( 0.409 )	0.741 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
C2D5: 240 h (n=0,2,10,6,1,7,0,0,2)	99999 ( 99999 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 0.00 )	0.00 ( 99999 )	0.00 ( 0.00 )	99999 ( 99999 )	99999 ( 99999 )	0.00 ( 0.00 )

No statistical analyses for this end point

Secondary: Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa

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End point title

Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa ^[9]

End point description

The PK population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least 1 measurable serum concentration of nemvaleukin alfa at any scheduled PK time point. Here, "number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at specified timepoints. Here, "99999" means data could not be calculated due to less subject. Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts. C1D1 (n=5,4,6,8,12,3,6,44,27,3, 34,24,26,36,3,20,2,6,34); C1D5 (n=5,4,6,7,9,3,4,35,15,3,33,19, 22,33,2,16,2,5,33); C2D1 (n=4,3,6,6,7,3,3,41,22,2, 23,20,35,3,17,1,6,29); C2D5 (n=3,4,5,5,7,2,3,35,19, 3,21,17,32,2,15,2,6,25)

End point type

Secondary

End point timeframe

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	6	8	12	3	6	44	27	3	24	26	36	3	20	2	6	34
Units: hournanogram per milliliter (hng/mL)
geometric mean (geometric coefficient of variation)
C1D1	2.96 ( 53.1 )	17.0 ( 35.6 )	66.5 ( 36.5 )	195 ( 252.1 )	557 ( 28.7 )	616 ( 42.3 )	719 ( 39.7 )	608 ( 30.1 )	723 ( 23.2 )	84.1 ( 39.5 )	296 ( 35.0 )	276 ( 31.4 )	222 ( 77.2 )	698 ( 21.7 )	715 ( 37.6 )	543 ( 25.0 )	248 ( 23.4 )	286 ( 22.1 )
C1D5	2.52 ( 17.3 )	14.4 ( 23.6 )	48.2 ( 55.9 )	106 ( 205.5 )	379 ( 46.0 )	323 ( 84.1 )	346 ( 47.8 )	292 ( 61.4 )	312 ( 40.6 )	56.7 ( 18.8 )	158 ( 41.6 )	130 ( 40.5 )	139 ( 53.4 )	343 ( 6.8 )	368 ( 56.7 )	393 ( 45.8 )	121 ( 68.5 )	143 ( 26.2 )
C2D1	2.47 ( 32.4 )	15.3 ( 45.4 )	69.2 ( 50.3 )	274 ( 39.0 )	478 ( 30.7 )	512 ( 35.6 )	573 ( 36.8 )	517 ( 44.5 )	594 ( 25.9 )	56.1 ( 12.9 )	243 ( 41.5 )	212 ( 39.6 )	224 ( 85.0 )	625 ( 12.5 )	562 ( 33.5 )	590 ( 99999 )	195 ( 50.1 )	235 ( 30.8 )
C2D5	2.61 ( 16.6 )	11.5 ( 18.4 )	40.8 ( 21.2 )	167 ( 51.5 )	361 ( 50.4 )	439 ( 3.5 )	312 ( 131.0 )	287 ( 60.9 )	329 ( 45.3 )	52.0 ( 18.5 )	134 ( 35.4 )	128 ( 36.6 )	153 ( 73.4 )	275 ( 15.0 )	346 ( 43.9 )	413 ( 57.6 )	120 ( 72.3 )	135 ( 54.3 )

No statistical analyses for this end point

Secondary: Parts A, B and C: Maximum Observed Serum Concentration (Cmax) of Nemvaleukin Alfa

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End point title

Parts A, B and C: Maximum Observed Serum Concentration (Cmax) of Nemvaleukin Alfa ^[10]

End point description

The PK population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least 1 measurable serum concentration of nemvaleukin alfa at any scheduled PK time point. Here, "number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at specified timepoints. Here, "99999" means data could not be calculated due to less subject. Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts. Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts. C1D1 (n=5,4,6,8,11,3,6,44,27,3,23,25,36,3,18,2,6,34); C1D5 (n=5,4,6,8,9,3,4,36,15,3,19,22,33,2,16,2,5,33); C2D1 (n=4,2,6,8,6,3,3,40,22,2,23,20,35,3,17,1,6,27); C2D5 (n=3,4,6,5,7,2,3,35,19,3,21,19,32,2,15,2,6,24).

End point type

Secondary

End point timeframe

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	6	8	11	3	6	44	27	3	23	25	36	3	18	2	6	34
Units: ng/mL
geometric mean (geometric coefficient of variation)
C1D1	2.09 ( 41.4 )	6.72 ( 21.3 )	20.5 ( 26.8 )	47.6 ( 177.8 )	113 ( 33.7 )	151 ( 36.7 )	157 ( 19.4 )	99.4 ( 40.8 )	124 ( 34.2 )	18.1 ( 15.4 )	57.5 ( 86.5 )	59.5 ( 32.6 )	45.8 ( 48.8 )	131 ( 15.8 )	133 ( 31.7 )	89.3 ( 3.0 )	65.6 ( 24.4 )	61.4 ( 22.8 )
C1D5	1.99 ( 10.3 )	6.36 ( 24.5 )	37.4 ( 19.2 )	41.8 ( 178.7 )	108 ( 22.5 )	112 ( 13.5 )	104 ( 12.5 )	82.1 ( 32.3 )	95.1 ( 33.8 )	19.2 ( 21.7 )	53.1 ( 57.9 )	54.4 ( 51.8 )	47.0 ( 40.1 )	118 ( 1.8 )	101 ( 51.5 )	104 ( 1.8 )	46.5 ( 41.6 )	55.8 ( 37.5 )
C2D1	1.72 ( 35.1 )	5.34 ( 2.2 )	19.8 ( 32.3 )	65.3 ( 27.5 )	113 ( 24.7 )	112 ( 13.0 )	116 ( 33.1 )	108 ( 86.7 )	119 ( 27.6 )	15.6 ( 18.1 )	58.1 ( 81.2 )	55.6 ( 31.4 )	47.2 ( 47.7 )	112 ( 15.3 )	128 ( 30.6 )	124 ( 99999 )	52.9 ( 21.9 )	55.8 ( 26.9 )
C2D5	1.90 ( 11.0 )	6.39 ( 12.7 )	16.7 ( 18.5 )	52.9 ( 48.1 )	97.4 ( 29.0 )	95.7 ( 37.0 )	83.8 ( 57.4 )	103 ( 69.5 )	99.6 ( 18.3 )	14.6 ( 24.0 )	51.7 ( 52.0 )	51.0 ( 25.9 )	49.8 ( 52.6 )	99.2 ( 20.3 )	96.6 ( 29.7 )	94.4 ( 12.5 )	40.8 ( 26.9 )	50.3 ( 67.9 )

No statistical analyses for this end point

Secondary: Parts A, B and C: Time to Reach Cmax (Tmax) of Nemvaleukin Alfa

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End point title

Parts A, B and C: Time to Reach Cmax (Tmax) of Nemvaleukin Alfa ^[11]

End point description

The PK population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least 1 measurable serum concentration of nemvaleukin alfa at any scheduled PK time point. Here, "number of subjects analyzed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at specified timepoints. Here, "99999" means data could not be calculated due to less subject. Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts. Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts. C1D1 (n=5,4,6,8,11,3,6,44,27,3,23,25,36,3,18,2,6,34); C1D5 (n=5,4,6,7,9,3,4,36,15,3,19,22,33,2,16,2,5,33); C2D1 (n=4,2,6,6,6,3,3,44,22,2,23,20,35,3,17,1,6,27); C2D5 (n=3,4,5,5,7,2,3,35,19,3,21,19,32,2,15,2,6,24).

End point type

Secondary

End point timeframe

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg

Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab

Number of subjects analysed

Units: hours

median (full range (min-max))

C1D1

0.60 (0.57 to 0.83)

0.63 (0.52 to 0.73)

0.55 (0.50 to 0.78)

0.57 (0.50 to 0.75)

0.57 (0.50 to 0.70)

0.57 (0.53 to 0.57)

0.51 (0.50 to 0.62)

0.52 (0.50 to 0.75)

0.50 (0.50 to 0.67)

0.75 (0.57 to 0.98)

0.55 (0.50 to 0.73)

0.52 (0.40 to 0.63)

0.50 (0.50 to 0.82)

0.50 (0.50 to 0.67)

0.53 (0.45 to 1.00)

0.78 (0.50 to 1.07)

0.73 (0.58 to 0.75)

0.55 (0.48 to 1.00)

C1D5

0.70 (0.50 to 0.80)

0.60 (0.48 to 0.82)

0.54 (0.50 to 0.80)

0.55 (0.50 to 0.67)

0.58 (0.53 to 0.73)

0.53 (0.53 to 0.58)

0.53 (0.50 to 0.68)

0.51 (0.50 to 0.80)

0.50 (0.43 to 0.58)

0.58 (0.55 to 0.72)

0.53 (0.30 to 0.85)

0.55 (0.48 to 0.68)

0.50 (0.50 to 0.75)

0.58 (0.58 to 0.58)

0.52 (0.45 to 0.63)

0.83 (0.57 to 1.08)

0.73 (0.55 to 0.77)

0.57 (0.50 to 1.00)

C2D1

0.67 (0.58 to 0.80)

0.73 (0.72 to 0.75)

0.53 (0.50 to 0.58)

0.55 (0.50 to 0.87)

0.58 (0.55 to 0.73)

0.53 (0.52 to 0.58)

0.52 (0.50 to 0.63)

0.50 (0.50 to 0.77)

0.50 (0.50 to 0.60)

0.71 (0.60 to 0.82)

0.53 (0.47 to 1.00)

0.53 (0.50 to 0.58)

0.50 (0.50 to 0.77)

0.55 (0.50 to 0.58)

0.52 (0.48 to 0.68)

1.00 (1.00 to 1.00)

0.68 (0.57 to 0.80)

0.55 (0.50 to 1.00)

C2D5

0.63 (0.55 to 0.80)

0.57 (0.50 to 0.68)

0.55 (0.50 to 0.75)

0.68 (0.52 to 1.58)

0.60 (0.50 to 0.75)

0.58 (0.58 to 0.58)

0.52 (0.50 to 0.52)

0.50 (0.50 to 0.77)

0.50 (0.50 to 0.67)

0.72 (0.55 to 0.73)

0.55 (0.50 to 1.08)

0.50 (0.48 to 0.62)

0.50 (0.50 to 0.62)

0.56 (0.50 to 0.62)

0.52 (0.50 to 0.58)

0.77 (0.53 to 1.00)

0.68 (0.58 to 0.78)

0.55 (0.52 to 1.00)

No statistical analyses for this end point

Secondary: Parts A, B, and C: Proportion of Positive Anti-Nemvaleukin Alfa Antibodies (ADA)

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End point title

Parts A, B, and C: Proportion of Positive Anti-Nemvaleukin Alfa Antibodies (ADA) ^[12]

End point description

Overall proportion was calculated as: Number of subjects (overall positive)/total number of subjects in the cohort. Overall positive: Subjects with at least 1 treatment-emergent ADA positive sample at any time during the treatment period. Immunogenicity analysis set included all subjects who received at least one dose of active study drug and had at least one post baseline blood sample collected to assess immunogenicity.

End point type

Secondary

End point timeframe

From first dose of study drug up to 9 months (for Part A); up to 40.3 months (for Part B); up to 50.5 months (for Part C)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	7	8	12	3	5	45	26	3	24	24	43	3	20	2	6	34
Units: proportion of positive ADA
number (not applicable)	0.00	0.00	0.143	0.125	0.417	0.333	0.600	0.467	0.500	0.00	0.250	0.208	0.581	0.667	0.200	0.00	0.667	0.294

No statistical analyses for this end point

Secondary: Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)

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End point title

Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)

End point description

iORR was defined as the percentage of subjects with objective evidence of immune CR (iCR) or immune PR (iPR) based on iRECIST guidelines. Data collection or analysis based on immune-related response criteria (irRC) and iRECIST was not performed as iRECIST was implemented during the middle of the study conduct to replace irRC. Hence, no data was reported in this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Number of subjects analysed

0 ^[13]

0 ^[14]

0 ^[15]

0 ^[16]

0 ^[17]

0 ^[18]

0 ^[19]

0 ^[20]

0 ^[21]

0 ^[22]

0 ^[23]

0 ^[24]

0 ^[25]

0 ^[26]

0 ^[27]

0 ^[28]

0 ^[29]

Units: Percentage of subjects

number (confidence interval 95%)

( to )

Notes
[13] - Data collection or analysis based on irRC and iRECIST was not performed.
[14] - Data collection or analysis based on irRC and iRECIST was not performed.
[15] - Data collection or analysis based on irRC and iRECIST was not performed.
[16] - Data collection or analysis based on irRC and iRECIST was not performed.
[17] - Data collection or analysis based on irRC and iRECIST was not performed.
[18] - Data collection or analysis based on irRC and iRECIST was not performed.
[19] - Data collection or analysis based on irRC and iRECIST was not performed.
[20] - Data collection or analysis based on irRC and iRECIST was not performed.
[21] - Data collection or analysis based on irRC and iRECIST was not performed.
[22] - Data collection or analysis based on irRC and iRECIST was not performed.
[23] - Data collection or analysis based on irRC and iRECIST was not performed.
[24] - Data collection or analysis based on irRC and iRECIST was not performed.
[25] - Data collection or analysis based on irRC and iRECIST was not performed.
[26] - Data collection or analysis based on irRC and iRECIST was not performed.
[27] - Data collection or analysis based on irRC and iRECIST was not performed.
[28] - Data collection or analysis based on irRC and iRECIST was not performed.
[29] - Data collection or analysis based on irRC and iRECIST was not performed.

No statistical analyses for this end point

Secondary: Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1

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End point title

Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1

End point description

Disease control rate was defined as the percentage of subjects with objective evidence of CR, PR, or SD based on RECIST v.1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The antitumor evaluable population consisted of subjects who complete 2 cycles of therapy and had at least one follow-up scan.

End point type

Secondary

End point timeframe

From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Number of subjects analysed

Units: percentage of subjects

number (confidence interval 95%)

0.0 (0.0 to 60.2)

25.0 (0.6 to 80.6)

20.0 (0.5 to 71.6)

60.0 (14.7 to 94.7)

33.3 (7.5 to 70.1)

33.3 (0.8 to 90.6)

25.0 (0.6 to 80.6)

47.8 (32.9 to 63.1)

50.0 (28.2 to 71.8)

0.0 (0.0 to 70.8)

30.6 (16.3 to 48.1)

22.7 (7.8 to 45.4)

47.6 (25.7 to 70.2)

46.2 (30.1 to 62.8)

66.7 (9.4 to 99.2)

50.0 (26.0 to 74.0)

100 (15.8 to 100.0)

No statistical analyses for this end point

Secondary: Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1

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End point title

Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1

End point description

iDCR was defined as the percentage of subjects with objective evidence of iCR, iPR (where iCR or iPR required confirmation), or immune stable disease (iSD) (where the iSD requires to occur at Cycle 4 or later). Data collection or analysis based on irRC and iRECIST was not performed as iRECIST was implemented during the middle of the study conduct to replace irRC. Hence, no data was reported in this outcome measure.

End point type

Secondary

End point timeframe

From first dose of study drug up to 9 months for Part A; up to 40.3 months for Part B; up to 50.5 months for Part C

Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg

Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg

Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Number of subjects analysed

0 ^[30]

0 ^[31]

0 ^[32]

0 ^[33]

0 ^[34]

0 ^[35]

0 ^[36]

0 ^[37]

0 ^[38]

0 ^[39]

0 ^[40]

0 ^[41]

0 ^[42]

0 ^[43]

0 ^[44]

0 ^[45]

0 ^[46]

Units: percentage of subjects

number (confidence interval 95%)

( to )

Notes
[30] - Data collection or analysis based on irRC and iRECIST was not performed
[31] - Data collection or analysis based on irRC and iRECIST was not performed.
[32] - Data collection or analysis based on irRC and iRECIST was not performed.
[33] - Data collection or analysis based on irRC and iRECIST was not performed.
[34] - Data collection or analysis based on irRC and iRECIST was not performed.
[35] - Data collection or analysis based on irRC and iRECIST was not performed.
[36] - Data collection or analysis based on irRC and iRECIST was not performed.
[37] - Data collection or analysis based on irRC and iRECIST was not performed.
[38] - Data collection or analysis based on irRC and iRECIST was not performed.
[39] - Data collection or analysis based on irRC and iRECIST was not performed.
[40] - Data collection or analysis based on irRC and iRECIST was not performed.
[41] - Data collection or analysis based on irRC and iRECIST was not performed.
[42] - Data collection or analysis based on irRC and iRECIST was not performed.
[43] - Data collection or analysis based on irRC and iRECIST was not performed.
[44] - Data collection or analysis based on irRC and iRECIST was not performed.
[45] - Data collection or analysis based on irRC and iRECIST was not performed.
[46] - Data collection or analysis based on irRC and iRECIST was not performed.

No statistical analyses for this end point

Secondary: Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1

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End point title

Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1 ^[47]

End point description

DOR: time from the first documentation of response (CR or PR) to first documentation of objective tumor progression or death due to any cause. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Antitumor evaluable population. "Number of subjects analysed" signifies subjects who had CR or PR. "99999" means data could not be estimated due to insufficient events.

End point type

Secondary

End point timeframe

From the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause (up to 40.3 months for Part B and up to 50.5 months for Part C)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	6	4	0 ^[48]	6	1	7	5	2	2	1
Units: weeks
median (confidence interval 95%)	18.43 (6.14 to 99999)	28.86 (12.43 to 99999)	( to )	35.14 (8.29 to 160.14)	99999 (99999 to 99999)	63.14 (6.86 to 99999)	99999 (7.14 to 99999)	99999 (99999 to 99999)	39.07 (13.14 to 65.00)	27.86 (-99999 to 99999)

Notes
[48] - No subjects had CR or PR.

No statistical analyses for this end point

Secondary: Parts B, and C: Immune DOR (iDOR) Based on iRECIST

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End point title

Parts B, and C: Immune DOR (iDOR) Based on iRECIST ^[49]

End point description

iDOR was defined as the time from the first documentation of response (iCR or iPR) to the first documentation of objective tumor progression (immune confirmed progressive disease [iCPD]) or death due to any cause based on iRECIST. Data collection or analysis based on irRC and iRECIST was not performed as iRECIST was implemented during the middle of the study conduct to replace irRC. Hence, no data was reported in this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	0 ^[50]	0 ^[51]	0 ^[52]	0 ^[53]	0 ^[54]	0 ^[55]	0 ^[56]	0 ^[57]	0 ^[58]	0 ^[59]
Units: weeks
median (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )

Notes
[50] - Data collection or analysis based on irRC and iRECIST was not performed.
[51] - Data collection or analysis based on irRC and iRECIST was not performed.
[52] - Data collection or analysis based on irRC and iRECIST was not performed.
[53] - Data collection or analysis based on irRC and iRECIST was not performed.
[54] - Data collection or analysis based on irRC and iRECIST was not performed.
[55] - Data collection or analysis based on irRC and iRECIST was not performed.
[56] - Data collection or analysis based on irRC and iRECIST was not performed.
[57] - Data collection or analysis based on irRC and iRECIST was not performed.
[58] - Data collection or analysis based on irRC and iRECIST was not performed.
[59] - Data collection or analysis based on irRC and iRECIST was not performed.

No statistical analyses for this end point

Secondary: Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1

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End point title

Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1 ^[60]

End point description

DRR was defined as the percentage of subjects with an objective response (complete or partial response per RECIST 1.1) lasting continuously for 6 months and starting any time within 12 months of initiating the study drug. As pre-specified in statistical analysis plan (SAP), this endpoint of DRR was not summarized and hence, no data was reported in this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	0 ^[61]	0 ^[62]	0 ^[63]	0 ^[64]	0 ^[65]	0 ^[66]	0 ^[67]	0 ^[68]	0 ^[69]	0 ^[70]
Units: percentage of subjects
number (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )

Notes
[61] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[62] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[63] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[64] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[65] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[66] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[67] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[68] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[69] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.
[70] - As pre-specified in SAP, this endpoint was not summarized and hence, no data was reported.

No statistical analyses for this end point

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST

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End point title

Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST ^[71]

End point description

iDRR was defined as the percentage of subjects with an objective response (complete or partial response per iRECIST) lasting continuously for 6 months and starting any time within 12 months of initiating the study drug. Data collection or analysis based on irRC and iRECIST was not performed as iRECIST was implemented during the middle of the study conduct to replace irRC. Hence, no data was reported in this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	0 ^[72]	0 ^[73]	0 ^[74]	0 ^[75]	0 ^[76]	0 ^[77]	0 ^[78]	0 ^[79]	0 ^[80]	0 ^[81]
Units: percentage of subjects
number (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )	( to )

Notes
[72] - Data collection or analysis based on irRC and iRECIST was not performed.
[73] - Data collection or analysis based on irRC and iRECIST was not performed.
[74] - Data collection or analysis based on irRC and iRECIST was not performed.
[75] - Data collection or analysis based on irRC and iRECIST was not performed.
[76] - Data collection or analysis based on irRC and iRECIST was not performed.
[77] - Data collection or analysis based on irRC and iRECIST was not performed.
[78] - Data collection or analysis based on irRC and iRECIST was not performed.
[79] - Data collection or analysis based on irRC and iRECIST was not performed.
[80] - Data collection or analysis based on irRC and iRECIST was not performed.
[81] - Data collection or analysis based on irRC and iRECIST was not performed.

No statistical analyses for this end point

Secondary: Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1

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End point title

Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1 ^[82]

End point description

Progression-free survival was defined as the time from the first dose of nemvaleukin to the first documentation of objective tumor progression or death due to any cause. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The antitumor evaluable population consisted of subjects who complete 2 cycles of therapy and had at least one follow-up scan. "99999" means data could not be estimated due to insufficient events.

End point type

Secondary

End point timeframe

From first dose of study drug up to the first documentation of objective tumor progression or death due to any cause (up to 40.3 months for Part B and up to 50.5 months for Part C)

Notes
[82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	46	22	3	18	2
Units: weeks
median (confidence interval 95%)	16.14 (10.57 to 17.14)	12.43 (4.43 to 22.57)	99999 (10.29 to 99999)	18.64 (6.14 to 27.14)	35.57 (18.71 to 52.43)

No statistical analyses for this end point

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS)

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End point title

Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS) ^[83]

End point description

iPFS was defined as the time from the first dose of study medication to the first documentation of objective tumor progression based on iRECIST (immune confirmed progressive disease [iCPD]) or death due to any cause. Data collection or analysis based on irRC and iRECIST was not performed as iRECIST was implemented during the middle of the study conduct to replace irRC. Hence, no data was reported in this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug up to 40.3 months for Part B; up to 50.5 months for Part C

Notes
[83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	0 ^[84]	0 ^[85]	0 ^[86]	0 ^[87]	0 ^[88]
Units: weeks
number (confidence interval 95%)	( to )	( to )	( to )	( to )	( to )

Notes
[84] - Data collection or analysis based on irRC and iRECIST was not performed.
[85] - Data collection or analysis based on irRC and iRECIST was not performed.
[86] - Data collection or analysis based on irRC and iRECIST was not performed.
[87] - Data collection or analysis based on irRC and iRECIST was not performed.
[88] - Data collection or analysis based on irRC and iRECIST was not performed.

No statistical analyses for this end point

Secondary: Parts A, B and C: Maximum Cell Count of Whole Blood FoxP3+ T Cells (Tregs), Total Cluster of Differentiation (CD)8+ T Cells and Natural Killer (NK) Cells

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End point title

Parts A, B and C: Maximum Cell Count of Whole Blood FoxP3+ T Cells (Tregs), Total Cluster of Differentiation (CD)8+ T Cells and Natural Killer (NK) Cells ^[89]

End point description

The pharmacodynamic (PD) population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least one available postbaseline PD measurement. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at specified timepoints. Here, "99999" means data could not be calculated due to less subject. Whole Blood FoxP3+ T Cells (Tregs) (n=5,4,7,8,12,3,7,27,47,3,25,26,39,3,21,1,6,36); Total CD8+ T Cells (n=5,4,7,8,12,3,7,27,47,3,25,26,39,3,21,2,6,36); NK Cells (n=5,4,7,8,12,3,7,27,47,3,25,26,39,3,21,2,6,36).

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (Cycle 1 length = 14 days for Part A and 21 days for Part B)

Notes
[89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	7	8	12	3	7	47	27	3	25	26	39	3	21	2	6	36
Units: cells per microliters (cells/mcL)
arithmetic mean (standard deviation)
Whole Blood FoxP3+ T Cells (Tregs)	32.0 ( 11.3 )	50.5 ( 53.7 )	56.6 ( 22.3 )	46.3 ( 21.8 )	43.3 ( 28.2 )	57.4 ( 14.4 )	51.3 ( 36.0 )	47.9 ( 24.0 )	40.3 ( 23.5 )	27.4 ( 7.31 )	37.8 ( 24.5 )	41.6 ( 27.7 )	44.3 ( 22.5 )	51.1 ( 9.85 )	52.6 ( 31.3 )	33.1 ( 99999 )	50.9 ( 23.9 )	42.6 ( 28.3 )
Total CD8+ T Cells	247 ( 107 )	204 ( 89.2 )	262 ( 64.2 )	466 ( 255 )	610 ( 570 )	704 ( 559 )	703 ( 502 )	773 ( 422 )	1392 ( 1053 )	262 ( 186 )	533 ( 328 )	688 ( 384 )	718 ( 567 )	924 ( 638 )	762 ( 538 )	445 ( 349 )	551 ( 433 )	562 ( 373 )
NK Cells	197 ( 61.4 )	343 ( 20.6 )	467 ( 313 )	685 ( 307 )	1053 ( 660 )	978 ( 400 )	1038 ( 1028 )	1470 ( 873 )	1279 ( 642 )	531 ( 296 )	760 ( 458 )	813 ( 436 )	889 ( 438 )	1081 ( 787 )	1064 ( 445 )	1298 ( 334 )	804 ( 196 )	771 ( 503 )

No statistical analyses for this end point

Secondary: Parts A, B and C: Maximum Cell Count of Interferon-gamma (INF-γ) and Interleukin 6 (IL-6)

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End point title

Parts A, B and C: Maximum Cell Count of Interferon-gamma (INF-γ) and Interleukin 6 (IL-6) ^[90]

End point description

The PD population consisted of all subjects who received at least 1 dose of nemvaleukin alfa and had at least one available postbaseline PD measurement. Here, "99999" means data could not be calculated due to less subject. INF-γ: C1D1 (n=5,4,7,8,10,1,7,12,15,0,4,3,21,1,5,0,2,29); INF-γ: C1D5 (n=5,4,5,7,8,2,4,34,13,0,14,17, 17,2,17,2,4,29); INF-γ: C2D1 (n=4,4,5,5,1,2,1,16,4, 0,5,4,4,1,3,0,1,7); INF-γ: Cycle 2 Day 5 (n=3,4,6,5,6,2,3,33,10, 0,10,17,21,2,12,2,4,20); IL-6: C1D1 (n=5,3,7,8,10,2,6,29,13, 0,16,18,14,2,15,0,5,29); IL-6: C1D5 (n=5,4,7,7,9,2,4,33,15,1,17,20,16,2,18,2,5,31); IL-6: C2D1 (n=5,4,7,6,6,2,4,31,12,1,15, 12,11,2,12,0,6,23); IL-6: C2D5 (n=3,4,7,5,5,2,3,30,10, 3,17,12,15,2,12,2,6,21).

End point type

Secondary

End point timeframe

Cycle 1 Days 1 and 5; Cycle 2 Days 1 and 5 (Cycle 1 length = 14 days for Part A and 21 days for Part B and C; Cycle 2 length= 21 days for all parts)

Notes
[90] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only descriptive data was planned.

End point values	Part A, Dose Escalation: Nemvaleukin Alfa 0.1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 0.3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 1 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 3 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 6 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 8 mcg/kg	Part A, Dose Escalation: Nemvaleukin Alfa 10 mcg/kg	Part B, Dose Expansion, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, Dose Expansion, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab	Part C, Safety Run-in: Nemvaleukin Alfa 3 mcg/kg	Part C, Cohort 1: Nemvaleukin Alfa + Pembrolizumab
Number of subjects analysed	5	4	7	8	10	2	2	7	15	3	17	20	21	2	18	2	6	31
Units: nanogram per liter (ng/L)
arithmetic mean (standard deviation)
INF-γ: C1D1	23.0 ( 10.3 )	19.8 ( 10.4 )	14.9 ( 6.10 )	31.3 ( 12.7 )	108 ( 130 )	26.4 ( 99999 )	18.0 ( 99999 )	34.7 ( 22.7 )	18.6 ( 4.19 )	99999 ( 99999 )	34.5 ( 15.6 )	18.9 ( 3.71 )	84.4 ( 87.8 )	68.3 ( 99999 )	31.7 ( 24.2 )	99999 ( 99999 )	23.3 ( 7.40 )	77.0 ( 106 )
INF-γ: C1D5	24.7 ( 10.8 )	29.1 ( 10.7 )	13.8 ( 7.71 )	173 ( 199 )	129 ( 84.1 )	585 ( 313 )	335 ( 74.3 )	209 ( 191 )	162 ( 183 )	99999 ( 99999 )	94.3 ( 103 )	70.9 ( 54.7 )	64.4 ( 61.5 )	390 ( 530 )	279 ( 526 )	87.7 ( 42.1 )	48.2 ( 30.3 )	92.6 ( 86.4 )
INF-γ: C2D1	28.0 ( 24.1 )	18.3 ( 3.70 )	12.2 ( 4.56 )	43.3 ( 28.4 )	33.9 ( 99999 )	19.8 ( 4.81 )	15.7 ( 99999 )	43.3 ( 41.9 )	50.4 ( 22.7 )	99999 ( 99999 )	21.1 ( 6.39 )	19.7 ( 3.87 )	62.4 ( 20.7 )	43.5 ( 99999 )	25.8 ( 1.04 )	99999 ( 99999 )	15.4 ( 99999 )	70.9 ( 102 )
INF-γ: C2D5	31.2 ( 19.2 )	24.3 ( 10.8 )	16.3 ( 8.03 )	53.2 ( 15.3 )	45.1 ( 28.5 )	171 ( 78.4 )	84.8 ( 58.6 )	141 ( 139 )	120 ( 178 )	99999 ( 99999 )	47.7 ( 43.5 )	38.5 ( 22.2 )	54.0 ( 36.1 )	326 ( 124 )	101 ( 71.0 )	41.9 ( 1.42 )	60.3 ( 19.5 )	73.3 ( 77.7 )
IL-6: C1D1	104 ( 61.8 )	118 ( 33.0 )	169 ( 280 )	938 ( 845 )	254 ( 177 )	148 ( 14.6 )	1826 ( 3474 )	323 ( 630 )	211 ( 143 )	99999 ( 99999 )	274 ( 234 )	306 ( 181 )	706 ( 1757 )	200 ( 101 )	757 ( 2165 )	99999 ( 99999 )	506 ( 137 )	667 ( 1020 )
IL-6: C1D5	116 ( 121 )	113 ( 51.9 )	223 ( 229 )	2022 ( 1491 )	802 ( 797 )	677 ( 751 )	5240 ( 5279 )	699 ( 538 )	723 ( 1077 )	151 ( 99999 )	513 ( 585 )	527 ( 538 )	273 ( 244 )	1049 ( 1288 )	635 ( 500 )	232 ( 13.8 )	524 ( 180 )	1269 ( 1807 )
IL-6: C2D1	41.9 ( 14.7 )	106 ( 76.4 )	191 ( 240 )	883 ( 570 )	351 ( 448 )	169 ( 18.1 )	519 ( 475 )	311 ( 447 )	254 ( 151 )	95.7 ( 99999 )	276 ( 249 )	372 ( 279 )	282 ( 176 )	718 ( 649 )	264 ( 379 )	99999 ( 99999 )	254 ( 99.4 )	669 ( 1075 )
IL-6: C2D5	56.2 ( 19.1 )	95.2 ( 45.3 )	125 ( 89.3 )	1145 ( 700 )	399 ( 243 )	252 ( 124 )	1372 ( 1841 )	341 ( 252 )	318 ( 174 )	116 ( 33.0 )	290 ( 296 )	269 ( 155 )	269 ( 174 )	165 ( 98.6 )	267 ( 172 )	123 ( 19.0 )	425 ( 339 )	929 ( 1962 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug until 30 days after last dose (up to 10 months for Part A; up to 41.3 months for Part B; up to 51.5 months for Part C)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Part A: Nemvaleukin Alfa 0.1 mcg/kg

Reporting group description

Subjects with advanced solid tumors received nemvaleukin alfa 0.1 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Reporting group title

Part A: Nemvaleukin Alfa 0.3 mcg/kg

Reporting group description

Reporting group title

Part A: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part A: Nemvaleukin Alfa 3 mcg/kg

Reporting group description

Reporting group title

Part A: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part A: Nemvaleukin Alfa 8 mcg/kg

Reporting group description

Reporting group title

Part A: Nemvaleukin Alfa 10 mcg/kg

Reporting group description

Reporting group title

Part B, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Reporting group title

Part B, RCC: Nemvaleukin Alfa 6 mcg/kg

Reporting group description

Subjects with RCC received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in Cycle 1 (Cycle length = 14 days) and then in Cycle 2 and subsequent cycles (each Cycle length = 21 days) until disease progression or the subject met any discontinuation criteria.

Reporting group title

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Reporting group description

Reporting group title

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Reporting group description

Subjects with PD-1/L1 unapproved tumor types (PD-1/L1 treatment naive) received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation. The Safety Run-in for nemvaleukin alfa 3 mcg/kg was combined with Cohort 1 of Part C due to same dosing level and regimen.

Reporting group title

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Reporting group description

Subjects rollover from Parts A or B received nemvaleukin alfa 3 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Reporting group title

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Reporting group title

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Subjects with NSCLC received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Reporting group title

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Reporting group description

Subjects with SCCHN received nemvaleukin alfa 6 mcg/kg IV infusion administration daily from Days 1 to 5 in combination with pembrolizumab 200 mg IV infusion on Day 1 in each Cycle (cycle length = 21 days) for a maximum of 2 years for as long as the subject appeared to be deriving clinical benefit (i.e., objective response or SD) and had tolerated therapy well. Subjects could continue nemvaleukin alfa as monotherapy beyond the maximum of 2 years of treatment by switching to monotherapy at the joint discretion of the Investigator and Sponsor and if they did not meet any other criteria for discontinuation.

Part A: Nemvaleukin Alfa 0.1 mcg/kg

Part A: Nemvaleukin Alfa 0.3 mcg/kg

Part A: Nemvaleukin Alfa 1 mcg/kg

Part A: Nemvaleukin Alfa 3 mcg/kg

Part A: Nemvaleukin Alfa 6 mcg/kg

Part A: Nemvaleukin Alfa 8 mcg/kg

Part A: Nemvaleukin Alfa 10 mcg/kg

Part B, Melanoma: Nemvaleukin Alfa 6 mcg/kg

Part B, RCC: Nemvaleukin Alfa 6 mcg/kg

Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg

Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab

Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab

Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab

Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 5 (40.00%)

0 / 4 (0.00%)

2 / 7 (28.57%)

3 / 8 (37.50%)

5 / 12 (41.67%)

0 / 3 (0.00%)

5 / 7 (71.43%)

11 / 47 (23.40%)

12 / 27 (44.44%)

0 / 3 (0.00%)

19 / 42 (45.24%)

10 / 26 (38.46%)

11 / 26 (42.31%)

14 / 43 (32.56%)

2 / 3 (66.67%)

12 / 21 (57.14%)

2 / 2 (100.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Pancreatic carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Bladder transitional cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Embolism arterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Extravasation

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fatigue

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

2 / 42 (4.76%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Asthenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

2 / 21 (9.52%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Immune system disorders

Anaphylactic reaction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cytokine release syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

2 / 21 (9.52%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Reproductive system and breast disorders

Pelvic pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vaginal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Aspiration

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

1 / 2 (50.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Asthma

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chronic obstructive

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cough

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

2 / 21 (9.52%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumothorax

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary oedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hallucination

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mental status changes

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

1 / 3 (33.33%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood bilirubin increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Electrocardiogram T wave abnormal

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Troponin I increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Infusion related reaction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

2 / 42 (4.76%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

2 / 21 (9.52%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

1 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Overdose

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vaccination complication

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Stomal hernia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute myocardial infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

2 / 27 (7.41%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

2 / 21 (9.52%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac arrest

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Cardiac failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac tamponade

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

1 / 2 (50.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Supraventricular extrasystoles

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Brain oedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depressed level of consciousness

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

2 / 42 (4.76%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ischaemic stroke

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lethargy

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolic encephalopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myelopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Febrile neutropenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

2 / 27 (7.41%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

1 / 26 (3.85%)

4 / 43 (9.30%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 4

2 / 3

0 / 0

1 / 1

0 / 0

0 / 1

6 / 10

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Immune thrombocytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

1 / 3 (33.33%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

1 / 1

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Iritis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vitritis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

1 / 5 (20.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

3 / 42 (7.14%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Ascites

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ileus

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune-mediated enterocolitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestine perforation

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Nausea

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

2 / 42 (4.76%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 2

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Biliary obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholangitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholecystitis acute

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperbilirubinaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

2 / 27 (7.41%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertransaminasaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune-mediated hepatitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Dermatitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematuria

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydronephrosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary retention

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

1 / 7 (14.29%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myositis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abscess neck

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

1 / 2 (50.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Arthritis infective

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

2 / 27 (7.41%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Catheter site infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

1 / 27 (3.70%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peritoneal abscess

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

2 / 7 (28.57%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pyelonephritis acute

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

3 / 42 (7.14%)

2 / 26 (7.69%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 5

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

1 / 7 (14.29%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urosepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

2 / 26 (7.69%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular device infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 43 (2.33%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection enterococcal

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diabetic ketoacidosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Failure to thrive

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypercalcaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

1 / 7 (14.29%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypocalcaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

1 / 47 (2.13%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoglycaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

2 / 42 (4.76%)

1 / 26 (3.85%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hypovolaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Starvation

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

1 / 42 (2.38%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Syncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

0 / 43 (0.00%)

0 / 3 (0.00%)

1 / 21 (4.76%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Type 1 diabetes mellitus

subjects affected / exposed

0 / 5 (0.00%)

0 / 4 (0.00%)

0 / 7 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

0 / 7 (0.00%)

0 / 47 (0.00%)

0 / 27 (0.00%)

0 / 3 (0.00%)

0 / 42 (0.00%)

0 / 26 (0.00%)

1 / 26 (3.85%)

0 / 43 (0.00%)

0 / 3 (0.00%)

0 / 21 (0.00%)

0 / 2 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part A: Nemvaleukin Alfa 0.1 mcg/kg	Part A: Nemvaleukin Alfa 0.3 mcg/kg	Part A: Nemvaleukin Alfa 1 mcg/kg	Part A: Nemvaleukin Alfa 3 mcg/kg	Part A: Nemvaleukin Alfa 6 mcg/kg	Part A: Nemvaleukin Alfa 8 mcg/kg	Part A: Nemvaleukin Alfa 10 mcg/kg	Part B, Melanoma: Nemvaleukin Alfa 6 mcg/kg	Part B, RCC: Nemvaleukin Alfa 6 mcg/kg	Part C, Safety Run-in: Nemvaleukin Alfa 1 mcg/kg	Part C,Cohort 1 +Safety Run-in: Nemvaleukin Alfa+Pembrolizumab	Part C, Cohort 2: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 3: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 4, Rolled Over: Nemvaleukin Alfa +Pembrolizumab	Part C, Cohort 5: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 6: Nemvaleukin Alfa + Pembrolizumab	Part C, Cohort 7: Nemvaleukin Alfa + Pembrolizumab
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	4 / 4 (100.00%)	7 / 7 (100.00%)	8 / 8 (100.00%)	12 / 12 (100.00%)	3 / 3 (100.00%)	7 / 7 (100.00%)	46 / 47 (97.87%)	27 / 27 (100.00%)	3 / 3 (100.00%)	42 / 42 (100.00%)	26 / 26 (100.00%)	26 / 26 (100.00%)	38 / 43 (88.37%)	3 / 3 (100.00%)	21 / 21 (100.00%)	2 / 2 (100.00%)
Vascular disorders
Embolism
subjects affected / exposed	0 / 5 (0.00%)	2 / 4 (50.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypertension
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	2 / 12 (16.67%)	2 / 3 (66.67%)	0 / 7 (0.00%)	4 / 47 (8.51%)	3 / 27 (11.11%)	0 / 3 (0.00%)	4 / 42 (9.52%)	3 / 26 (11.54%)	6 / 26 (23.08%)	1 / 43 (2.33%)	1 / 3 (33.33%)	4 / 21 (19.05%)	0 / 2 (0.00%)
occurrences all number	1	1	1	6	5	6	0	15	3	0	5	6	18	6	2	7	0
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	3 / 8 (37.50%)	7 / 12 (58.33%)	1 / 3 (33.33%)	4 / 7 (57.14%)	20 / 47 (42.55%)	5 / 27 (18.52%)	0 / 3 (0.00%)	18 / 42 (42.86%)	4 / 26 (15.38%)	6 / 26 (23.08%)	4 / 43 (9.30%)	0 / 3 (0.00%)	6 / 21 (28.57%)	1 / 2 (50.00%)
occurrences all number	0	2	0	3	16	1	7	65	8	0	67	4	11	7	0	54	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 7 (28.57%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	2 / 42 (4.76%)	1 / 26 (3.85%)	1 / 26 (3.85%)	2 / 43 (4.65%)	2 / 3 (66.67%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	0	0	3	0	0	0	5	2	1	4	2	5	0
Chills
subjects affected / exposed	0 / 5 (0.00%)	2 / 4 (50.00%)	5 / 7 (71.43%)	8 / 8 (100.00%)	11 / 12 (91.67%)	3 / 3 (100.00%)	2 / 7 (28.57%)	21 / 47 (44.68%)	14 / 27 (51.85%)	1 / 3 (33.33%)	32 / 42 (76.19%)	16 / 26 (61.54%)	18 / 26 (69.23%)	9 / 43 (20.93%)	3 / 3 (100.00%)	13 / 21 (61.90%)	2 / 2 (100.00%)
occurrences all number	0	8	16	29	52	32	2	226	47	3	171	62	95	29	7	65	42
Fatigue
subjects affected / exposed	4 / 5 (80.00%)	1 / 4 (25.00%)	2 / 7 (28.57%)	3 / 8 (37.50%)	4 / 12 (33.33%)	2 / 3 (66.67%)	3 / 7 (42.86%)	11 / 47 (23.40%)	8 / 27 (29.63%)	1 / 3 (33.33%)	19 / 42 (45.24%)	8 / 26 (30.77%)	11 / 26 (42.31%)	9 / 43 (20.93%)	3 / 3 (100.00%)	6 / 21 (28.57%)	2 / 2 (100.00%)
occurrences all number	6	1	2	4	5	9	7	28	14	2	33	8	39	28	6	11	18
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 7 (14.29%)	5 / 47 (10.64%)	1 / 27 (3.70%)	2 / 3 (66.67%)	8 / 42 (19.05%)	3 / 26 (11.54%)	5 / 26 (19.23%)	1 / 43 (2.33%)	2 / 3 (66.67%)	2 / 21 (9.52%)	1 / 2 (50.00%)
occurrences all number	2	1	0	3	1	1	2	6	1	7	13	3	10	1	3	2	1
Pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	6 / 42 (14.29%)	3 / 26 (11.54%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	1	0	1	0	0	0	0	0	10	3	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	4 / 27 (14.81%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	6	0	0	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	2 / 4 (50.00%)	5 / 7 (71.43%)	8 / 8 (100.00%)	12 / 12 (100.00%)	2 / 3 (66.67%)	3 / 7 (42.86%)	33 / 47 (70.21%)	17 / 27 (62.96%)	1 / 3 (33.33%)	30 / 42 (71.43%)	17 / 26 (65.38%)	16 / 26 (61.54%)	7 / 43 (16.28%)	2 / 3 (66.67%)	10 / 21 (47.62%)	2 / 2 (100.00%)
occurrences all number	0	2	8	24	59	10	7	104	27	1	148	80	45	33	7	37	29
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	0 / 7 (0.00%)	6 / 47 (12.77%)	3 / 27 (11.11%)	0 / 3 (0.00%)	5 / 42 (11.90%)	2 / 26 (7.69%)	2 / 26 (7.69%)	0 / 43 (0.00%)	0 / 3 (0.00%)	3 / 21 (14.29%)	0 / 2 (0.00%)
occurrences all number	0	2	0	0	1	1	0	13	4	0	5	5	3	0	0	4	0
Dyspnoea
subjects affected / exposed	2 / 5 (40.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	2 / 12 (16.67%)	1 / 3 (33.33%)	2 / 7 (28.57%)	5 / 47 (10.64%)	8 / 27 (29.63%)	1 / 3 (33.33%)	8 / 42 (19.05%)	4 / 26 (15.38%)	6 / 26 (23.08%)	0 / 43 (0.00%)	1 / 3 (33.33%)	11 / 21 (52.38%)	0 / 2 (0.00%)
occurrences all number	2	1	1	8	2	1	2	6	9	1	10	5	14	0	1	40	0
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	1 / 26 (3.85%)	4 / 26 (15.38%)	2 / 43 (4.65%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	5	2	0	2	0
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	5 / 42 (11.90%)	2 / 26 (7.69%)	0 / 26 (0.00%)	2 / 43 (4.65%)	0 / 3 (0.00%)	5 / 21 (23.81%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	7	2	0	2	0	7	1
Tachypnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	1 / 26 (3.85%)	1 / 43 (2.33%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	4	1	1	0	10	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 47 (8.51%)	2 / 27 (7.41%)	0 / 3 (0.00%)	5 / 42 (11.90%)	0 / 26 (0.00%)	4 / 26 (15.38%)	1 / 43 (2.33%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	2	0	6	0	4	1	0	0	0
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	3 / 12 (25.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	3	0	0	0	0	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 7 (42.86%)	1 / 8 (12.50%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	4 / 47 (8.51%)	4 / 27 (14.81%)	0 / 3 (0.00%)	6 / 42 (14.29%)	1 / 26 (3.85%)	3 / 26 (11.54%)	3 / 43 (6.98%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	3	1	0	1	0	10	7	0	7	1	3	4	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)	2 / 7 (28.57%)	17 / 47 (36.17%)	6 / 27 (22.22%)	0 / 3 (0.00%)	4 / 42 (9.52%)	3 / 26 (11.54%)	8 / 26 (30.77%)	5 / 43 (11.63%)	1 / 3 (33.33%)	5 / 21 (23.81%)	1 / 2 (50.00%)
occurrences all number	0	0	0	2	3	1	4	27	8	0	11	5	17	27	1	9	3
Aspartate aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	2 / 12 (16.67%)	0 / 3 (0.00%)	3 / 7 (42.86%)	18 / 47 (38.30%)	7 / 27 (25.93%)	0 / 3 (0.00%)	6 / 42 (14.29%)	3 / 26 (11.54%)	8 / 26 (30.77%)	5 / 43 (11.63%)	1 / 3 (33.33%)	3 / 21 (14.29%)	1 / 2 (50.00%)
occurrences all number	1	0	0	1	3	0	6	27	10	0	9	6	19	24	1	5	2
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	2 / 12 (16.67%)	1 / 3 (33.33%)	1 / 7 (14.29%)	4 / 47 (8.51%)	2 / 27 (7.41%)	0 / 3 (0.00%)	6 / 42 (14.29%)	0 / 26 (0.00%)	4 / 26 (15.38%)	2 / 43 (4.65%)	0 / 3 (0.00%)	5 / 21 (23.81%)	1 / 2 (50.00%)
occurrences all number	0	0	0	1	2	1	1	4	2	0	20	0	7	2	0	14	1
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	2 / 7 (28.57%)	4 / 47 (8.51%)	1 / 27 (3.70%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	3	3	4	9	0	0	0	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	3 / 7 (42.86%)	4 / 8 (50.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 47 (4.26%)	6 / 27 (22.22%)	0 / 3 (0.00%)	8 / 42 (19.05%)	1 / 26 (3.85%)	4 / 26 (15.38%)	4 / 43 (9.30%)	0 / 3 (0.00%)	3 / 21 (14.29%)	0 / 2 (0.00%)
occurrences all number	0	0	4	4	0	2	0	5	8	0	17	2	5	6	0	3	0
Blood pressure
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	6 / 47 (12.77%)	6 / 27 (22.22%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	25	11	0	0	0	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	2 / 3 (66.67%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	7 / 42 (16.67%)	2 / 26 (7.69%)	3 / 26 (11.54%)	3 / 43 (6.98%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	0	0	0	1	1	2	0	0	0	0	28	2	15	8	0	24	3
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	1	2	0	0	0	0	0	0	0	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	2 / 27 (7.41%)	1 / 3 (33.33%)	6 / 42 (14.29%)	1 / 26 (3.85%)	4 / 26 (15.38%)	0 / 43 (0.00%)	1 / 3 (33.33%)	6 / 21 (28.57%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	9	3	1	73	2	53	0	1	35	2
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 47 (2.13%)	5 / 27 (18.52%)	0 / 3 (0.00%)	4 / 42 (9.52%)	4 / 26 (15.38%)	2 / 26 (7.69%)	1 / 43 (2.33%)	1 / 3 (33.33%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	5	17	0	18	19	2	1	3	8	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	2 / 27 (7.41%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	2	0	0	0	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 47 (6.38%)	1 / 27 (3.70%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	5	1	0	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	4 / 47 (8.51%)	2 / 27 (7.41%)	0 / 3 (0.00%)	3 / 42 (7.14%)	3 / 26 (11.54%)	3 / 26 (11.54%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	7	0	2	0	5	4	0	3	8	9	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	3 / 7 (42.86%)	0 / 8 (0.00%)	4 / 12 (33.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	7 / 47 (14.89%)	5 / 27 (18.52%)	0 / 3 (0.00%)	16 / 42 (38.10%)	2 / 26 (7.69%)	6 / 26 (23.08%)	4 / 43 (9.30%)	0 / 3 (0.00%)	6 / 21 (28.57%)	1 / 2 (50.00%)
occurrences all number	0	1	4	0	23	0	0	10	18	0	59	2	24	6	0	20	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	2 / 7 (28.57%)	2 / 8 (25.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	6 / 47 (12.77%)	1 / 27 (3.70%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	1 / 3 (33.33%)	6 / 21 (28.57%)	1 / 2 (50.00%)
occurrences all number	0	2	3	4	0	2	1	12	1	0	0	0	0	0	1	8	2
Headache
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	3 / 12 (25.00%)	2 / 3 (66.67%)	1 / 7 (14.29%)	13 / 47 (27.66%)	6 / 27 (22.22%)	0 / 3 (0.00%)	10 / 42 (23.81%)	8 / 26 (30.77%)	9 / 26 (34.62%)	8 / 43 (18.60%)	2 / 3 (66.67%)	4 / 21 (19.05%)	0 / 2 (0.00%)
occurrences all number	0	1	1	2	3	2	1	26	40	0	19	9	32	15	2	7	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	3 / 7 (42.86%)	3 / 8 (37.50%)	1 / 12 (8.33%)	2 / 3 (66.67%)	5 / 7 (71.43%)	15 / 47 (31.91%)	8 / 27 (29.63%)	2 / 3 (66.67%)	13 / 42 (30.95%)	5 / 26 (19.23%)	11 / 26 (42.31%)	13 / 43 (30.23%)	1 / 3 (33.33%)	9 / 21 (42.86%)	0 / 2 (0.00%)
occurrences all number	1	0	3	12	1	5	7	38	17	2	35	9	32	34	1	38	0
Iron deficiency anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	1 / 42 (2.38%)	1 / 26 (3.85%)	2 / 26 (7.69%)	1 / 43 (2.33%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	2	1	0	12	3
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 47 (6.38%)	2 / 27 (7.41%)	1 / 3 (33.33%)	7 / 42 (16.67%)	3 / 26 (11.54%)	4 / 26 (15.38%)	0 / 43 (0.00%)	0 / 3 (0.00%)	8 / 21 (38.10%)	1 / 2 (50.00%)
occurrences all number	0	1	0	3	0	0	0	7	2	1	51	4	26	0	0	72	10
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	31 / 47 (65.96%)	11 / 27 (40.74%)	0 / 3 (0.00%)	8 / 42 (19.05%)	4 / 26 (15.38%)	10 / 26 (38.46%)	15 / 43 (34.88%)	2 / 3 (66.67%)	7 / 21 (33.33%)	1 / 2 (50.00%)
occurrences all number	0	0	0	3	0	0	0	152	49	0	58	5	68	83	15	33	1
Thrombocytopenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 47 (10.64%)	3 / 27 (11.11%)	0 / 3 (0.00%)	10 / 42 (23.81%)	1 / 26 (3.85%)	3 / 26 (11.54%)	2 / 43 (4.65%)	2 / 3 (66.67%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	1	0	0	1	1	0	0	8	4	0	42	1	8	2	2	7	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 7 (14.29%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	1	2	1	0	0	0	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	2 / 7 (28.57%)	2 / 8 (25.00%)	1 / 12 (8.33%)	3 / 3 (100.00%)	2 / 7 (28.57%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	11 / 42 (26.19%)	3 / 26 (11.54%)	5 / 26 (19.23%)	4 / 43 (9.30%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	2	5	1	9	2	0	0	0	12	4	6	6	0	3	0
Abdominal pain upper
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	3 / 47 (6.38%)	1 / 27 (3.70%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	1	0	1	2	0	2	0	4	1	0	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	3	0	0	1	0	2	0	0	0	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	2 / 5 (40.00%)	1 / 4 (25.00%)	2 / 7 (28.57%)	4 / 8 (50.00%)	1 / 12 (8.33%)	3 / 3 (100.00%)	1 / 7 (14.29%)	6 / 47 (12.77%)	3 / 27 (11.11%)	0 / 3 (0.00%)	15 / 42 (35.71%)	5 / 26 (19.23%)	5 / 26 (19.23%)	3 / 43 (6.98%)	0 / 3 (0.00%)	5 / 21 (23.81%)	0 / 2 (0.00%)
occurrences all number	2	1	5	4	1	8	1	12	3	0	20	6	6	6	0	5	0
Diarrhoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 7 (14.29%)	6 / 47 (12.77%)	3 / 27 (11.11%)	1 / 3 (33.33%)	10 / 42 (23.81%)	5 / 26 (19.23%)	8 / 26 (30.77%)	11 / 43 (25.58%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	1	0	2	3	1	1	1	26	3	1	15	5	13	20	0	6	1
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 47 (10.64%)	1 / 27 (3.70%)	0 / 3 (0.00%)	4 / 42 (9.52%)	2 / 26 (7.69%)	2 / 26 (7.69%)	1 / 43 (2.33%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	5	1	0	6	2	2	1	0	0	0
Flatulence
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	1 / 12 (8.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 5 (40.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	2 / 5 (40.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	4 / 8 (50.00%)	5 / 12 (41.67%)	3 / 3 (100.00%)	0 / 7 (0.00%)	24 / 47 (51.06%)	8 / 27 (29.63%)	0 / 3 (0.00%)	21 / 42 (50.00%)	13 / 26 (50.00%)	9 / 26 (34.62%)	8 / 43 (18.60%)	1 / 3 (33.33%)	12 / 21 (57.14%)	1 / 2 (50.00%)
occurrences all number	3	1	4	8	13	6	0	90	10	0	45	22	36	64	1	29	1
Vomiting
subjects affected / exposed	2 / 5 (40.00%)	2 / 4 (50.00%)	2 / 7 (28.57%)	4 / 8 (50.00%)	5 / 12 (41.67%)	3 / 3 (100.00%)	0 / 7 (0.00%)	13 / 47 (27.66%)	3 / 27 (11.11%)	1 / 3 (33.33%)	15 / 42 (35.71%)	8 / 26 (30.77%)	10 / 26 (38.46%)	4 / 43 (9.30%)	2 / 3 (66.67%)	8 / 21 (38.10%)	2 / 2 (100.00%)
occurrences all number	4	2	2	10	9	14	0	29	3	1	27	13	23	49	2	13	2
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 47 (2.13%)	3 / 27 (11.11%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	2	2	0	4	1	3	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	3 / 27 (11.11%)	3 / 3 (100.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	9	4	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	3 / 7 (42.86%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 47 (8.51%)	2 / 27 (7.41%)	0 / 3 (0.00%)	3 / 42 (7.14%)	5 / 26 (19.23%)	6 / 26 (23.08%)	4 / 43 (9.30%)	0 / 3 (0.00%)	3 / 21 (14.29%)	0 / 2 (0.00%)
occurrences all number	0	3	4	0	1	0	0	9	7	0	6	6	8	5	0	5	0
Rash
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 47 (10.64%)	3 / 27 (11.11%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	6	3	0	0	0	0	0	0	0	0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	1	1	0	1	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	3 / 12 (25.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	4 / 47 (8.51%)	2 / 27 (7.41%)	0 / 3 (0.00%)	8 / 42 (19.05%)	8 / 26 (30.77%)	5 / 26 (19.23%)	2 / 43 (4.65%)	0 / 3 (0.00%)	4 / 21 (19.05%)	0 / 2 (0.00%)
occurrences all number	0	0	0	1	4	4	0	7	2	0	24	10	7	3	0	5	0
Arthralgia
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)	0 / 7 (0.00%)	7 / 47 (14.89%)	3 / 27 (11.11%)	1 / 3 (33.33%)	7 / 42 (16.67%)	2 / 26 (7.69%)	4 / 26 (15.38%)	4 / 43 (9.30%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	2	0	1	2	3	3	0	19	8	1	9	2	6	7	0	10	1
Back pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 7 (28.57%)	7 / 47 (14.89%)	2 / 27 (7.41%)	0 / 3 (0.00%)	6 / 42 (14.29%)	3 / 26 (11.54%)	7 / 26 (26.92%)	7 / 43 (16.28%)	1 / 3 (33.33%)	4 / 21 (19.05%)	0 / 2 (0.00%)
occurrences all number	0	0	2	0	1	0	2	7	2	0	7	3	26	15	1	4	0
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	2 / 27 (7.41%)	0 / 3 (0.00%)	2 / 42 (4.76%)	1 / 26 (3.85%)	3 / 26 (11.54%)	3 / 43 (6.98%)	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	5	6	0	7	1	3	7	0	1	0
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	4 / 42 (9.52%)	1 / 26 (3.85%)	2 / 26 (7.69%)	1 / 43 (2.33%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	6	1	5	1	0	5	0
Pain in extremity
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 47 (6.38%)	1 / 27 (3.70%)	0 / 3 (0.00%)	7 / 42 (16.67%)	0 / 26 (0.00%)	2 / 26 (7.69%)	3 / 43 (6.98%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	1	0	1	4	1	0	0	14	1	0	9	0	6	4	0	11	0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	3 / 27 (11.11%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	3	0	0	0	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	3 / 21 (14.29%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	2	0	0	0	5	1
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 47 (4.26%)	3 / 27 (11.11%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	3	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 47 (6.38%)	3 / 27 (11.11%)	1 / 3 (33.33%)	3 / 42 (7.14%)	1 / 26 (3.85%)	3 / 26 (11.54%)	5 / 43 (11.63%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	0	0	0	0	0	0	0	3	4	1	9	3	4	8	0	6	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 5 (20.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	1 / 12 (8.33%)	1 / 3 (33.33%)	2 / 7 (28.57%)	11 / 47 (23.40%)	7 / 27 (25.93%)	0 / 3 (0.00%)	13 / 42 (30.95%)	3 / 26 (11.54%)	13 / 26 (50.00%)	2 / 43 (4.65%)	1 / 3 (33.33%)	6 / 21 (28.57%)	0 / 2 (0.00%)
occurrences all number	1	1	1	3	1	1	4	21	7	0	15	3	15	5	2	6	0
Dehydration
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	3 / 42 (7.14%)	2 / 26 (7.69%)	1 / 26 (3.85%)	0 / 43 (0.00%)	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 2 (50.00%)
occurrences all number	1	0	1	1	0	0	0	0	0	0	4	2	1	0	0	6	1
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	0 / 42 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)	0 / 43 (0.00%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	1	0	2	0	0	1	0	0	0	0	0	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	1 / 3 (33.33%)	2 / 42 (4.76%)	1 / 26 (3.85%)	3 / 26 (11.54%)	3 / 43 (6.98%)	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	14	1	5	4	0	2	0
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 47 (0.00%)	0 / 27 (0.00%)	0 / 3 (0.00%)	5 / 42 (11.90%)	0 / 26 (0.00%)	2 / 26 (7.69%)	1 / 43 (2.33%)	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	15	0	5	1	0	0	0
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 47 (2.13%)	4 / 27 (14.81%)	0 / 3 (0.00%)	4 / 42 (9.52%)	4 / 26 (15.38%)	2 / 26 (7.69%)	1 / 43 (2.33%)	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 2 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	7	0	5	5	2	1	0	2	0
Myalgia
subjects affected / exposed	1 / 5 (20.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	5 / 47 (10.64%)	3 / 27 (11.11%)	0 / 3 (0.00%)	6 / 42 (14.29%)	1 / 26 (3.85%)	3 / 26 (11.54%)	1 / 43 (2.33%)	0 / 3 (0.00%)	1 / 21 (4.76%)	1 / 2 (50.00%)
occurrences all number	1	0	1	3	0	2	0	18	3	0	13	1	3	1	0	1	6

More information

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Were there any global substantial amendments to the protocol? Yes

13 Oct 2015

Protocol Version 2: • Updated the Schedule of Assessments and study visits for PK and extent of disease assessment. • Further clarified the definition and criteria for DLTs. • Further clarified additional dose escalations via formal protocol amendment, if required.

10 Feb 2016

Protocol Version 3: • Updated the number of subjects planned for Part B to 84 (21 subjects in each of the 4 cohorts). • Modified the nemvaleukin dosing schedule in Cycle 1 to permit the closest possible matching of exposure for nemvaleukin as compared with IL-2 during Days 1 to 28. • Updated the RCC tumor type to include 2 cohorts (subjects who received prior treatment with anti-PD-1 or anti-PD-L1 therapy and subjects who received no prior checkpoint inhibitor therapy). • Deleted the NSCLC, bladder cancer, and triple negative breast cancer from solid tumor types to be studied. • Clarified study procedures.

11 Oct 2016

Protocol Version 4: • Revised or clarified inclusion criteria #4 and #10 and exclusion criterion #7. • Removed PD according to both irRC and RECIST from the reasons for withdrawal or discontinuation from study and added clinical progression as a criterion. The protocol then stated that PD (according to irRC), or clinical progression (worsening of symptoms or declining performance status), would result in subject discontinuation. • Revised the DLT definition from “febrile neutropenia” to “Grade 3 febrile neutropenia (ie, ANC <1,000/mm^3 with a single temperature >38.3°C [101°F] or a sustained temperature of >=38°C [100.4°F] for more than 1 hour).” • Clarified throughout the document that all 16-hour PK and cytokine samples and Day 6 (ie, Day 5, 24-hour) PK samples were optional. • Added language and guidance around intrapatient dose escalation. • Added details regarding determination of sample size for Part B, based on methodology described by Simon regarding optimal 2-stage designs for Phase 2 trials. Also added details regarding uninteresting and desirable response rates, number of subjects, and number of responders needed for Part B.

08 Jun 2017

Protocol Version 5: • Increased number of subjects enrolled from 6 to 7, in Cohorts 3 and beyond of Part A, and increased number of participating sites from “3 to 8 in the US” to “up to 20 in North America”. • Clarified that the minimum number of DLT-evaluable subjects for Part A remained at 6. • Clarified that subjects deemed not evaluable for DLTs in Part A of the study could be replaced, resulting in enrollment beyond the 7 subjects planned in each cohort. • Included analysis of CA125 tumor marker in serum chemistry panel for ovarian cancer subjects only. The Schedule of Assessments and serum chemistry panel were updated accordingly. • Corrected the definition of PK and Pharmacodynamics Populations.

06 Oct 2017

Protocol Version 6: • Two DLT criteria were revised in order to more clearly define what would pose a true risk to subjects who experienced AEs meeting these criteria; Grade 4 hypoalbuminemia was added as a DLT criterion. • Restrictions around pretreatment with certain medications beginning on Cycle 1 Day 1 were revised. • Clarified the reporting period for SAEs and pregnancies, and clarified language around the permissible length of cycle delay for AE resolution. • Revised dose levels (added 6 mcg/kg and 15 mcg/kg, and removed 30 mcg/kg).

20 Dec 2017

Protocol Version 7: • Clarified DLT criteria for Grade 4 neutropenia and for febrile neutropenia. • Added language detailing the hospitalization and monitoring of subjects who experienced Grade 4 neutropenia or Grade 3 febrile neutropenia. • Included language around the recording of results from microbiology specimens that were cultured to investigate potential infections.

12 Jan 2018

Protocol Version 8: • Clarified that Grade 4 neutropenia requiring hospitalization was specific to instances of Grade 4 neutropenia where ANC <100/mm^3. • Included language allowing for the outpatient treatment of subjects who experienced Grade 4 neutropenia if ANC was between 100 and 500/mm^3.

22 May 2018

Protocol Version 9: • A Part C dose-expansion cohort was added to explore administration of nemvaleukin in combination with a PD-1 inhibitor (pembrolizumab). The implementation of combination therapy included a safety lead-in of 3 to 6 subjects at a dose that was adequately tolerated in a monotherapy setting for nemvaleukin (1 mcg/kg). Revisions were made to indicate that once safety was demonstrated, an expanded number of subjects were to be enrolled at an increased dose level of nemvaleukin (3 mcg/kg). Both nemvaleukin dose levels were to be administered in combination with pembrolizumab, and pembrolizumab was to be used in accordance with the FDA-approved label. • Revisions were made to indicate that the ovarian and immunotherapy treatment-naïve renal cell carcinoma expansion cohorts in Part B would no longer be explored, and ovarian carcinoma would be included in a Part C cohort in combination with pembrolizumab.

09 Aug 2018

Protocol Version 10: • The DLT criteria were revised to reflect the investigators' opinions and to bring the definitions in line with other cytokine-based agents in development. • The timeframe for administration of nemvaleukin after completion of the pembrolizumab infusion in Part C was adjusted to a range, rather than a specific amount of time, to provide greater flexibility in the timing of nemvaleukin administration and prevent unnecessary protocol deviations due to overly specific dosing instructions. • Further explanation of the definition and considerations surrounding AEs was included.

01 May 2019

Protocol Version 11: • Updated the global reach of the study, sample size, inclusion and exclusion criteria, study requirements and restrictions, schedules of procedures and assessments, study objectives and endpoints, methodology, planned statistical analyses to be used during and after the study, and types of tumors being studied.

20 Feb 2020

Protocol Version 12: • Clarified primary objectives for Part B and specified that antitumor activity would be characterized by ORR for Parts B and C; and clarified that the incidence and severity of AEs was a primary endpoint in all 3 parts of the study. • Additional inclusion criteria for Part B melanoma and RCC expansion cohorts specified the allowed prior therapies. • Exclusion criteria were updated to include clarifications on prior therapies and treatments, exclusionary conditions, and exclusion due to association with the site or Sponsor/CRO. • Added 12 and 14 mcg/kg dose levels (Cohorts 8 and 9) to Part A. • Updated assessments for blood-based biomarkers and added circulating tumor DNA assessment. • Updates to reflect changes in sample size calculation. • Clarified study procedures.

08 Sep 2022

Protocol Version 13: • The addition of an Extension Phase (aimed at assessing long-term effectiveness and safety, while minimizing the burden of repeated assessments), including the definition of procedures and clarification of treatment duration, for subjects completing or who had completed 1 year of treatment in Part B or in Part C of the 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

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of ALKS 4230 Administered Intravenously as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors –ARTISTRY-1

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Number of Subjects With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE)

Primary: Part A: Number of Subjects With Dose-limiting Toxicities (DLTs) Based on Common Terminology Criteria for Adverse Events (CTCAE)

Primary: Parts A, B, and C: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Parts A, B, and C: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

Primary: Parts A, B, and C: Number of Subjects With TEAEs by Severity Grading

Primary: Parts A, B, and C: Number of Subjects With TEAEs by Severity Grading

Primary: Parts B and C: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Primary: Parts B and C: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Secondary: Parts A and B: Serum Concentrations of Nemvaleukin Alfa

Secondary: Parts A and B: Serum Concentrations of Nemvaleukin Alfa

Secondary: Parts C: Serum Concentrations of Nemvaleukin Alfa

Secondary: Parts C: Serum Concentrations of Nemvaleukin Alfa

Secondary: Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa

Secondary: Parts A, B and C: Area Under Concentration From Time Zero to the Last Quantifiable Concentration (AUClast) of Nemvaleukin Alfa

Secondary: Parts A, B and C: Maximum Observed Serum Concentration (Cmax) of Nemvaleukin Alfa

Secondary: Parts A, B and C: Maximum Observed Serum Concentration (Cmax) of Nemvaleukin Alfa

Secondary: Parts A, B and C: Time to Reach Cmax (Tmax) of Nemvaleukin Alfa

Secondary: Parts A, B and C: Time to Reach Cmax (Tmax) of Nemvaleukin Alfa

Secondary: Parts A, B, and C: Proportion of Positive Anti-Nemvaleukin Alfa Antibodies (ADA)

Secondary: Parts A, B, and C: Proportion of Positive Anti-Nemvaleukin Alfa Antibodies (ADA)

Secondary: Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)

Secondary: Parts A, B, and C: Immune ORR (iORR) Based on Immune RECIST (iRECIST)

Secondary: Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1

Secondary: Parts A, B, and C: Disease Control Rate (DCR) Based on RECIST v.1.1

Secondary: Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1

Secondary: Parts A, B, and C: Immune DCR (iDCR) Based on iRECIST v1.1

Secondary: Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1

Secondary: Parts B, and C: Duration of Response (DOR) Based on RECIST v1.1

Secondary: Parts B, and C: Immune DOR (iDOR) Based on iRECIST

Secondary: Parts B, and C: Immune DOR (iDOR) Based on iRECIST

Secondary: Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1

Secondary: Part B and Part C Cohorts C5, C6, C7: Durable Response Rate (DRR) Based on RECIST v.1.1

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune DRR (iDRR) Based on iRECIST

Secondary: Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1

Secondary: Part B and Part C Cohorts C5, C6, C7: Progression-free Survival (PFS) Based on RECIST v.1.1

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS)

Secondary: Part B and Part C Cohorts C5, C6, C7: Immune PFS (iPFS)

Secondary: Parts A, B and C: Maximum Cell Count of Whole Blood FoxP3+ T Cells (Tregs), Total Cluster of Differentiation (CD)8+ T Cells and Natural Killer (NK) Cells

Secondary: Parts A, B and C: Maximum Cell Count of Whole Blood FoxP3+ T Cells (Tregs), Total Cluster of Differentiation (CD)8+ T Cells and Natural Killer (NK) Cells

Secondary: Parts A, B and C: Maximum Cell Count of Interferon-gamma (INF-γ) and Interleukin 6 (IL-6)

Secondary: Parts A, B and C: Maximum Cell Count of Interferon-gamma (INF-γ) and Interleukin 6 (IL-6)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 Study of ALKS 4230 Administered Intravenously as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors –ARTISTRY-1