Conditions: Ovarian Cancer
Keywords: Avelumab Carboplatin Primary Peritoneal Cancer Fallopian Tube Cancer Platinum sensitive ovarian cancer Deoxy ribonucleic acid (DNA)-damage response inhibition
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The study was to evaluate the efficacy and safety of avelumab in combination with M6620 + carboplatin in participants with PARPi-resistant, recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer.

Detailed description:
The study was intended to be a phase Ib/II trial, but after completing Phase 1b and confirming the safe combination dose, the sponsor decided not to conduct Phase II.

Arms:
arm 1: None

Interventions: intervention 1: M6620 intervention 2: Avelumab intervention 3: Carboplatin
Intervention descriptions: intervention 1: Participants received 90 milligrams per square meter (mg/m\^2) of M6620, intravenously (IV) on Day 2 of every 3 weeks (Q3W) cycle for a maximum of 6 cycles in combination treatment with carboplatin and avelumab on Day 1. The M6620 dose may be de-escalated to 60 mg/m\^2, or 40 mg/m\^2. intervention 2: Participants received IV infusion of avelumab 1600 mg on Day 1 of each Q3W cycle for maximum of 6 cycles in combination treatment with carboplatin and M6620. Thereafter, avelumab 800 mg intravenously on Day 1 of every two weeks as a maintenance mono-therapy until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. intervention 3: Participants received carboplatin area under the concentration-time curve 5 on Day 1 of each Q3W cycle for a maximum of 6 cycles in combination treatment with avelumab and M6620.

Protocol document:
Prot_000.pdf: 
Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant
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Ovarian Cancer
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Phase Ib Safety Run-in and Randomized 
Phase
II, Open-label Study to Evaluate the 
Efficacy, 
Safety,
Tolerability, 
and 
Pharmacokinetics of M6620 in Combination with 
Avelumab and Carboplatin in Comparison to 
Standard of Care Therapy in Participants with 
PARPi-resistant
Recurrent 
Ovarian, 
Primary 
Peritoneal, or Fallopian Tube Cancer
Study Number:
MS201943-0029
Amendment Number
Amendment 2
Merck Compound Number:
G.20194301
Short Title:
Phase Ib/II Study of Carboplatin + M6620 + 
Avelumab in PARPi-resistant Ovarian Cancer
Coordinating Investigator:
 
Telephone 
: 
Telephone 
: 
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Sponsor Name and Legal Registered 
Address:
For all countries except the US: 
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
In the US: 
EMD Serono Research & Development 
Institute, Inc.
An affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike 
Billerica, MA 01821-3936, USA
Medical Responsible:
 
Merck KGaA
Frankfurter Str. 250
64293 Darmstadt, Germany
Post code: 
Phone:
Fax:
Sponsor Legal Representative in the 
European Union:
Merck KGaA
Frankfurter Str. 250
64293 Darmstadt, Germany
Regulatory 
Agency 
Identifying 
Numbers:
EudraCT # 2018-001534-17
US IND # 
Protocol Version:
30 Nov 2018/Version 2.0
Replaces Version:
24 Jul 2018/Version 1.0
Approval Date:
30 Nov 2018
Medical Monitor Name and Contact 
Information:
 (mobile)
 (landline)
mailto: 
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
24 Jul 2018
1.1-BEL
Local Protocol Amendment
06 Nov 2018
2.0
Global Protocol Amendment
30 Nov 2018
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
In general, this global amendment incorporates clarifications and changes to allow investigative 
sites additional ease in enrolling and adhering to the protocol.
Section # and 
Name
Description of Change
Brief Rationale
Title Page
“Phase 1b Safety Run-in” was added to the 
study title
The title now reflects the Part A, Phase 1b 
Safety Run-in portion of the trial which was 
previously not included.
Throughout, 
where 
applicable
The order of study drugs was modified
where applicable to carboplatin + M6620 + 
avelumab therapy. Avelumab maintenance 
therapy compared to the standard of care 
(SoC) now includes optional bevacizumab 
(that is platinum-containing chemotherapy 
with optional bevacizumab).
To establish consistent study intervention 
naming conventions throughout the 
document, where applicable.
Synopsis and 
Section 3: 
Objectives and 
Endpoints 
(Parts A and B)
Deleted irRECIST for response assessment.
Assessment by CA-125 and RECIST is 
relevant for ovarian cancer and irRECIST was 
not necessary given that prior trials with 
avelumab do not identify any clinically 
relevant differences in irRECIST compared to 
RECIST v1.1.
Synopsis and 
Section 3:
Objectives and 
Endpoints 
(Part A only)
Deleted secondary objective to characterize 
immunogenicity.
Part A is expected to have as few as 
3 participants and up to 18 participants; given 
the low rate of immunogenicity observed in 
other avelumab trials, it is unlikely to reliably 
characterize immunogenicity from only Part A 
participants. The Part B objective to 
characterize immunogenicity will include all 
participants treated with avelumab from both
Parts A or B. 
Tables 1, 2, 
and 3: 
Schedule of 
Assessments
Added clarifying language for evaluating 
progression as per GCIG guidelines.
To provide clarification of guidelines for 
response/progression.
Synopsis Study 
Intervention 
Groups and 
Section 6
Clarification that after a completion of 
6 cycles, participants will continue in 
maintenance treatment with avelumab 
(800 mg every 2 weeks as monotherapy) 
until PD, unacceptable toxicity, withdrawal of 
consent, death, or a minimum of 12 months 
of treatment following confirmed CR.
For consistency with other avelumab 
monotherapy protocols.
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Section # and 
Name
Description of Change
Brief Rationale
Synopsis Study 
Intervention 
Groups and 
Section 6
Added SoC option: carboplatin AUC 5 on 
Day 1 + pegylated liposomal doxorubicin 
(PLD) 30 mg/m2 every 4 weeks for up to 
6 cycles with or without bevacizumab.
To address the concern that participants may 
not be eligible to receive paclitaxel or 
gemcitabine as part of a 3rd line or later 
carboplatin combination therapy, given that 
participants may have received these other 
agents earlier.
Synopsis Study 
Intervention 
Groups and 
Section 6
Added that the recommended dosage for the 
SoC regimen may be adapted per 
Investigator discretion and in accordance to 
the local institutional guidelines.
To provide allowance for the Investigator to 
adjust the starting dose of either the 
carboplatin or combination chemotherapy 
agent, given that some participants may not 
be able to tolerate the usual recommended 
dose if they have previously received the 
agents.
Section 5.1: 
Inclusion 
Criteria
Reduced minimum time of prior PARPi 
treatment from at least 6 to 4 months.
Following discussions with investigators, it 
was recommended to reduce the minimum 
time of PARPi treatment to at least 4 months 
as sufficient minimum treatment to evaluate 
PARP resistance and to reduce screen 
failures due to PARP treatment time without 
impacting ability to evaluate treatment in 
patients with PARP resistance aligned with
the rationale for the combination treatment.
Section 5.1: 
Inclusion 
Criteria
Made the Part A two (2) paired biopsies 
optional instead of mandatory. 
Feedback from clinical sites reported 
feasibility of paired biopsies to be very low 
and could result in difficulty recruiting 
participants to Part A of trial, given that 
pharmacodynamics is a tertiary objective and 
safety is the primary determinant to accept the 
dose
Section 5.1: 
Inclusion 
Criteria and 
Appendix 3
Contraception criteria was changed to: 
Contraception from 1 menstrual cycle before 
the cycle preceding the start of the first dose 
during the study intervention period (Parts A 
and B), and for at least 6 months after the 
last dose of carboplatin, M6620 or the 
defined SoC combination treatments, or at 
least 60 days after the last dose of 
maintenance with avelumab or 
bevacizumab, whichever is later.
To bring the protocol into alignment with the 
SmPC for carboplatin and defined SoC 
combination treatments, as well as the M6620 
IB, which specify to continue contraception for 
at least 6 months after the last treatment.
Section 5.3.1: 
Meals and 
Dietary 
Restrictions
Deleted restrictions on food and beverages 
and specified no restrictions on meals or 
diet.
Deleted food and beverage restrictions 
because M6620 is administered intravenously 
and will not be affected by food and 
beverages.
Section 6.3.2: 
Blinding
Added the following sentence: However, any 
aggregate summary of data, if required, will 
be provided only in a blinded way during the 
study, to limit bias in the conduct of the 
study.
To further protect study integrity.
Section 6.6.1: 
Definition of 
Dose-limiting 
Toxicity
The definition of a DLT was clarified to:
To provide clarification of when an IRR is a 
DLT.
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Section # and 
Name
Description of Change
Brief Rationale
“…any death not clearly due to the 
underlying disease or extraneous causes or 
any ≥Grade 3 nonhematologic or ≥Grade 4 
hematologic toxicity that is possibly, 
probably, or definitely related to any of the 
study interventions…except for any of the 
following:
-
Grade 3 infusion-related reaction 
resolving within 6 hours from the end of 
infusion and controlled with medical 
management.
Section 6.11: 
Management of 
Adverse Events 
of Interest 
(Avelumab)
Clarified that infusion-related reactions and 
irAEs should be handled according to the 
2018 ASCO guidelines.
To clarify source of current guidance for
management of infusion-related reactions and 
irAEs.
Section 8.2.5: 
Safety and 
Data Monitoring 
Committees
Added:
“For Part B, a data monitoring committee 
(IDMC) will be constituted by Sponsor’s 
members independent from the project team 
and if needed may include external medical 
expert to regularly review the data in Part B of 
the study to ensure safety of the participants 
as well validity and integrity of the study. The 
participants, data reporting details and 
specific working procedures will be defined in
the DMC charter prior to start of enrollment in 
Part B.”
To ensure integrity of the trial data by 
including a Data Monitoring Committee 
consisting of internal Sponsor staff not 
associated with the clinical study to review 
data during Part B of the study.
Throughout
Minor editorial and document formatting 
revisions.
Minor; therefore, have not been summarized.
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Protocol History
..............................................................................................................3
Table of Contents
..............................................................................................................6
Table of Tables
............................................................................................................10
Table of Figures
............................................................................................................11
1
Protocol Summary ..............................................................................12
1.1
Synopsis..............................................................................................12
1.2
Schema................................................................................................15
1.3
Schedule of Activities.........................................................................17
2
Introduction.........................................................................................38
2.1
Study Rationale...................................................................................38
2.2
Background.........................................................................................38
2.3
Benefit/Risk Assessment ....................................................................41
3
Objectives and Endpoints ...................................................................42
3.1
Part A..................................................................................................42
3.2
Part B ..................................................................................................43
4
Study Design.......................................................................................44
4.1
Overall Design....................................................................................44
4.2
Scientific Rationale for Study Design ................................................46
4.3.1
M6620.................................................................................................46
4.3.2
Avelumab............................................................................................48
4.3.3
Reference Treatment: Standard of Care .............................................49
4.4
End of Study Definition......................................................................49
5
Study Population.................................................................................49
5.1
Inclusion Criteria ................................................................................50
5.2
Exclusion Criteria...............................................................................52
5.3
Lifestyle Considerations .....................................................................56
5.3.1
Meals and Dietary Restrictions...........................................................56
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5.3.2
Caffeine, Alcohol, and Tobacco .........................................................56
5.3.3
Sun/UV Light Exposure .....................................................................56
5.3.4
Activity ...............................................................................................56
5.4
Screen Failures....................................................................................56
6
Study Interventions.............................................................................56
6.1
Study Interventions Administration....................................................57
6.2
Study Interventions Preparation, Handling, Storage, and 
Accountability.....................................................................................59
6.2.1
Avelumab............................................................................................60
6.2.2
M6620.................................................................................................61
6.2.3
Carboplatin .........................................................................................61
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................61
6.3.1
Study Intervention Assignment ..........................................................61
6.3.2
Blinding ..............................................................................................61
6.4
Study Intervention Compliance..........................................................61
6.5
Concomitant Therapy .........................................................................62
6.5.1
Rescue Medicine.................................................................................62
6.5.2
Permitted Medicines...........................................................................62
6.5.2.1
Prophylactic Medications and Treatments..........................................63
6.5.3
Prohibited Medicines..........................................................................63
6.5.4
Other Interventions.............................................................................64
6.6
Dose Selection and Modification........................................................64
6.6.1
Definition of Dose-limiting Toxicity..................................................66
6.7
Study Intervention Beyond Progression .............................................66
6.7.1
Treatment Beyond Initial Progression................................................66
6.7.2
Treatment Beyond Confirmed Progression ........................................67
6.8
Continuation of Study Intervention After Local Treatment of 
Disease Progression............................................................................67
6.9
Study Intervention After the End of the Study...................................68
6.10
Special Precautions.............................................................................68
6.10.1
Avelumab............................................................................................68
6.10.2
M6620.................................................................................................69
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6.10.3
Carboplatin .........................................................................................69
6.10.4
Standard of Care Treatment................................................................69
6.11
Management of Adverse Events of Interest........................................70
6.11.1
Avelumab............................................................................................70
6.11.2
M6620.................................................................................................71
6.11.3
Carboplatin .........................................................................................73
6.11.4
Standard of Care Treatment................................................................73
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................73
7.1
Discontinuation of Study Interventions..............................................73
7.1.1
Temporary Discontinuation................................................................74
7.2
Participant Discontinuation/Withdrawal from the Study ...................75
7.3
Lost to Follow-up ...............................................................................75
8
Study Assessments and Procedures....................................................76
8.1
Efficacy Assessments and Procedures................................................76
8.1.1
Tumor Response Assessment .............................................................76
8.1.2
Response Evaluation Based on CA-125 According to Gynecologic 
Cancer Intergroup Recommendations ................................................78
8.1.3
Survival Follow-up .............................................................................78
8.1.4
Patient-reported Outcomes .................................................................79
8.1.4.1
EORTC QLQ-30.................................................................................79
8.1.4.2
EORTC QLQ-OV28...........................................................................80
8.1.4.3
Patient Global Impression of Severity................................................80
8.2
Safety Assessments and Procedures ...................................................80
8.2.1
Physical Examinations........................................................................80
8.2.2
Vital Signs ..........................................................................................81
8.2.3
Electrocardiograms.............................................................................81
8.2.4
Clinical Safety Laboratory Assessments ............................................82
8.2.5
Safety and Data Monitoring Committees ...........................................83
8.3
Adverse Events and Serious Adverse Events.....................................83
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................84
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...84
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8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............84
8.3.3.1
Monitoring of Specific Adverse Events .............................................85
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....85
8.3.5
Pregnancy ...........................................................................................86
8.4
Treatment of Overdose .......................................................................86
8.5
Pharmacokinetics................................................................................87
8.9
Medical Resource Utilization and Health Economics........................95
8.10
Immunogenicity Assessments ............................................................95
9
Statistical Considerations....................................................................95
9.1
Statistical Hypotheses.........................................................................96
9.2
Sample Size Determination ................................................................96
9.3
Populations for Analyses ....................................................................96
9.4
Statistical Analyses.............................................................................98
9.4.1
Efficacy Analyses ...............................................................................98
9.4.2
Safety Analyses ..................................................................................99
9.4.2.1
Adverse Events .................................................................................100
9.4.2.2
Laboratory Values ............................................................................100
9.4.3
Other Analyses..................................................................................100
9.4.3.1
Baseline Characteristics....................................................................100
9.4.3.2
Estimation of Individual PK Parameters ..........................................100
9.4.3.3
Immunogenicity Analysis.................................................................101
9.4.4
Sequence of Analyses.......................................................................101
10
References.........................................................................................101
11
Appendices .......................................................................................106
Appendix 1
Abbreviations....................................................................................107
Appendix 2
Study Governance.............................................................................110
Appendix 3
Contraception....................................................................................116
Appendix 4
Carboplatin Dosing...........................................................................118
Appendix 5
List of Selected Cytochrome P450 3A4 Inducers and Inhibitors .....119
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Appendix 6
Management of Immune-related Adverse Events ............................120
Appendix 7
Clinical Laboratory Tests .................................................................127
Appendix 8
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................128
Appendix 10
Protocol Amendment History...........................................................134
Appendix 11
Sponsor Signature Page....................................................................135
Appendix 12
Coordinating Investigator Signature Page........................................136
Appendix 13
Principal Investigator Signature Page...............................................137
Table of Tables
Table 1
Schedule of Study Procedures/Assessments (Parts A and B) –
Carboplatin- + M6620 + Avelumab (Every 3 Weeks Up to 6 
Cycles) ................................................................................................18
Table 2
Schedule of Study Procedures/Assessments (Parts A and B) –
Avelumab Maintenance Period (Every 2 Weeks Starting After the 
Last Cycle of Carboplatin-+ M6620 + Avelumab), End of 
Treatment, and Follow-up ..................................................................24
Table 3
Schedule of Study Procedures/Assessments (Part B) – Standard of 
Care (Every 3 or 4 Weeks for the First 6 Cycles), End of 
Treatment, and Follow-up ..................................................................30
Table 4
Part A Objectives and Endpoints – Carboplatin + M6620 + 
Avelumab in Recurrent PARPi-resistant Ovarian Cancer..................42
Table 5
Part B Objectives and Endpoints – Carboplatin + M6620 + 
Avelumab in Recurrent PARPi-resistant Ovarian Cancer..................43
Table 6
Summary of Safety Information for Carboplatin + M6620................47
Table 7
Overview of Study Interventions Formulation, Dosing, and 
Administration....................................................................................57
Table 8
Overview of Standard of Care Treatments Formulation, Dosing, 
and Administration .............................................................................58
Table 9
Prophylactic Medications Administered Prior to Avelumab and/or 
M6620.................................................................................................63
Table 10
Overview of Intended Study Interventions Dose and Timing of 
Treatments ..........................................................................................65
Table 11
Treatment Modification for Symptoms of Infusion-related 
Reactions Associated with Avelumab ................................................71
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Table 12
Guidelines for M6620 Dose Modification for Toxicity in 
Combination with Avelumab and Carboplatin...................................72
Table 13
Pharmacokinetics Parameters .............................................................87
Table 14
Acceptable Pharmacokinetic Sampling Windows..............................88
Table 16
Population Analysis Sets ....................................................................97
Table 17
Statistical Analysis Methods for Efficacy Endpoints, Part B.............99
Table 18
Statistical Analysis Methods for Safety Endpoints ............................99
Table 19
Management of Immune-related Adverse Events ............................120
Table 20
Protocol-required Clinical Laboratory Assessments ........................127
Table of Figures
Figure 1
Overall Study Design Schema............................................................15
Figure 2
Part A: Safety Run-in..........................................................................16
Figure 3
Part B: Randomized Study Intervention Versus Standard of Care.....16
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Phase Ib Safety Run-in and Randomized Phase II, Open-label Study to Evaluate 
the Efficacy, Safety, Tolerability, and Pharmacokinetics of M6620 in Combination with Avelumab
and Carboplatin in Comparison to Standard of Care Therapy in Participants with PARPi-resistant 
Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancer
Short Title: Phase Ib/ II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant Ovarian
Cancer
Rationale: The purpose of Study MS201943-0029 is to evaluate the safety of the recommended 
Phase II dose (RP2D) of carboplatin +M6620 (doublet) when used in combination with avelumab 
(Part A; triplet) and the efficacy and safety of carboplatin + M6620 + avelumab therapy with 
avelumab maintenance compared to the standard of care (SoC; platinum-containing doublet 
chemotherapy with optional bevacizumab) (Part B) in participants with recurrent ovarian, primary 
peritoneal, or fallopian tube cancer who have progressed on a poly (ADP-ribose) polymerase 
inhibitor (PARPi). Given that PARPi-resistant recurrent ovarian cancer with expected platinum 
sensitivity is associated with a high mutational load and homologous recombination deficiency, 
the combination treatment of a deoxyribonucleic acid (DNA)-damaging agent (carboplatin) with 
a DNA damage response inhibitor (DDRi; M6620) and an immune checkpoint inhibitor 
(avelumab) is expected to synergize and lead to insufficient DNA repair, increased DNA
mutations, immunologic cell death, and an increase in potential immunological targets within the 
tumor.
Objectives and Endpoints:
Part A (Safety Run-in Period)
Objectives
(Part A)
Endpoints (Outcome Measures)
Primary
To evaluate a safe, tolerable RP2D of carboplatin +
M6620 in combination with avelumab in participants with 
PARPi-resistant recurrent ovarian, primary peritoneal, or 
fallopian tube cancer
Occurrence of dose-limiting toxicities (DLTs) during the 
DLT observation period
Secondary
To evaluate the safety and tolerability of carboplatin +
M6620 at the RP2D when used in combination with 
avelumab in participants with PARPi-resistant recurrent 
ovarian, primary peritoneal, or fallopian tube cancer 
Occurrence of treatment-emergent adverse events 
(TEAEs) and treatment-related adverse events (AEs) 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE)
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Objectives
(Part A)
Endpoints (Outcome Measures)
To evaluate the antitumor activity of carboplatin + M6620 
at the RP2D in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
!
Confirmed best overall response (BOR)
!
Progression-free survival (PFS) from date of first 
dose of study intervention until progressive disease 
(PD) or death
!
Duration of response (DOR) as assessed from 
complete response (CR) or partial response (PR) 
until PD, death, or last tumor assessment
!
Time to progression (TTP) from first dose of study 
intervention until PD
All the above by Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1), and/or cancer 
antigen 125 (CA-125) response (Gynecologic Cancer 
Intergroup [GCIG] criteria), as assessed by the 
Investigator.
!
Time to first subsequent therapy (TFST)
To characterize the pharmacokinetic (PK) profiles of 
avelumab and M6620 when given in combination with 
carboplatin
!
PK parameter estimates for M6620 
!
PK summary statistics for avelumab
Part B (Randomized Treatment Period)
Objectives
(Part B)
Endpoints (Outcome Measures)
Primary
To evaluate antitumor activity of carboplatin + M6620 in 
combination with avelumab compared with the standard 
of care treatment in participants with PARPi-resistant 
recurrent ovarian, primary peritoneal, or fallopian tube 
cancer
PFS according to RECIST v1.1 as assessed by the 
Investigator 
Secondary
To evaluate the safety and tolerability of carboplatin + 
M6620 at the RP2D in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of TEAEs and treatment-related AEs and 
immune-related adverse events (irAEs) according to 
NCI-CTCAE
To further evaluate antitumor activity of carboplatin + 
M6620 in combination with avelumab compared with the 
standard of care treatment
!
PFS according to GCIG CA-125 as assessed by the 
Investigator
!
Confirmed BOR according to RECIST v1.1 and
GCIG CA-125
!
DOR assessed from CR or PR until PD, death, or 
last tumor assessment
!
TTP
!
TFST
To characterize the PK of avelumab and M6620 when 
given in combination with carboplatin
!
PK parameter estimates for M6620 
!
PK summary statistics for avelumab
To characterize the immunogenicity of avelumab in 
combination with M6620 + carboplatin
Immunogenicity of avelumab in combination therapy as 
measured by ADA assay from all participants treated 
with carboplatin + M6620 + avelumab in Part A and 
Part B
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Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant
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Overall Design: This Phase Ib / II study is an open-label, randomized, controlled study consisting 
of 2 parts. Part A is a safety run-in dose de-escalation to identify a safe dose of carboplatin + 
M6620 in combination with avelumab for Part B. In Part B, participants will be randomly assigned 
to receive open-label treatment with either the triplet combination (carboplatin + M6620 + 
avelumab) or SoC (platinum-based doublet therapy with optional bevacizumab). Participants will 
be randomized (stratified by BRCA [breast cancer gene] status) to one of the treatment arms.
Number of Participants: During Part A of the study, approximately 3 to 18 participants are 
expected to be enrolled to evaluate the safe dose for the triplet combination (a modified 3 + 3 
design, but dose reductions will be considered only if necessary). 
In Part B, a total of approximately 72 participants will be enrolled. Based on 50 events for 
progression-free survival (PFS), the probability to observe a hazard ratio (HR) of 0.6 or lower is 
74% under the assumption of a true HR of 0.5; whereas, if the true HR is 0.75 (a nonrelevant effect 
regarding further development of this combination therapy for such an indication), the probability 
to observe a HR of 0.6 or lower is 21.5%, and if there is no effect (i.e., if the true HR = 1), the 
probability for an observed HR of 0.6 is 3.5%. To observe 50 PFS events, a sample size of N = 72 
(with a 1:1 randomization, stratified by BRCA status) has been chosen.
Study Intervention Groups and Duration: During Part A, participants will receive the triplet 
combination at starting doses of area under the concentration-time curve (AUC) 5 for carboplatin,
90 mg/m2 for M6620, and 1600 mg for avelumab, for up to six 3-week cycles. The M6620 dose 
may be de-escalated to 60 mg/m2, 40 mg/m2, or another dose level upon recommendations by the 
Safety Monitoring Committee. After completion of the 6-cycles participants will continue in the 
maintenance treatment with avelumab, (800 mg every 2 weeks as monotherapy) until PD, 
unacceptable toxicity, withdrawal of consent, death, or a minimum of 12 months of treatment 
following confirmed CR.
During Part B, participants will be randomly assigned to receive either carboplatin + M6620 (at 
the RP2D evaluated in Part A) in combination with avelumab or SoC treatment for up to 6 cycles.
The SoC regimen is to be chosen by the Investigator among the following options: 
! Carboplatin AUC 5 + paclitaxel 175 mg/m2 on Day 1; every 3 weeks for up to 6 cycles with or 
without bevacizumab, or 
! Carboplatin AUC 4 on Day 1 + Gemcitabine 1000 mg/m2 on Days 1 and 8; every 3 weeks for 
up to 6 cycles, with or without bevacizumab, or
! Carboplatin AUC 5 on Day 1 + pegylated liposomal doxorubicin (PLD) 30 mg/m2; every 
4 weeks for up to 6 cycles, with or without bevacizumab.
Recommended dosage for the SoC regimen may be adapted per Investigator discretion and in 
accordance to the local institutional guidelines. 
Thereafter, for those who were randomized to receive triplet study intervention (carboplatin + 
M6620 + avelumab), avelumab will be administered as maintenance therapy (800 mg 
every 2 weeks as monotherapy) until PD, unacceptable toxicity, withdrawal of consent, death, or 
minimum 12 months therapy after confirmed CR if agreed to by the participant.
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Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant
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For participants in either part (Part A and Part B), the study periods consist of a 28-day Screening 
Period, an up to 6 cycle Treatment Period (six 3-week cycles or six 4-week cycles), an avelumab 
or optional bevacizumab Maintenance Treatment Period until PD, 30-day and 90-day Safety 
Follow-up Periods after last dose of study drug, and survival follow-up.
Involvement of Special Committee(s): Safety Monitoring Committee and Data Monitoring 
Committee.
1.2
Schema
Figure 1
Overall Study Design Schema
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Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant
MS201943-0029
Ovarian Cancer
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Figure 2
Part A: Safety Run-in
AUC=area under the concentration-time curve; DL=dose level; DLT=dose-limiting toxicity; RP2D=recommended 
Phase II dose; SMC=Safety Monitoring Committee.
Figure 3
Part B: Randomized Study Intervention Versus Standard of Care
BRCA=breast cancer gene (BRCA1, BRCA2); CR=complete response; PARPi=poly (ADP-ribose) polymerase
inhibitor; PR=partial response; Q2W=every 2 weeks; Q3W=every 3 weeks; SoC=standard of care; see Section 6.1 for 
permitted regimens.
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Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant
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1.3
Schedule of Activities
A detailed schedule of study procedures and assessments are provided in Table 1 for the 6 cycles 
of combination study intervention in Parts A and B; in Table 2 for avelumab maintenance 
treatment, end of treatment, and safety follow-up in Parts A and B; and in Table 3 for SoC
treatment, end of treatment, and safety follow-up in Part B. 
All Part A and Part B procedures are permitted to be performed up to 3 days before or 1 day after 
the scheduled visit, except as otherwise noted. The treatment schedule should be strictly adhered 
to, returning to the target date for Day 1 even if the previous treatment was off schedule. 
All participants discontinuing study intervention for any reason will undergo an End of Treatment 
(EoT) Visit within 7 days after the decision to discontinue study intervention, but (if possible) 
before any new antineoplastic therapy is started. 
The 30-day Safety Follow-up Visit (± 5 days) and 90-day Safety Follow-up Phone Call (± 5 days) 
should be conducted, if possible, prior to the start of any new antineoplastic therapy. 
Participants without PD at the EoT Visit will be followed for disease progression (CT/MRI scans 
every 9 weeks, and after 6 months from randomization, every 12 weeks) or start of subsequent 
anticancer therapy, whichever comes first.
Follow-up post study treatment discontinuation includes collection of subsequent anticancer 
treatment information and long-term survival status. Survival follow-up information will be 
documented every 12 weeks until participant’s death or end of study. Progression and survival 
follow-up will continue until end of study defined as 1 year after the last participant has received 
the last dose or dies, whichever comes first.
Re-initiation of avelumab is possible for participants who experience a CR, discontinue treatment, 
progress, and later re-initiate treatment. The re-initiation Schedule of Activities (SoA) is presented 
in Table 2, without M6620 and carboplatin treatment.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Table 1
Schedule of Study Procedures/Assessments (Parts A and B) – Carboplatin- + M6620 + Avelumab
(Every 3 Weeks Up to 6 Cycles)
Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
Informed consent
X
Confirm also the additional pharmacogenetics consent (Section 8.7)
Inclusion and 
exclusion criteria
X
No deviations or waivers are permitted
Demography
X
Age, date of birth, gender
Medical history
X
Medical history, cancer history, prior anticancer therapy (surgery, medications, 
radiation, etc.) and their corresponding response assessments.
Concomitant 
medications and 
procedures
X
X
X
X 
(Cycle 1 
only)
X
Verify if any prohibited medications are given. If systemic steroids are used, 
confirm indication is for irAEs. Otherwise this is a deviation. Confirm any steroids 
for irAEs have documented tapered dosing over a minimum of 4 weeks.
Document all biopsies, excisions or aspirations with procedure name and date. If
indicated for suspected recurrences, ensure pathology or cytology reports are 
available and document results in the eCRF.  
Physical 
examination
X
X
X
Screening and Day 1 (window = Day -3 to Day 1) of each cycle should include a 
full physical examination prior to study intervention administration. A PE after 
study intervention is a deviation
All other visits should have a symptom-oriented physical examination with 
emphasis on irAEs. 
ECOG PS
X
X
Performed prior to study intervention administration.
Height
X
Weight
X
X
Vital signs
X
X
X
X 
(Cycle 1 
only)
X
Assess vital signs (blood pressure and pulse, respiratory rate, temperature) 
preceded by at least 5 minutes of rest and taken sitting at the following 
timepoints: predose (within 15 minutes prior to BOI of any study intervention 
administration at a given visit), at EOI (+ 15 minutes), and 1 hour after EOI (± 15 
minutes). 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
12-lead ECG
X
X
X
X 
(Cycle 1 
only)
All participants require a single ECG measurement at Screening. Perform 
on-treatment ECGs on Day 1 predose (within 4 hours before avelumab infusion 
and before carboplatin dose) and on Day 2 (before M6620 administration) of 
Cycles 1 and 2. 
Collect ECGs matched to PK time points as follows:
!
Cycle 1, Day 2: predose, and 1, 2, 3, 6, and 47 hours (Day 4) after M6620 
EOI.
!
Cycle 2, Day 2: predose and M6620 EOI.
For ECGs matched to PK time points: perform 3 consecutive 12-lead ECGs 
(triplicates) approximately 2 minutes apart to determine mean QTc (average of 
triplicates) with digital upload for centralized analysis. Perform ECG assessment 
within 10 minutes prior to PK blood sample collection, such that the blood 
sample is collected at the nominal time. If ECG measurement is not feasible 
before PK collection, then perform ECG 10 minutes after sample collection to 
allow participants to recover to normal heart rate. See Section 8.2.3 for ECG 
assessment details in case of concurrent cardiac or neurologic AEs.
Tumor evaluation
X
Q9W
Radiologic imaging and CA-125 assessment at Screening should be performed 
within 4 weeks of Cycle 1, Day 1, and; should be performed every 9 weeks for 
the first 3 assessments, i.e., at the end of Weeks 9, 18, and 27, and then every 
12 weeks thereafter (Weeks 39, 51, etc.) with a time window of up to 5 days prior 
to original scheduled D1 of next cycle, until PD according to RECIST v1.1.
Timing of imaging/CA-125 assessment is independent from treatment delays. 
See Section 8.1.1 for procedures for tumor evaluation to confirm tumor response 
and after initial assessment of PD.
Brain CT 
scan/MRI, bone 
scan/imaging
X
Brain CT/MRI scan (either, with contrast preferred) is required at Screening 
unless previously done within 6 weeks prior to the Screening visit. Thereafter, 
brain imaging should be done only if clinically indicated. A bone scan should be 
done for clinically indicated tumors at Screening. Bone metastases detected at 
Screening need to be followed at subsequent tumor evaluation visits.
CA-125
X
X
Screening: To evaluate for response as per GCIG guidelines: if baseline CA-125 
is 2 × ULN and >2 weeks prior to dosing, then collect a repeat CA-125 to obtain 
required pretreatment value. 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
Treatment and Follow-up: Collect CA-125 on Day 1 (unless performed within 7 
days prior) for each of the 6 treatment cycles, and at every tumor evaluation visit 
or more frequently as clinically indicated. If at any time the CA-125 values 
decrease by at least 50% from pretreatment value, then repeat CA-125 at least 
28 days later to confirm response by CA-125.
To evaluate for progression as per GCIG guidelines: 
(1) if pretreatment CA-125 value is elevated, and during treatment CA-125 
normalizes, and later elevates to at least 2 × ULN, then collect repeat CA-
125 at least 7 days later to confirm progression by CA-125. 
(2) If pretreatment CA-125 value is elevated, and during treatment CA-125 
never normalizes, then elevates to 2 x the nadir value, then collect repeat 
CA-125 at least 7 days later to confirm progression by CA-125
(3) If pretreatment CA-125 value is normal, and during treatment or later 
elevates to 2 × ULN then collect repeat CA-125 at least 7 days later to 
confirm progression by CA-125.
Patient-reported 
outcomes (Part B 
only)
(X)
X
Baseline assessments should be completed at Screening prior to any 
intervention. Otherwise they may be done at Visit 1 (Day 1). All subsequent 
assessments should be completed on Day 1 of each cycle prior to any 
intervention.
Documentation of 
AEs
X
X
X
X 
(Cycle 1 
only)
X
Any SAE assessed as related to study intervention must be reported within 
24 hours of learning of the event regardless of the time elapsed since the last 
administration of study intervention(s).
Study Interventions (Experimental Treatment)
Prophylactic 
medication for 
carboplatin
X
Premedication for carboplatin (e.g., antiemetics, etc.) according to the local 
institutional guidelines.
Carboplatin 
X
Administered on D1; up to a maximum of 6 cycles
Prophylactic 
medication for 
avelumab
X
Premedication, with the following approximately 30 to 60 minutes prior to the first 
4 doses of avelumab, is mandatory:
!
Antihistamines (e.g., either 10 mg of chlorphenamine or 25 mg of 
diphenhydramine iv)
!
Paracetamol (acetaminophen) 500-650 mg. 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
Avelumab
X
For Cycles 1 through 6 (triplet therapy Q3W regimen), avelumab administered
on D1 at 1600 mg dose given iv immediately after completion of carboplatin 
administration.
Prophylactic 
medication for 
M6620
X
Premedication with the following drugs should be given to participants who have 
developed acute hypersensitivity or pruritus with M6620 infusion and who 
continue to receive treatment with M6620:
!
Antihistamines (e.g., either 10 mg of chlorphenamine or 25 mg of 
diphenhydramine iv) approximately 30-60 minutes before the infusions
!
100-200 mg hydrocortisone iv approximately 60 minutes (± 15 minutes) 
before M6620 infusion
M6620
X
On D2 of each cycle up to maximum of 6 cycles by iv or central line 
administration; 
Laboratory Studies
HBV, HCV
X
Hepatitis B screening: HBsAg, HBsAb, HBcAb IgG and IgM.
Hepatitis C screening: HCVAb with reflex to HCV RNA.
Hematology
X
X
X
Hematology results must be available and reviewed by a study Investigator at 
least prior to D1 dose administration for every Cycle, and weekly during Cycle 1 
(i.e., Day 8, Day 15, and Day 22 [which is C2D1, if treatment not delayed]).
Full serum 
chemistry
X
X
Full serum chemistry results must be available and reviewed by a study 
Investigator prior to D1 dose administration. Full serum chemistries include core 
chemistries in addition to: direct bilirubin, amylase, lipase, creatine kinase, LDH.
Core serum 
chemistry
X
Core serum chemistry results must be available and reviewed by a study 
Investigator on D8. Core serum chemistries include: Na+, K+, Cl-, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, AST, ALT, alkaline
phosphatase. and total bilirubin.
Urinalysis
X
X
Microscopic (sediment) examination at Screening, End of Treatment Visit, and if 
urinalysis is positive for protein or blood. Urinalysis results must be available and 
reviewed by a study Investigator prior to D1 dose administration.
β-hCG pregnancy 
test (if applicable)
X
X
Pregnancy tests are performed for WOCBP. Serum pregnancy test is done at 
Screening only. Urine pregnancy tests are done at Day 1 of each cycle, and 
results must be available prior to dosing at any given visit.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
Free T4, TSH
X
X
Every 6 weeks 
M6620 plasma PK 
collection
X
X
(Cycle 1 
only)
!
Cycle 1, Day 2: predose (before BOI), and at 0 (EOI), 1, 2, 3, and 6 hours 
after EOI of M6620. 
!
Cycle 1, Day 4: 47 hours after EOI of M6620.
!
Cycle 2, Day 2: predose (before BOI), and at 0 (EOI) hours after EOI of 
M6620.
Avelumab serum 
PK collection
X
Collect predose within 2 hours prior to avelumab BOI on Day 1 of every cycle at 
Weeks 1, 4, 7, 10, 13, and 16.
If carboplatin+M6620+avelumab is discontinued before completing the 6 cycles 
(i.e. before Week 16), then collect serum for PK every 12 weeks from date of first 
maintenance dose through Week 49. 
EOI: Weeks 1, 4, and 13.
Avelumab serum 
ADA collection
X
Collect predose within 2 hours prior to avelumab BOI on Day 1 of every cycle 
every 3 weeks during 6 treatment cycles at Weeks 1, 4, 7, 10, 13, 16, and then
during maintenance at Week 19, 25, 37, and 49. 
If carboplatin+M6620+ avelumab is discontinued before completing the 6 cycles,
then collect serum ADA every 12 weeks from date of first maintenance dose.
Paired FFPE 
tumor biopsies, 
optional
(Part A only)
(Not applicable 
for Part B)
X
Part A only: Optional paired tumor biopsies are collected at Cycle 1, Day 2, 
before (within 2 h before M6620 BOI) and after (1-3 h after M6620 EOI) M6620 
administration. 
The collection is permitted on Cycle 2, Day 2, if not feasible to collect the post 
infusion biopsy or if neither biopsy collected in Cycle 1. 
If available, additional archival tissue samples from previous biopsy or surgical 
procedures (pre-PARPi) should also be provided for exploratory 
 
analysis.
FFPE tumor 
biopsy and 
archival tissue
(Required for Part 
B)
X
(FFPE 
biopsy and 
archival 
tissue)
X
End of 
Cycle 
3 at 
Week 
9 only 
Screening sample: 
Part B required for all participants
Availability of fresh FFPE tumor biopsy or archival biopsy is accepted if obtained 
after latest progression on PARPi. Otherwise, a fresh biopsy is required. For 
FFPE samples, either block or sections (> 15 slides) may be provided. 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
23/137
Assessments 
and Procedures
Avelumab + 
M6620+ 
Carboplatin 
Screening
Parts A and B
Notes
Day -28 
to -1
Cycles C1 up to C6 (Q3W)
Day 1
(-3/+1)
Day 2
(±0)
Day 4 
(± 1)
Day 8 
(± 1)
(FFPE 
biopsy)
If available, additional archival tissue samples from previous biopsy or surgical 
procedures (pre-PARPi) should also be provided for exploratory 
 
analysis.
On-treatment biopsy Week 9: 
FFPE tumor biopsy of a lesion at the time of the first tumor assessment
(Week 9), can be from the same lesion as for the screening biopsy if possible.
ADA=antidrug antibody; AE=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase; β-hCG=β-human chorionic gonadotropin; 
BOI=beginning of infusion; BUN=blood urea nitrogen; CT=computed tomography; DC=discontinue; ECG=electrocardiogram; ECOG PS=Eastern Cooperative 
Oncology Group Performance Status; eCRF= electronic case report form; EOI=end of infusion; FFPE=formalin-fixed, paraffin-embedded; GCIG=gynecologic 
cancer intergroup; HBV=hepatitis B virus; HCV=hepatitis C virus; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B 
surface antigen; HCVAb=hepatitis C virus antibody; IgG=immunoglobulin G; IgM=immunoglobulin M; irAE=immune-related adverse event; iv=intravenous; 
LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PARPi=poly (ADP-ribose) polymerase inhibitor; PD=progressive disease; PK=pharmacokinetics; 
Q3W=every 3 weeks; Q9W=every 9 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious adverse event; 
T4=thyroxine; TSH=thyroid-stimulating hormone; Tx=treatment; WOCBP=women of childbearing potential.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
24/137
Table 2
Schedule of Study Procedures/Assessments (Parts A and B) –
Avelumab Maintenance
Period
(Every 2 Weeks Starting After the Last Cycle of Carboplatin-+ M6620 + Avelumab), End of Treatment, and 
Follow-up
Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
Concomitant 
medications 
and procedures
X
X
X
X
Verify if any prohibited medications given, if systemic 
steroids are used confirm indication for irAEs otherwise 
deviation; confirm any steroids for irAE have 
documented dosing taper over minimum 4 weeks.
Document all biopsies or excisions or aspirations 
procedure name, date and if indicated for suspected 
recurrences ensure pathology or cytology reports 
available with results documented in eCRF.  
Physical 
examination
X
X
X
A symptom-oriented physical examination with 
emphasis on irAEs should be done on Day 1 of each 
2-week cycle with full physical examination at least 
every 12 weeks or as clinically indicated. End of
Treatment and Safety Follow-up Visits should include a 
full physical examination.
ECOG PS
X
X
X
Performed prior to avelumab administration.
Vital signs
X
X
X
Vital signs (after 5 min seated rest - blood pressure, 
pulse, respiratory rate, temperature) should be 
assessed predose (within 15 minutes prior to BOI), at 
EOI (+ 15 minutes), and 1 hour after EOI 
(± 15 minutes). 
12-lead ECG
Q8W to Q12W
X
X
ECGs will be performed on first maintenance dose and 
may be performed as clinically indicated. See 
Section 8.2.3 for ECG assessment details in case of 
concurrent cardiac or neurologic AEs.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
Tumor 
evaluation
Q9W to Q12W
X
During avelumab maintenance therapy, tumor 
evaluations, should continue according to the initial 
schedule regardless of when avelumab maintenance 
was started and independent of treatment delays (every 
9 weeks for the first 3 assessments, i.e., at the end of 
Weeks 9, 18, and 27), and then every 12 weeks 
thereafter (Weeks 39, 51, etc.) until PD according to 
RECIST v1.1.
See Section 8.1.1 for procedures for tumor evaluation 
to confirm tumor response and after initial assessment 
of PD.
Brain CT 
scan/MRI, bone 
scan/imaging
If clinically 
indicated
A bone scan should be done for clinically indicated 
tumors at Screening. Bone metastases detected at 
Screening must be followed at subsequent tumor 
evaluation visits.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
26/137
Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
CA-125
X
(Wk 27 and 
Q12W)
X
Follow-up:  Collect CA-125 at every tumor evaluation 
visit and more frequently as clinically indicated. If at any 
time the CA-125 value decreases by at least 50% from 
pretreatment value, then repeat CA-125 at least 
28 days later to confirm response by CA-125.
To evaluate for progression as per GCIG guidelines: 
(1) if pretreatment CA-125 value is elevated, and 
during treatment CA-125 normalizes, and later 
elevates to at least 2 × ULN, then collect repeat 
CA-125 at least 7 days later to confirm progression 
by CA-125. 
(2) If pretreatment CA-125 value is elevated, and 
during treatment CA-125 never normalizes, then 
elevates to 2 × the nadir value, then collect repeat 
CA-125 at least 7 days later to confirm progression 
by CA-125
(3) If pretreatment CA-125 value is normal, and during 
treatment or later elevates to 2 × ULN then collect 
repeat CA-125 at least 7 days later to confirm 
progression by CA-125
Overall survival
X
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
Documentation 
of AEs
X
X
X
X
X (as 
applicable
)
After the 30-day Safety Follow-up Visit, all SAEs, 
AESIs, and treatment-related nonserious AEs must be 
documented until the 90-day Safety Follow-up Phone 
Call. Participants with an ongoing SAE at the 90-day 
Safety Follow-up Phone Call must be followed by the 
Investigator until stabilization or until the outcome is 
known, unless the participant is documented as “lost to 
follow-up.” Any SAE assessed as related to study 
intervention must be reported within 24 hours of 
learning of the event, regardless of the time elapsed 
since the last administration of study intervention(s).
Prophylactic 
medication for 
avelumab
X
Optional premedication 30 to 60 minutes before the 
infusion after the 4th dose, should be administered
based upon clinical judgement and presence/severity of 
prior infusion-related reactions). with:
!
Antihistamines (e.g., either 10 mg of 
chlorphenamine or 25 mg of diphenhydramine iv)
!
Paracetamol (acetaminophen) 500-650 mg
Avelumab 
monotherapy
X
After completion of the last chemotherapy combination 
treatment cycle, avelumab will be administered as 
maintenance monotherapy at 800 mg Q2W until PD or 
unacceptable toxicity or minimum 12 months of therapy 
following a confirmed CR without recurrence. 
Hematology
X
X
X
Hematology results must be available and reviewed by 
a study Investigator prior to dose administration.
Full serum 
chemistry
X
X
Full (and core) serum chemistry results must be 
available and reviewed prior to dose administration by a 
study Investigator. Full serum chemistries include core 
chemistries in addition to direct bilirubin, amylase, 
lipase, creatine kinase, and LDH. 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
28/137
Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
Core serum 
chemistry
X
Core serum chemistries include Na+, K+, Cl-, BUN, 
creatinine, glucose, calcium, magnesium, phosphorus, 
AST, ALT, alk phos, and total bilirubin.
Urinalysis
X
X
X
Microscopic (sediment) examination at Screening, End 
of Treatment, 30-day Safety Follow-up Visit, and if 
urinalysis is positive for protein or blood. Urinalysis 
results must be available and reviewed by a study 
Investigator prior to dose administration.
β-hCG 
pregnancy test 
(if applicable)
Q4W
X
Pregnancy tests are performed for WOCBP. Urine 
pregnancy test on Day 1 of every other cycle (once per 
month) during maintenance. Results of urine pregnancy 
test must be available prior to dosing at any given visit.
Urine pregnancy test must be performed at 30 days 
after last dose safety follow-up.
Free T4, TSH
Q6W
X
Avelumab 
serum PK 
collection
X (see Notes)
X (see 
Notes)
Collect predose, within 2 hours prior to avelumab BOI, 
at Weeks 1, 4, 7, 10, 13, and 16 and at start of 
avelumab maintenance at Weeks 19, 25, 37, and 49.
Collect EOI at Weeks 1, 4, and 13.
If avelumab maintenance starts earlier, collect the BOI 
every 12 weeks through Week 49.
At the 30-day Safety Follow-up Visit, samples will be 
collected only from participants whose last treatment is 
on Week 49 or earlier.
Avelumab 
serum ADA 
collection
X (see Notes)
X (see 
Notes)
Collect predose, within 2 hours prior to avelumab BOI, 
at Weeks 1, 4, 7, 10, 13, and 16 and at start of 
avelumab maintenance on Week 19, 25, 37, and 49.
If avelumab maintenance starts earlier, collect every 
12 weeks through Week 49.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
29/137
Assessments 
& Procedures
Avelumab 
Maintenance
Parts A and B
End of 
Treatment 
Visit
Safety Follow-up Visits
Long-
term 
Follow-up
Notes
Maintenance 
doses
(M1 to Mx) until 
PD
Q2W
Within 7 Days 
of Decision to 
Discontinue
Visit: 30 D 
(± 5) after 
Last Tx
Phone Call: 
90 D (± 5)
after Last 
Tx
Every 
12 Wks 
(± 1)
after Last 
Tx
Maintenance period begins after the end of the last 
cycle of the carboplatin + M6620 + avelumab 
regimen (3 weeks after last dose)
At the 30-day Safety Follow-up Visit, samples will be 
collected only from participants whose last treatment is 
on Week 49 or earlier.
ADA=antidrug antibody; AE=adverse events; AESI=adverse event of special interest; alk phos=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; β-hCG=β-human chorionic gonadotropin; BOI=beginning of infusion; BUN=blood urea nitrogen; CT=computed tomography; 
D=Day(s); DC=discontinue; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOI=end of infusion; iv=intravenous;
LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PD=progressive disease; PK=pharmacokinetics; Q2W=every 2 weeks; Q3W=every 3 weeks; 
Q6W=every 6 weeks; Q8W=every 8 weeks; Q12W=every 12 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious 
adverse event; T4=thyroxine; TSH=thyroid-stimulating hormone; Tx=treatment; WOCBP=women of childbearing potential.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
30/137
Table 3
Schedule of Study Procedures/Assessments (Part B) – Standard of Care (Every 3 or 4 Weeks for the First 
6 Cycles), End of Treatment, and Follow-up
Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
Informed consent
X
Inclusion and 
exclusion criteria
X
Demography
X
Medical history
X
Medical history, cancer history, prior 
anticancer therapy (surgery, 
medications, radiation, etc.)
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
Physical examination
X
X
X
X
Screening, Day 1 of each cycle, End of 
Treatment Visits, and Safety Visits 
should include a full physical 
examination prior to any study 
intervention administration.
ECOG PS
X
X
X
X
Performed prior to study intervention 
administration.
Height
X
Weight
X
X
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
Vital signs 
X
X
X
X
Assess vital signs (blood pressure, 
pulse, respiratory rate, temperature) 
predose (within 15 minutes prior to BOI 
of any study intervention administration 
at a given visit), at EOI (+ 15 minutes), 
and 1 hour after EOI (± 15 minutes).
12-lead ECG
X
X
X
All participants require a single ECG 
measurement at Screening. 
On-treatment triplicate ECGs will be 
performed on Day 1 of each cycle after 
chemotherapy infusions within 
15 minutes of EOI. See Section 8.2.3
for ECG assessment details in case of 
concurrent cardiac or neurologic AEs.
Tumor evaluation
X
Q9W
Q9W until Wk 
27 then 
Q12W until 
PD
X
Radiologic imaging and CA-125 
assessment each have a time window 
of up to 5 days prior to Day 1 dosing 
and should be performed at Screening 
and every 9 weeks for the first 
3 assessments (i.e., at the end of 
Weeks 9, 18, and 27), and then every 
12 weeks thereafter (Weeks 39, 51, 
etc.) until PD per RECIST v1.1.
See Section 8.1.1 for procedures for 
tumor evaluation to confirm tumor 
response and after initial assessment 
of PD.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
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Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
Brain CT scan/MRI, 
bone scan/imaging
X
Brain CT/MRI scan (either, with 
contrast preferred) is required at 
Screening unless previously done
within 6 weeks prior to start of 
Screening. Thereafter, brain imaging 
should be done only if clinically 
indicated. A bone scan should be done 
for clinically indicated tumors at 
Screening. Bone metastasis detected 
at Screening need to be followed at 
subsequent tumor evaluation visits.
CA-125
X
X
X 
(Wk 27 and 
Q12W)
X
Screening: To evaluate for response 
as per GCIG guidelines: if baseline 
CA-125 is 2 × ULN and >2 weeks prior 
to dosing, then collect a repeat CA-125 
to obtain required pretreatment value.
Treatment and Follow-up: Collect 
CA-125 on Day 1 for each of the 
6 treatment cycles, at every tumor 
evaluation visit and more frequently as 
clinically indicated. If at any time the 
CA-125 value decreases by at least 
50% from pretreatment value, then 
repeat CA-125 at least 28 days later to 
confirm response by CA-125.
To evaluate for progression as per 
GCIG guidelines: 
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
(1) if pretreatment CA-125 value is 
elevated, and during treatment 
CA-125 normalizes, and later 
elevates to at least 2 × ULN, then 
collect repeat CA-125 at least 
7 days later to confirm 
progression by CA-125. 
(2) If pretreatment CA-125 value is 
elevated, and during treatment 
CA-125 never normalizes, then 
elevates to 2 x the nadir value, 
then collect repeat CA-125 at 
least 7 days later to confirm 
progression by CA-125
(3) If pretreatment CA-125 value is 
normal, and during treatment or 
later elevates to 2 × ULN then 
collect repeat CA-125 at least 
7 days later to confirm 
progression by CA-125
Overall survival
X
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
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Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
Documentation of AEs
X
X
X
X
X
X (as 
applicable)
After the 30-day Safety Follow-up Visit, 
all SAEs and all treatment-related 
nonserious AEs must be documented 
until the 90-day Safety Follow-up 
Phone Call. 
Participants with an ongoing SAE at 
the 90-day Safety Follow-up Phone 
Call must be followed by the 
Investigator until stabilization or until 
the outcome is known, unless the 
participant is documented as “lost to 
follow-up.”
Any SAE assessed as related to study 
intervention must be reported within 
24 hours of learning of the event, 
regardless of the time elapsed since 
the last administration of study 
intervention(s).
Standard of Care Treatment
Prophylactic 
medication
X
Depending on the regimen and 
according to the local institutional 
guidelines.
Platinum-containing 
chemotherapy-with or 
without bevacizumab
X
X
Up to a maximum of 6 cycles; 
depending on SoC agent combined 
with platinum schedule is either every 
3-week cycle or every 4-week cycle
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
35/137
Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
Laboratory Studies
HBV, HCV
X
Hepatitis B screening: HBsAg, HBsAb, 
HBcAb IgG and IgM.
Hepatitis C screening: HCVAb with 
reflex to HCV RNA.
Hematology
X
X
X
X
Hematology results must be available 
and reviewed prior to dose 
administration by a study Investigator. 
Additional assessments must be 
performed as clinically indicated and 
results collected
Full serum chemistry
X
X
X
X
Full (and core) serum chemistry results 
must be available and reviewed prior 
to dose administration by a study 
Investigator. Full serum chemistries 
include core chemistries in addition to 
direct bilirubin, amylase, lipase, 
creatine kinase, and LDH. 
Urinalysis
X
X
X
X
Microscopic (sediment) examination at 
Screening, End of Treatment Visit, 
30-day Safety Follow-up Visit, and if 
urinalysis is positive for protein or 
blood. Urinalysis results must be 
available and reviewed prior to dose 
administration by a study Investigator.
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
36/137
Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
β-hCG pregnancy test 
(if applicable)
X
X
X
Serum pregnancy test is done at 
Screening only; urine pregnancy tests 
are done at Day 1 of each cycle, and 
at the 30 days after last dose safety 
follow-up
Free T4, TSH
X
X
X
Every 6 weeks only
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Avelumab + M6620
Phase Ib/II Study of Avelumab + M6620 + Carboplatin in PARPi-resistant Ovarian Cancer
MS201943-0029
37/137
Assessments & 
Procedures
SoC
Screening
Part B
Part B
End of 
Treatment 
Visit
Safety 
Follow-up 
Visits
Long-
term 
Follow-up
Notes
Day -28
to -1
Cycles 
C1 to C6 
(Q3W/Q4W)
Optional
bevacizumab 
(M1 to Mx) to 
PD
Within 
7 Days of 
Decision 
to DC
Visit: 
30 D 
(± 5) 
after 
Last 
Tx
Phone 
Call: 
90 D 
(± 5)
after 
Last 
Tx
Every 
12 Wks 
(± 1) after 
Last Tx
Day 1
(-3/+1)
Q3W
FFPE Tumor biopsy
and archival tissue
(Required for Part B)
X
(FFPE 
biopsy and 
archival 
tissue)
X
End of Cycle 3 
at Week 9 only
(FFPE biopsy)
(optional for 
SOC)
Part B required for all participants; 
Screening sample:
Availability of fresh FFPE tumor biopsy 
or archival biopsy is accepted if 
obtained after the most recent 
progression prior to study entry. For 
FFPE samples, either block or sections 
(> 15 slides) may be provided. 
If available, additional archival tissue 
samples from previous biopsy or 
surgical procedures (pre-PARPi) 
should also be provided for exploratory 
 analysis.
On-treatment biopsy Week 9: 
Optional for SOC arm; on-treatment 
biopsy of a lesion at the time of the first 
tumor assessment (Week 9), can be 
from the same lesion of the baseline 
biopsy if possible.
AE=adverse events; β-hCG=β-human chorionic gonadotropin; BOI=beginning of infusion; CT=computed tomography; D=Day(s); DC=discontinue; 
ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOI=end of infusion; FFPE=formalin-fixed, paraffin-embedded; 
HCV=hepatitis C virus; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HCVAb=hepatitis C virus 
antibody; IgG=immunoglobulin G; IgM=immunoglobulin M; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PD=progressive disease; 
Q3W=every 3 weeks; Q4W=every 4 weeks; Q9W=every 9 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious 
adverse event; T4=thyroxine; TSH=thyroid-stimulating hormone; Tx=treatment.
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Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant 
MS201943-0029
Ovarian Cancer
38/137
2
Introduction
Avelumab is an intravenously administered programmed death ligand 1 (PD-L1)-blocking human 
antibody. M6620 is a novel, intravenously administered ataxia telangiectasia and Rad3-related 
(ATR) inhibitor (ATRi). This study will investigate carboplatin + M6620 in combination with 
avelumab in the treatment of participants with recurrent ovarian, primary peritoneal, or fallopian 
tube cancer who have progressed on a maintenance treatment with a poly (ADP-ribose) 
polymerase (PARP) inhibitor (PARPi).
Complete information on the chemistry, pharmacology, efficacy, and safety of avelumab and 
M6620 is in the respective Investigator’s Brochures (IBs).
2.1
Study Rationale
The purpose of this study is to evaluate the safe RP2D of carboplatin + M6620 in combination 
with avelumab (Part A) and to evaluate the efficacy and safety of carboplatin + M6620 + avelumab
compared with the standard of care (SoC; platinum-containing chemotherapy) (Part B) in 
participants with recurrent ovarian, primary peritoneal, or fallopian tube cancer who have 
progressed with a PARPi. Given that PARPi-resistant recurrent ovarian cancer and expected 
platinum sensitivity is associated with a high mutational load and homologous recombination 
deficiency (HRD) (Parmar 2003), the combination treatment of a DNA-damaging agent 
(carboplatin) with a deoxyribonucleic acid (DNA) damage response inhibitor (DDRi; M6620) and 
an immune checkpoint inhibitor (avelumab) is expected to synergize and lead to insufficient DNA 
repair, increased DNA mutations, immunologic cell death, and an increase in potential 
immunological targets within the tumor.
For discussion of the scientific rationale for the study design, see Section 4.2, and for justification 
for dose, see Section 4.3.
2.2
Background
Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most common 
cause of cancer mortality in women. Although many patients achieve complete remission after 
primary treatment with cytoreductive surgery and platinum- and taxane-based chemotherapy, up to 
80% of patients experience disease recurrence (Herzog 2017). Patients with recurrent 
platinum-sensitive ovarian cancer may undergo second-line therapy with platinum-containing 
regimens. In such patients, typically a median PFS time of around 9 months and a median overall 
survival (OS)
time of around 30
months (ICON
4
[Parmar 2003],
CALYPSO
[Pujade-Lauraine 2010], and OCEANS [Aghajanian 2012] studies) is observed. For most patients, 
the benefit from treatment with platinum salts (carboplatin and cisplatin) is limited due to highly 
proficient cellular processes that can detect and repair damaged DNA. Nonclinical and clinical 
studies have shown that concurrent inhibition of DNA damage repair pathways enhances the 
cytotoxic effect of platinum compounds (Sundar 2017, Martin 2008, Hosoya 2014, Reaper 2011).
Alterations in genes of the DNA repair pathway involving homologous recombination have been 
observed in approximately 50% of high-grade serous ovarian cancer (the most common histology) 
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Avelumab + M6620
Phase Ib/II Study of Carboplatin + M6620 + Avelumab in PARPi-resistant 
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(Murai 2017). These include 25% to 30% of mutations in BRCA1/2 genes that lead to HRD,
resulting in loss of heterozygosity (loss of entire genes and surrounding chromosomal regions) 
(Dockery 2017). DNA is repaired by multiple, partially redundant pathways with BRCA1/2 
involved in error-free double-stranded DNA (dsDNA) break repair by homologous recombination 
(Vanderstichele 2017). 
The presence of HRD is associated with favorable prognosis due to an enhanced sensitivity to 
platinum-based therapies as well as treatment with a DNA damage response inhibitor (DDRi), 
including PARPi (Ventriglia 2017). PARP repairs single-strand DNA breaks, which if left 
unrepaired, lead to dsDNA breaks during replication. When treated with PARPi, homologous 
recombination-deficient ovarian cancer cells rely on error-prone dsDNA repair systems and 
accumulate mutations or chromosomal changes, leading to cell death and substantial antitumor 
efficacy (Dockery 2017, Vanderstichele 2017, George 2017) Maintenance therapy with PARP 
inhibitors (olaparib [SOLO2; Pujade-Lauraine 2017], niraparib [NOVA; Mirza 2016), and 
rucaparib (ARIEL3; Coleman 2017]) has been shown to significantly prolong PFS compared to 
placebo following response to platinum-based chemotherapy in women with platinum-sensitive 
epithelial ovarian cancer. Some patients continue maintenance therapy for more than 5 years. 
However, apart from some patients with primary resistance, the majority of patients eventually 
develop resistance to PARP inhibition. The optimal treatment following progression on a PARPi is 
not currently known. There is limited literature on treatment following PARPi progression in 
clinical practice. The majority of patients are re-challenged with platinum-based chemotherapy if 
the time of progression from last dose of platinum is greater than 6 months. The median time for 
PFS in participants who have received treatment with platinum-containing chemotherapy after 
failure to PARPi maintenance treatment has been reported to be approximately 6 months 
(Ang 2013), depending on prior lines of treatment and the platinum-free interval. Multiple potential 
mechanisms of PARP inhibitor resistance have been reported (Konstantinopoulos 2015). For 
example, based on preclinical experiments, PARPi-resistant, BRCA1-deficient cells are 
increasingly dependent on the ATR pathway for survival. ATR inhibitors (ATRi) disrupt 
BRCA1-independent RAD51 loading to DNA DSBs in PARPi-resistant, BRCA1-deficient cells, 
overcoming such resistance mechanisms (Yazinski 2017). ATRi may therefore potentially 
overcome PARPi-resistance in BRCA-deficient cancers. As another mechanism, PARPi treatment 
upregulates tumor cell PD-L1 expression, which attenuates PARPi efficacy via cancer-associated 
immunosuppression (Jiao 2017). This provides a rationale for combined treatment with a DDRi and 
a PD-L1-targeting agent.
Avelumab is an intravenously administered PD-L1-blocking human antibody. PD-L1 is a ligand 
of programmed death 1 (PD-1), a negative regulator of T cell activity that limits the activity of 
T cells at a variety of stages of the immune response (Ishida 1992, Keir 2006, Freeman 2000). 
When engaged by a ligand, PD-1 inhibits pathways that normally lead to T cell activation. 
Blocking PD-1, for example with a PD-L1 antibody, thus can restore an inhibited T cell activation 
and lead to effective tumor reduction. Furthermore, PD-L1-blocking antibodies such as avelumab 
also enhance the function of tumor-infiltrating lymphocytes (TILs), which augments antitumor 
immunity within the tumor microenvironment. Thus, PD-1+ TILs have been shown to be 
indicators of response to immune checkpoint blockade, and a lack of TILs may be a predictive 
marker for lack of response to PD-1/L1 blockade (Curran 2010, Huang 2011, Herbst 2014). A 
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number of antibodies that disrupt the PD-1 axis are approved and/or are in clinical development 
for several tumor indications.
Avelumab is currently being evaluated in monotherapy or in combination with several 
chemotherapies in a number of clinical studies, including a Phase III study in combination with 
carboplatin/paclitaxel versus carboplatin/paclitaxel alone in previously untreated epithelial ovarian 
cancer (JAVELIN Ovarian 100; NCT02718417). A total of 951 participants are planned for 
enrollment. As of 11 December 2017, 790 participants had received treatment. Another Phase III 
study is exploring avelumab alone or in combination with PEGylated liposomal doxorubicin versus 
PEGylated liposomal doxorubicin alone in patients with platinum resistant/refractory ovarian 
cancer (JAVELIN Ovarian 200; NCT02580058). In total, 546 participants (550 planned) were 
dosed as of the data cutoff date of 11 December 2017 (current avelumab Investigator’s Brochure 
[IB]). The preliminary safety data from these and other studies with different tumor types suggest 
an acceptable safety profile of the compound as expected in participants with advanced tumor 
disease or in line with class effects of mAb blocking the PD 1/PD L1 axis (Avelumab IB version 8, 
16 May 2018).
Inhibition of DNA damage response (DDR) is expected to synergize with PD-L1-targeting agents 
such as avelumab, because insufficient DNA repair may lead to increased DNA mutations, 
resulting in an increase in potential immunological targets (“neoantigens”) within the tumor. This 
could increase the antitumor efficacy of a treatment acting by improving a patient’s immune 
response toward a tumor.
Furthermore, the synthetic lethality observed after ATR inhibition in tumors with additional 
DDR-gene deficiencies in situations of replicative stress may result in the induction of 
immunogenic cell death. This is expected to synergize with PD-L1-directed activation of the 
patient’s immune response against the tumor and result in clinical benefit. In the Phase I 
Study VX13-970-002, participants with advanced solid tumors received treatment with different 
doses of M6620 + DNA-damaging chemotherapy, including carboplatin. Among participants who 
received M6620 (90 mg/m2) and carboplatin AUC 5:
! 1 participant had a RECIST v1.1 partial response (PR) of advanced BRCA mutant high-grade 
serous ovarian cancer with a TP53 mutation. This participant had previously progressed through 
multiple lines of chemotherapies and targeted agents, including a PARPi twice, and was 
platinum refractory. 
! 8 other participants had a best response of RECIST v1.1 disease stabilization (median duration 
16 weeks [range: 5 to 33 weeks]) (Sundar 2017).
In preclinical studies, chemotherapy agents that induce DNA damage have been shown to promote 
immune antitumor activity in addition to inducing direct cytotoxic activity (Zhao 2017,
Ursic 2018) and, as a result, are expected to synergize with immunotherapies, such as avelumab. 
Consistent with these observations, the combination of avelumab with DNA-damaging agents
results in robust synergistic antitumor activity in murine models. 
The cytotoxic activity of DNA-damaging agents, including carboplatin, can be further enhanced 
in vivo when combined with M6620. M6620 also enhances in vitro immunogenic cell death 
induced by DNA-damaging agents. In addition, the combination of chemotherapy with M6620 is 
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hypothesized to increase neoantigen load in tumors, thereby sensitizing cancer cells to 
immunotherapies, such as avelumab (Mouw 2017). 
Finally, it has been reported that combining DNA-damaging agents with DDR inhibitors results in 
greater and more persistent DNA damage, and it is expected that such combination may promote 
stimulator of interferon genes (STING) pathway activation and expression of Th1 cytokines 
(Hartlova 2015, Chen 2016). Altogether, these data support the rationale of combining avelumab 
with a DNA-damaging chemotherapy agent and M6620. 
2.3
Benefit/Risk Assessment
The combination of carboplatin (area under the concentration-time curve [AUC] 5) + M6620 at 
the dose of 90 mg/m2 has shown an acceptable safety profile and early signs of efficacy in the
first-in-human clinical studies. With an established safety and efficacy profile, avelumab is 
currently approved in several countries for the treatment of metastatic Merkel cell carcinoma and 
in the United States and Israel for locally advanced or metastatic urothelial carcinoma. Additional 
indications (e.g., non-small cell lung, gastric, and ovarian cancers) are currently being evaluated 
in several ongoing Phase III studies. Based on the mechanisms of action and the available 
nonclinical information, and except for potential infusion-related reactions, no synergistic toxicities 
for the triplet combination that includes avelumab are expected. The proposed study intervention 
provides the possibility of substantial antitumor efficacy in ovarian cancer patients who are resistant to 
PARP inhibition and thus have limited treatment options. Together with the safety profile of the 
compounds, this results in a positive benefit-risk ratio in these patients. 
Specific risks associated with the use of avelumab as a monoclonal antibody have been observed. 
The primary risks of exposure to avelumab include: 
! infusion-related reactions 
! immune-related adverse events (irAEs).
Specific risks associated with the use of M6620 with platinum therapy have been observed. The 
primary risks of exposure to carboplatin + M6620 include: 
! infusion-related reactions 
! enhanced myelosuppressive effect of carboplatin (especially thrombocytopenia, neutropenia, 
and anemia).
Currently, no safety data on the doublet combination of avelumab and M6620 are available; 
however, apart from infusion-related reactions that have been observed for both avelumab and 
M6620 and that are considered to be manageable by premedication and nonparallel infusions, no 
synergistic toxicity for this combination is expected. This is further indirectly supported by 
published data on the combination of the ATRi AZD6738 with the anti-PD-L1 antibody 
durvalumab (MEDI4736) (Yap 2016, Sundar 2017), which reported the combination was well 
tolerated. Nonetheless, the triplet combination of carboplatin, M6620, and avelumab at the RP2D 
for carboplatin + M6620 will be evaluated during a Safety Run-in Period (Part A) prior to the start 
of the Randomized Treatment Period (Part B) of the study.
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More detailed information about the known and expected benefits and risks and reasonably
expected adverse events (AEs) of avelumab and M6620 may be found in Section 4.2 (Scientific 
Rationale for Study Design) and the respective IBs.
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable from a benefit/risk perspective.
3
Objectives and Endpoints
The objectives and endpoints are defined in Table 4 for Part A and in Table 5 for Part B. See 
Section 9.4 for statistical aspects of the endpoints.
3.1
Part A
Table 4
Part A Objectives and Endpoints – Carboplatin + M6620 + Avelumab in 
Recurrent PARPi-resistant Ovarian Cancer
Objectives
(Part A)
Endpoints (Outcome Measures)
Primary
To evaluate a safe, tolerable RP2D of carboplatin + 
M6620 when given in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of DLTs during the DLT observation period
Secondary
To evaluate the safety and tolerability of carboplatin + 
M6620 at the RP2D in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of TEAEs and treatment-related AEs 
according to NCI-CTCAE
To evaluate the antitumor activity of carboplatin + M6620
at the RP2D in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
!
Confirmed best overall response (BOR)
!
Progression-free survival (PFS) from date of first 
dose of study intervention until progressive disease 
(PD) or death
!
Duration of response (DOR) as assessed from 
complete response (CR) or partial response (PR) 
until PD, death, or last tumor assessment
!
Time to progression (TTP) from first dose of study 
intervention until PD
All the above by Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1), and/or cancer 
antigen 125 (CA-125) response (Gynecologic Cancer 
Intergroup [GCIG] criteria) as assessed by the 
Investigator.
!
Time to first subsequent therapy (TFST)
To characterize the PK profiles of M6620 and avelumab 
when given in combination with carboplatin
!
PK parameter estimates for M6620
!
PK summary statistics for avelumab
Tertiary/Exploratory
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Objectives
(Part A)
Endpoints (Outcome Measures)
ADA=antidrug antibody; ADME=absorption, distribution, metabolism, and excretion; AE=adverse event; BOR=best 
overall response; CA-125=cancer antigen 125; CR=complete response; CTCAE=Common Terminology Criteria for 
Adverse Events; ctDNA=circulating tumor DNA; DNA=deoxyribonucleic acid; DLT=dose-limiting toxicity; 
DOR=duration of response; FcγR=Fc receptor of IgG; ir=immune response; mRNA=messenger ribonucleic acid; 
NCI=National Cancer Institute; PD=progressive disease; PGt=pharmacogenetics; PK=pharmacokinetics; PR=partial 
response; RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=recommended Phase II dose; SNP=single 
nucleotide polymorphism; SoA=Schedule of Activities; TEAE=treatment-emergent adverse event.
3.2
Part B
Table 5
Part B Objectives and Endpoints – Carboplatin + M6620 + Avelumab in 
Recurrent PARPi-resistant Ovarian Cancer
Objectives
Endpoints (Outcome Measures)
Primary
To evaluate antitumor activity of carboplatin + M6620 + 
avelumab compared with the standard of care treatment 
in participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
PFS according to RECIST v1.1 as assessed by the 
Investigator
Secondary
To evaluate the safety and tolerability of carboplatin + 
M6620 at the RP2D in combination with avelumab in 
participants with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of TEAEs and treatment-related AEs and 
immune-related adverse events (irAEs) according to 
NCI-CTCAE
To further evaluate antitumor activity of carboplatin + 
M6620 + avelumab compared with the standard of care 
treatment
!
PFS according to GCIG CA-125 as assessed by the 
Investigator
!
Confirmed BOR according to RECIST v1.1 and 
GCIG CA-125
!
DOR assessed from CR or PR until PD, death, or 
last tumor assessment
!
TTP
!
TFST
To characterize the PK profiles of M6620 and avelumab 
when given in combination with carboplatin
!
PK parameter estimates for M6620
!
PK summary statistics for avelumab.
To characterize the immunogenicity of avelumab in 
combination with carboplatin + M6620
Immunogenicity of avelumab in combination therapy, as 
measured by ADA assay from all participants treated 
with carboplatin+M6620+avelumab in Part A and 
Part B.
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Objectives
Endpoints (Outcome Measures)
Tertiary/Exploratory
ADA=antidrug antibodies; ADME=absorption, distribution, metabolism, and excretion; AE=adverse event; BOR=best 
overall response; CA-125=Cancer Antigen 125; CR=complete response; CTCAE=Common Terminology Criteria for 
Adverse Events; ctDNA=circulating tumor DNA; DNA=deoxyribonucleic acid; DLT=dose-limiting toxicity; 
DOR=duration of response; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core-30; EORTC QLQ-OV28=European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire – Ovarian Cancer; GCIG=Gynecologic Cancer Intergroup; mRNA=messenger 
ribonucleic acid; NCI=National Cancer Institute; PD=progressive disease; PFS=progression-free survival; 
PGIS=Patient Global Impression of Severity; PGt=pharmacogenetics; PK=pharmacokinetics; PR=partial response; 
PRO=patient-reported outcome; RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=recommended 
Phase II dose; SNP=single nucleotide polymorphism; SoA=Schedule of Activities; TEAE=treatment-emergent 
adverse event; TFST=time to first subsequent therapy; TMB=tumor mutation burden.
4
Study Design
4.1
Overall Design
This is a 2-part (Part A: safety run-in; Part B: randomized), open-label, controlled, Phase II study 
to evaluate the efficacy and safety of avelumab in combination with carboplatin + M6620 in 
participants with PARPi-resistant recurrent ovarian, primary peritoneal, or fallopian tube cancer.
Part A is a safety run-in that will evaluate a safe RP2D dose of the triplet combination 
(carboplatin + M6620 + avelumab). Participants will be enrolled following a modified 3 + 3 design
starting with the established doses of avelumab and the carboplatin + M6620 combination with
de-escalation of M6620 doses if needed. 
Participants in Part A will receive carboplatin + M6620 + avelumab every 3 weeks for 6 cycles. 
Treatment with avelumab will continue beyond carboplatin + M6620. Participants will be 
monitored for dose-limiting toxicities (DLTs) (defined in Section 6.6.1) by a Safety Monitoring 
Committee (SMC) (see Section 8.2.5). The DLT observation period is defined as 21 days inclusive 
of the day of first treatment. If at any time ≥2 DLTs are observed, treatment with the corresponding 
dose will be stopped and the next lower dose will be considered, as shown in the Part A Schema (
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Figure 2). Participants are considered evaluable for dose de-escalation decisions when they have 
received the first planned full doses of M6620, avelumab, and carboplatin (including 
premedication) and completed all planned safety assessments in Cycle 1 or received any treatment 
and experience a DLT. Participants who do not complete the DLT observation period for reasons 
other than a DLT will be replaced. 
Upon selection of a safe RP2D of the triplet combination in Part A, any participants who are 
receiving the triplet combination at a dose level higher than the RP2D will be de-escalated to the 
safe RP2D for the remaining every-3-week cycles, for a total of 6 infusions of the triplet 
combination. After receiving 6 infusions of the triplet combination during Part A, participants with 
ongoing treatment will receive avelumab maintenance therapy every 2 weeks until progressive 
disease (PD), unacceptable toxicity, withdrawal of consent, or death. 
In Part B of the study, to investigate the efficacy of the recommended triplet combination dose (as 
established in Part A), 72 participants (N = 36/treatment arm) will be stratified by BRCA status 
and randomized (1:1) to receive either the study intervention, (a treatment regimen of 
carboplatin + M6620 + avelumab for 6 cycles) or SoC (a treatment regimen with Investigator
choice 
of 
platinum-based 
doublet 
treatment 
for 
6 
cycles)
(
AUC=area under the concentration-time curve; DL=dose level; DLT=dose-limiting toxicity; RP2D=recommended 
Phase II dose; SMC=Safety Monitoring Committee.
Figure 3). Standard of care consisting of Investigator choice among the following platinum 
containing doublet therapies: carboplatin + paclitaxel, carboplatin + gemcitabine, and carboplatin 
+ pegylated lipid doxorubicin with or without bevacizumab (see Section 6.1 for details). For 
participants in the study intervention triplet combination arm only, after M6620 and carboplatin 
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treatment has been discontinued, avelumab will be administered as maintenance therapy 
(every 2 weeks) until PD, unacceptable toxicity, withdrawal of consent, or death.
For participants in the SoC arm of Part B, the treatment cycle duration is 3 or 4 weeks depending 
on the chemotherapy agents administered with platinum as the chosen doublet combination. A 
total of 6 cycles will be administered as the planned treatment regimen. Bevacizumab may be 
administered with the SoC doublet combination as clinically indicated per discretion of the 
Investigator. 
For participants in either Part A or Part B, the study consists of:
! a 4-week Screening Period 
! a Treatment Period including for the study intervention triplet combination, is 18 weeks based 
on six 3-week cycles; for the SoC treatment 6 cycle for a total of to 18 weeks if 3-week cycles 
or 24 weeks if 4-week cycles, depending on chemotherapy agents administered;
! an avelumab Maintenance Treatment Period for the study intervention arm until PD or other 
reason for discontinuation; for the SoC treatment arm,
! a 7-day End of Treatment, 30-day Safety and 90-day Safety Follow-up Period, 
! a Survival follow-up including collection of subsequent treatments and response data and 
survival status up to 1 year after last patient last treatment).
The study design schema is presented in Section 1.2, and the SoA is presented in Section 1.3. See 
Section 6.7 for details on study intervention after the end of the study.
4.2
Scientific Rationale for Study Design
The RP2D of M6620 in combination with carboplatin has previously been established. Because 
no overlapping toxicity, except for potential infusion-related reactions, with addition of avelumab 
is expected, the same RP2D has been selected as the starting dose in Part A and will be confirmed, 
or, if required, de-escalated to lower dose levels for M6620.
See Section 2 for a discussion of the relevance of mode of action for the target disease, preclinical 
and clinical data supporting potential activity for the study.
The study population consists of participants with recurrent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who have progressed on maintenance treatment with a PARPi. The 
scientific rationale for the study population is provided in Section 2.
See Section 5.1 and Section 5.2 for detailed inclusion and exclusion criteria, respectively.
A randomized, controlled design comparing investigational versus SoC treatment has been 
selected for Part B of the study because no prospectively assessed historical data exist for the 
clinical endpoints to be evaluated in PARPi-resistant ovarian cancer upon treatment with SoC.
The primary objective of Part B of the study is to evaluate the antitumor activity of the 
investigational triplet combination regimen (carboplatin + M6620 + avelumab) compared with 
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SoC treatment. In recurrent ovarian cancer, PFS reported by Investigator according to 
RECIST v1.1 is considered an appropriate and feasible endpoint for this Phase II proof-of-concept 
study.
Secondary endpoints relating to safety, PK, confirmed best overall response (BOR), time to 
progression (TTP), and duration of response (DOR) as assessed by the Investigator using 
RECIST v1.1 as well as CA-125 according to the Gynecologic Cancer Intergroup (GCIG) criteria 
are also standard measurements. 
The patient-reported outcome (PRO) assessments were selected based on the hypothesized 
symptoms and functional impacts associated with ovarian cancer. These will contribute to the 
understanding of how the participant is feeling and functioning.
The exploratory 
 assessments were selected based on the hypothesized mechanism of 
action and effects of M6620 and are relevant to the response, 
 
. These will contribute to the understanding of AEs and help in the determination of 
the RP2D of M6620 in combination with avelumab and carboplatin.
4.3
Justification for Dose
4.3.1
M6620
In a M6620 monotherapy dose escalation study, no participants experienced any DLTs with a 
maximum administered dose of 480 mg/m2 (O’Carrigan 2016). M6620 was generally well 
tolerated as a single agent, with few AEs leading to study drug discontinuation. 
The RP2D of M6620 in combination with carboplatin (AUC 5) has been established at 90 mg/m2
from Phase I studies of M6620 (refer to the M6620 IB for additional details). Among participants 
treated at this dose level (M6620 90 mg/m2 + carboplatin AUC 5), 1 DLT of Grade 3 febrile 
neutropenia was reported (Study MS201923-0002 Part B1). The combination treatment was 
otherwise well tolerated (O’Carrigan 2016). Table 6 provides a summary of relevant data from the 
studies VX12-970-001/MS201923-0001 (Part C3) and VX13-970-002 (Parts B1 and C).
Table 6
Summary of Safety Information for Carboplatin + M6620
Combination of 
Carboplatin + M6620
(Study, Part, N)
VX12-970-001, 
Part C3
(N=10)
VX13-970-002, 
Part B1
(N=23)
VX13-970-002, 
Part C
(N=11)
Total
(N=44)
Dose range of M6620
90 mg/m2
60-240 mg/m2
90 mg/m2
Dose of carboplatin
AUC 5
AUC 4 or AUC 5
AUC 5
Participants with at least one AE
8 (80.0%)
23 (100%)
11 (100%)
42 (95.5%)
AEs Grade ≥3
6 (60.0%)a
11 (47.8%)b
7 (63.6%)c
24 (54.6%)
Discontinuation due to an AE
1 (10.0%)
4 (17.4%)
4 (36.4%)d
9 (20.5%)
Deaths due to an AE
0
0
1 (9.1%)e
1 (2.3%)
a AEs Grade ≥3 occurring in ≥2 participants: Thrombocytopenia, neutropenia, anemia, platelet count decreased.
b Neutropenia was the only Grade ≥3 AE that occurred in more than 10% of participants.
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c AEs Grade ≥3 occurring in ≥2 participants: Thrombocytopenia, neutropenia and anemia.
d Discontinuation due to AE included 2 participants with serious infusion-related reactions.
e One participant had a fatal AE of bronchitis.
AE=adverse event; AUC=area under the concentration-time curve.
Reference: M6620 IB 2017.
4.3.1.1
Evidence of Pharmacodynamic Effects of M6620 in 
Combination with Carboplatin
DNA damage, such as that induced by carboplatin, results in ATR-dependent phosphorylation of 
Checkpoint kinase 1 (Chk1). In preclinical studies, ATR inhibition was shown to inhibit Chk1 
phosphorylation following DNA-damaging chemotherapy. Inhibition of Chk1 phosphorylation 
following ATR inhibitor treatment, as assessed by immunohistochemistry, was also observed in 
the clinical Study VX-12-970-002/MS201923-0002. In this study, paired biopsies were obtained 
before and after administration of M6620 in 12 participants who received carboplatin followed by 
M6620. Of these 5 participants had detectable levels of phospho-Chk1 prior to administration of 
M6620, 5 participants receiving 90 mg/m2 of M6620 had decreases of phospho-Chk1 of 29%, 
73%, and 73%, while 1 participant at 90 mg/m2 had a 69% increase in phospho-Chk1. One 
participant at 120 mg/m2 had a 94% decrease in phospho-Chk1. However, 120 mg/m2 of M6620 
was determined to be above the RP2D in combination with carboplatin. Collectively, these data 
support the selection of the 90-mg/m2 dose of M6620 in combination with carboplatin and 
avelumab.
4.3.2
Avelumab
Avelumab has been studied and shown to be well tolerated from 1 to 20 mg/kg every 2 weeks in 
Phase I dose escalation study where maximum tolerated dose was not reached. The clinically active 
dose of 10 mg/kg every 2 weeks has shown a tolerable and manageable safety profile in more than 
1700 participants across multiple tumor types. The avelumab dosing regimen of 10 mg/kg 
every 2 weeks has been approved by the US FDA, the EMA, and other regulatory authorities for
treatment of patients with metastatic Merkel cell carcinoma, and by the US FDA for urothelial 
carcinoma that have progressed following platinum-containing chemotherapy. 
Avelumab was originally dosed on a mg/kg basis with the aim of reducing interparticipant 
variability in drug exposure. However, modeling and simulation of a large body of avelumab PK 
data indicate that a flat dose (i.e., body weight independent) would lead to slightly less variability 
compared with body weight-based dosing due to a modest effect of body weight on avelumab 
clearance. A similar phenomenon has also been reported with other antibody drugs, which include 
the marketed anti-PD-1 and PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab, and 
atezolizumab (Wang 2009, Freshwater 2017, Zhao 2017, Stroh 2017). Given this finding, a 
flat-dose regimen is considered a favorable option which can also offer other advantages such as 
fewer dispensing errors, less drug wastage, shorter dose preparation times, and greater ease of 
administration. 
Consequently, a flat dose of avelumab of 800 mg every 2 weeks has been proposed as a regimen 
comparable to 10 mg/kg every 2 weeks based on the following considerations. The introduction 
of 800 mg every 2 weeks was based on population PK analysis, with data across 3 single-agent 
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avelumab studies in 1827 participants with 14 different types of cancer. PK simulations suggest 
that exposures to avelumab across the available range of body weights are less variable, with 
800 mg every 2 weeks compared with 10 mg/kg every 2 weeks; exposures were similar near the 
population median weight. Low-weight participants tended toward marginally lower exposures 
relative to the rest of the population when weight-based dosing was used, and marginally higher 
exposures when flat dosing was applied. However, the implications of these exposure differences 
are not expected to be clinically meaningful at any weight across the entire population. 
Furthermore, the dosing regimen of 800 mg every 2 weeks is expected to result in Ctrough > 1 μg/mL 
required to maintain avelumab serum concentrations at > 95% target occupancy (TO) throughout 
the entire 2-week dosing interval in all weight categories.
However, in the situation where avelumab is to be combined with chemotherapy that has a 3-week 
treatment cycle, avelumab dosing once every 3 weeks is expected to further improve convenience 
and compliance. For this purpose, exposures of different dose levels of avelumab given 
every 3 weeks were simulated. The results showed that 1600 mg every 3 weeks dosing would 
maintain avelumab exposure within the range demonstrated to provide high TO and meaningful 
antitumor activity. Specifically, avelumab concentration at 1600 mg every 3 weeks would remain
above the Ctrough of 10 mg/kg every 2 weeks for 18.2 days out of 21 days (the cycle duration) and
would be 10-fold higher than the concentration (1 μg/mL) required to achieve > 95% TO in 
peripheral blood mononuclear cells (based on in vitro TO experiments) for the whole 21-day 
duration. The simulated median AUC at 1600 mg every 3 weeks is 47% higher than that obtained 
with a 10-mg/kg dose every 2 weeks. The simulated median Cmax at 1600 mg every 3 weeks is 
comparable to that from a 20-mg/kg dose every 2 weeks, previously studied in the Phase I study, 
which did not show any safety concerns. 
In this study, the 2 regimens of avelumab (800 mg every 2 weeks and 1600 mg every 3 weeks) 
will be employed. The regimen of 1600 mg every 3 weeks was chosen for evaluation in the 
carboplatin + M6620 + avelumab combination to align with the 3-week treatment cycle for 
chemotherapy and M6620 administration. During the avelumab maintenance phase, avelumab will 
be administered as a monotherapy using a regimen of 800 mg every 2 weeks, as synchronization 
with the M6620 and carboplatin regimens will no longer be necessary.
4.3.3
Reference Treatment: Standard of Care
In accordance with the current clinical practice guidelines, participants randomized to the reference 
treatment will receive 1 of the defined SoC treatment regimens with a platinum-containing doublet 
chemotherapy at the recommended dosages. The regimen will be selected by the Investigator 
among the allowable options defined in Section 6.1. 
4.4
End of Study Definition
A participant has completed the study once all assessments have been completed, including the 
90-day Safety Follow-up Phone Call post study drug discontinuation and tumor assessments to 
confirmed progression and or survival status reported death and the last scheduled procedure 
shown in Section 1.3 (SoA).
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The end of the study is defined as the date of 1 year after the last participant received the last dose
or dies, whichever comes first. This clinical study protocol will be closed only if the following 
criteria are met:
! All participants have discontinued study drug treatment regimen and maintenance therapy.
! All protocol specified end of treatment and safety follow-up visits after last participant
discontinues study drug are completed.
! All protocol required procedures or interventions are completed.
! The Post-treatment Follow-up Period (including survival), defined above, has been reached.
The Sponsor may terminate the study at any time for any reason, and there may be allowance for 
participants to enter a rollover study, or other mechanism for avelumab access for Part A or Part B
participants if randomized to that treatment, as appropriate.
5
Study Population
The study population consists of participants with platinum-sensitive recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer that is resistant to maintenance treatment with a 
PARPi. 
The criteria in Section 5.1 (Inclusion Criteria) and Section 5.2 (Exclusion Criteria) are designed to 
enroll only participants who are appropriate for the study, thereby ensuring the study fulfills its 
objectives. All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative has 
provided written informed consent, as indicated in Appendix 2.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are ≥18 years of age, at the time of signing the informed consent.
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Type of Participant and Disease Characteristics
2. Female participants with recurrent epithelial ovarian cancer who have disease progression 
following maintenance treatment with a PARPi as defined below:
a.
Participant must have histologically diagnosed epithelial ovarian, primary 
peritoneal, or fallopian tube cancer, with nonmucinous histology
b. Participants must have completed at least 2 previous courses of platinum-containing 
therapy (e.g., carboplatin or cisplatin) and had documented response (complete 
response [CR] or partial response [PR]) to the last platinum-based treatment prior to 
treatment with a PARPi
c.
Participant has received the last dose of platinum-containing treatment at least 
6 months prior to study enrollment
d. Participant has documented disease progression (radiological) after at least 4 months 
of maintenance treatment with PARPi following a response to platinum-based 
chemotherapy.
3. Confirmed BRCA 1/2 mutation status or agree to its testing on samples collected in the 
study.
4. Available formalin-fixed, paraffin-embedded (FFPE) tumor biopsies.
a.
Part A: Optional - Two (2) paired on-treatment biopsies on Day 2 of Cycle 1 (first 
biopsy) and Day 2 of Cycle 1 or Cycle 2 (second biopsy), before and after M6620 
administration, respectively, if assessed as feasible at low risk by the interventional 
radiologist.
b. Part B: Histological tissue specimen (tissue block or 8 to 10 unstained slides) must 
be available. An archival tumor biopsy is acceptable if obtained after the last 
progression on PARPi treatment and is less than 6 months old. Otherwise,
participants must be willing to undergo mandatory biopsy during the Screening 
Period to obtain sufficient tissue for histological assessment. Participants need to 
have an attempted biopsy. However, participants who have measurable disease 
documented by a radiologist as not feasible or safe to be biopsied are eligible to 
enter the study.
5. Measurable disease according to RECIST v1.1.
6. Greater than 28 days from and recovered from prior radiation therapy or surgery.
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study 
entry at Screening.
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8. Adequate hematological function as defined below: 
a.
White blood cell count ≥3.0 × 109/L 
b. Absolute neutrophil count ≥1.5 × 109/L
c.
Lymphocyte count ≥0.5 × 109/L
d. Platelet count ≥100 × 109/L
e.
Hemoglobin > 9 g/dL.
9. Adequate hepatic function as defined below:
a.
A total bilirubin level ≤1.5 × the upper limit of normal (ULN) range. Participants 
with documented Gilbert disease are allowed if total bilirubin > 1.5, but less than 
3 × ULN
b. Aspartate aminotransferase (AST) levels ≤3.0 × ULN (≤5 × ULN in case of liver 
metastases)
c.
Alanine aminotransferase (ALT) levels ≤3.0 × ULN (≤5 × ULN in case of liver 
metastases)
d. Serum albumin concentrations ≥35 g/L (3.5 g/dL).
10. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min
according to the Cockcroft-Gault formula.
Contraception Use
11. A female participant is eligible if she is not pregnant (i.e., after a confirmed menstrual period 
and a negative serum pregnancy test), not breastfeeding, and at least 1 of the following 
conditions applies to her:
a.
Is not a woman of childbearing potential (WOCBP), as defined in Appendix 3.
OR
b. Is a WOCBP who agrees to use a highly effective contraceptive method (i.e., has a 
failure rate of less than 1% per year), as listed in Appendix 3 from 1 menstrual cycle 
before the cycle preceding the start of the first dose of study intervention (as 
appropriate), during the study intervention period (Parts A and B), and for at least 
6 months after the last dose of carboplatin, M6620, or the defined SoC combination 
treatments, or at least 60 days after the last dose of maintenance with avelumab or 
bevacizumab, whichever is later.
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Informed Consent
12. Can give signed informed consent, as indicated in Appendix 2, which includes compliance 
with the requirements and restrictions listed in the informed consent form (ICF) and this 
protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. All participants with brain metastases, except those meeting the following criteria:
a.
Brain metastases that have been treated locally and are clinically stable for at least 
4 weeks prior to randomization
b. No ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are 
acceptable)
c.
Participants must not be taking steroids.
2. Prior organ transplantation, including allogeneic stem cell transplantation.
3. Previous malignant disease (other than the indication for this study) within the last 5 years 
(except adequately treated nonmelanoma skin cancers or carcinoma in situ of any of the 
following tissues: skin, bladder, cervix, colon/rectum, or breast) unless a complete 
remission without further recurrence was achieved at least 2 years prior to study entry and 
the participant was deemed to have been cured with no additional therapy required or 
anticipated to be required.
4. Active infection requiring systemic therapy:
a.
Known history of human immunodeficiency virus or known acquired 
immunodeficiency syndrome
b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at Screening (positive 
HBV surface antigen or HCV ribonucleic acids [RNAs] if anti-HCV antibody 
screening test positive).
5. Active or history of autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent. Participants with type I diabetes mellitus, vitiligo, psoriasis, 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
6. Known severe hypersensitivity reactions to fully human monoclonal antibodies (Grade ≥3 
National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events 
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[CTCAE]) or to any components of the DDRi- or DNA-damaging anticancer therapy to be 
tested as well as known hypersensitivity to any of excipients.
7. Uncontrolled asthma
8. Persisting toxicity related to prior therapy (NCI-CTCAE Grade > 1); however, alopecia 
Grade ≤2, or other Grade ≤2 AEs not constituting a safety risk based on Investigator’s 
judgment are acceptable.
9. Uncontrolled intercurrent illness including, but not limited to:
a.
Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or 
lower)
b. Uncontrolled active infection
c.
Uncontrolled diabetes (e.g., glycosylated hemoglobin ≥8%).
10. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident or 
stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to 
enrollment), unstable angina, congestive heart failure (New York Heart Association 
Classification Class ≥II), or serious cardiac arrhythmia requiring medication.
11. Known 
history 
of 
inflammatory 
colitis, 
inflammatory 
bowel 
disease, 
pneumonitis/interstitial lung disease, or pulmonary fibrosis.
12. Other severe acute or chronic medical conditions; psychiatric conditions including recent 
(within the past year) or active suicidal ideation or behavior; or laboratory abnormalities 
that may increase the risk associated with study participation or study intervention 
administration or may interfere with the interpretation of study results and, in the judgment 
of the Investigator, would make the participant inappropriate for entry into this study.
13. Any participant with intercurrent bone fracture that may be at risk of delayed healing due 
to protocol therapy.
14. History of tumor bleeding.
15. History of congenital or active immunodeficiency, except for acquired treatment-related 
hypogammaglobulinemia requiring periodic intravenous immunoglobulin infusion.
16. Participants who have been diagnosed with Li-Fraumeni syndrome or ataxia telangiectasia.
Prior/Concomitant Therapy
17. Treatment with a nonpermitted drug/intervention as listed below:
a.
Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy, immune 
therapy, cytokine therapy, monoclonal antibody, or targeted small molecule 
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therapy) or any study intervention within 4 weeks prior to start of study intervention, 
or not recovered from AEs related to such therapies, with the following exceptions: 
i. Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are 
permitted (i.e., luteinizing hormone-releasing hormone agonist/antagonists). 
No other hormonal anticancer therapy is permitted.
ii. Investigational DNA-damaging treatment or chemotherapy as defined for 
the specific cohort in this study.
b. For prior chemotherapy with platinum-containing agents:
i. History of prior dose reductions or dose interruptions while receiving 
cisplatin or carboplatin due to toxicity from the platinum or intolerance to 
either agent, unless discussed with and approved by the Sponsor Medical 
Monitor.
c.
Major surgery (as deemed by Investigator) for any reason, except diagnostic biopsy, 
within 28 days prior to start of study intervention, or not fully recovered from 
surgery within 4 weeks prior to start of study intervention.
d. Prior treatment with a PD-1/PD-L1 targeting agent.
18. Current use of the following medications at the time of enrollment:
a.
Immunotherapy or immunosuppressive drugs (e.g., chemotherapy or systemic 
corticosteroids) EXCEPT for the following: 
i. Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection)
ii. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent
iii. Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication).
b. Growth factors (e.g., granulocyte colony stimulating factor or granulocyte 
macrophage colony stimulating factor) EXCEPT where indicated for treatment of 
study intervention-related myelosuppression and for prophylaxis of repeat 
myelosuppression after initial occurrence.
c.
Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or 
known to potentially interfere with major organ function (e.g., hypericin).
d. Other DNA damage repair inhibitors (except PARPi) (e.g., inhibitors of ATR, ataxia 
telangiectasia mutated [ATM] kinase, DNA-dependent protein kinase [DNA-PK], 
or Wee kinases).
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19. Administration of a live vaccine within 30 days prior to study enrollment.
20. Participants receiving treatment with ototoxic or nephrotoxic medications that cannot be 
discontinued at least 7 days before first dose of carboplatin as part of the study intervention 
and for the duration of the study.
21. Participants receiving treatment with medications that are known to be strong inhibitors or 
inducers of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for at least 1 week 
before the start of treatment and for the duration of the study (see Section 6.5.3).
Other Exclusions
22. Known alcohol or drug abuse as deemed by the Investigator.
23. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent or that would limit compliance with study requirements.
24. Legal incapacity or limited legal capacity.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
No restrictions on meals or diet.
5.3.2
Caffeine, Alcohol, and Tobacco
No restrictions on caffeine, alcohol, or tobacco use are required during the study.
5.3.3
Sun/UV Light Exposure
Nonclinical data indicate that M6620 has phototoxic potential. Thus, it is recommended that 
participants should avoid unnecessary direct or prolonged skin exposure to sunlight or artificial 
ultraviolet rays (e.g., sunray lamp, solarium) during treatment and for 10 days following treatment 
discontinuation in order to prevent photosensitization. The use of protective clothing and eyewear
and the application of a high-protection sunscreen formulation are recommended prior to and 
during sunlight exposure.
5.3.4
Activity
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities (e.g., watching 
television or reading).
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened and will be assigned a new participant number.
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If a participant is rescreened within the 28 days (4-week) Screening Period, the initial screening 
assessments may still be used. In such cases, only lab assessments for hematologic, hepatic, and 
renal function may need to be repeated (see Inclusion Criteria 7, 8, and 9 in Section 5.1).
6
Study Interventions
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol.
6.1
Study Interventions Administration
Table 7
Overview 
of 
Study 
Interventions 
Formulation, 
Dosing, 
and 
Administration
Study Intervention 
Name
Carboplatin
Avelumab
M6620
Dose Formulation
Refer to carboplatin SmPC 
or Package Insert for more 
information.
Sterile, clear, colorless to 
slightly yellow concentrate 
for solution for infusion
Sterile, clear, slightly 
yellow to yellow 
concentrate for solution for 
infusion
Unit Dose 
Strength(s)/
Dosage Level(s)
Refer to carboplatin SmPC 
or Package Insert for more 
information.
20 mg/mL in single-use 
glass vials
20 mg/mL in single-use 
glass vials
Route of 
Administration
Intravenous infusion
Intravenous infusion
Intravenous infusion
Dosing Instructions
AUC 5 on Day 1 of each 
Q3W cycle for a maximum 
of 6 cycles.
Administered before 
avelumab.
See Appendix 4
(Carboplatin dosing) for 
additional information.
During combination 
treatment with 
carboplatin and M6620 
6 cycles: Infusion of 
1600 mg over 1 hour on 
Day 1 of each Q3W cycle
for a maximum 6 cycles.
Administered after 
carboplatin following 
flushing of the intravenous
line.
After the last cycle of 
carboplatin with or 
without M6620: Initiate 
maintenance
monotherapy: 800 mg 
over 1 hour Q2W.
Starting dose: 90 mg/m2
(RP2D of the doublet 
carboplatin + M6620) 
across 60 minutes 
(± 10 minutes) on Day 2 of 
each Q3W cycle for a 
maximum of 6 cycles, only 
if carboplatin was 
administered on the prior 
Day 1.
De-escalated dose (if 
required): 60 mg/m2 or 
40 mg/m2
See also Section 6.6 (Dose Selection and Modification).
Supplier/
Manufacturer
Carboplatin will be sourced 
from the local hospital 
pharmacy or central 
pharmacy.
Avelumab will be supplied 
by the Sponsor and 
packaged, labeled, and 
distributed for clinical 
studies by a suitable 
service provider and finally 
released by a Sponsor 
qualified person under 
Good Manufacturing 
Practice conditions.
M6620 will be supplied by 
the Sponsor and 
packaged, labeled, and 
distributed for clinical 
studies by a suitable 
service provider and finally 
released by a Sponsor 
qualified person under 
Good Manufacturing 
Practice conditions.
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Study Intervention 
Name
Carboplatin
Avelumab
M6620
Packaging and 
Labeling
Refer to carboplatin SmPC 
or Package Insert for more 
information.
Avelumab is formulated as 
a 20.0 mg/mL solution and 
is supplied by the Sponsor 
in single-use glass vials, 
stoppered with a rubber 
septum and sealed with an 
aluminum polypropylene 
flip-off seal. 
Each vial will be packaged 
and labeled per all 
applicable regulatory 
requirements and Good 
Manufacturing Practice 
guidelines. The information 
on the label will be in 
accordance with approved 
submission documents.
Additional details of 
packaging and labeling of 
the study intervention will 
be defined in the separate 
Manual of Procedure.
M6620 is formulated as a 
20 mg/mL solution and is 
supplied by the Sponsor in 
single-use glass vials, 
closed with a rubber 
stopper and sealed with an 
aluminum polypropylene 
flip-off seal. 
Each vial will be packaged 
and labeled per all 
applicable regulatory 
requirements and Good 
Manufacturing Practice 
guidelines. The information 
on the label will be in 
accordance with approved 
submission documents.
Additional details of 
packaging and labeling of 
the study intervention will 
be defined in the separate 
Manual of Procedure.
AUC=area under the concentration-time curve; RP2D=recommended Phase II dose; Q2W=every 2 weeks; 
Q3W=every 3 weeks; SmPC=Summary of Product Characteristics.
Participants who are randomized to reference treatment will receive SoC platinum-containing 
chemotherapy consisting of 1 of the following options to be chosen by the Investigator: 
! Carboplatin AUC 5 + Paclitaxel 175 mg/m2 on Day 1; every 3 weeks for 6 cycles, with or 
without bevacizumab
! Carboplatin AUC 4 on Day 1 + Gemcitabine 1000 mg/m2 (on Days 1 and 8); every 3 weeks for 
6 cycles, with or without bevacizumab.
! Carboplatin AUC 5 on Day 1 + Pegylated liposomal doxorubicin (PLD) 30 mg/m2; every 
4 weeks for up to 6 cycles with or without bevacizumab.
Recommended dosage for the SoC regimen may be adapted per Investigator discretion and in 
accordance to the local institutional guidelines. See Table 8 for further details.
Table 8
Overview of Standard of Care Treatments Formulation, Dosing, and 
Administration
Study 
Intervention 
Name
Carboplatin
Paclitaxel
Gemcitabine
Bevacizumab
Pegylated 
Liposomal 
Doxorubicin (PLD)
Dose 
Formulation
Refer to corresponding SmPCs or Package Inserts for more information.
Unit Dose 
Strength(s)/
Dosage Level(s)
Refer to corresponding SmPCs or Package Inserts for more information.
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Study 
Intervention 
Name
Carboplatin
Paclitaxel
Gemcitabine
Bevacizumab
Pegylated 
Liposomal 
Doxorubicin (PLD)
Route of 
Administration
Intravenous infusion
Dosing 
Instructions
(may be adapted 
in accordance to 
the local 
institutional 
guidelines.)
As defined by corresponding SmPCs and applicable guidelines for recurrent ovarian cancer, 
for example:
AUC 5 (+ 
paclitaxel or 
PLD) or AUC 4 
(+ gemcitabine) 
on Day 1 of 
each Q3W or 
Q4W cycle for a 
maximum of 
6 cycles.
See Appendix 4
(Carboplatin 
dosing) for 
additional 
information.
175 mg/m2
on Day 1 of 
each Q3W 
cycle in 
combination 
with 
carboplatin 
for a 
maximum of 
6 cycles, or 
as clinically 
indicated by 
Investigator 
discretion
1000 mg/m2 on 
Days 1 and 8 of 
each Q3W cycle 
in combination 
with carboplatin 
for a maximum 
of 6 cycles
15 mg/kg on 
Day 1 of each 
Q3W cycle in 
combination with 
carboplatin/ 
paclitaxel or 
carboplatin/ 
gemcitabine 
followed by 
bevacizumab 
monotherapy 
until disease 
progression.
30 mg/m2
intravenously over 
60 minutes each
Q4W (28 days)
cycle in 
combination with 
Carboplatin for a 
maximum of 
6 cycles.
Supplier/
Manufacturer
SoC will be sourced from the local hospital pharmacy or central pharmacy.
Packaging and 
Labeling
Refer to corresponding SmPCs or Package Inserts for more information.
AUC=area under the concentration-time curve; Q3W=every 3 weeks; Q4W=every 4 weeks; SmPC=Summary of 
Product Characteristics.
Toxicities and dose reductions for the reference treatment arm (SoC) will be managed according 
to the Summaries of Product Characteristics (SmPCs) of the individual drugs and the local 
institutional standards.
6.2
Study Interventions Preparation, Handling, Storage, and 
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
! Upon receipt of the study interventions, the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate document and returning 
it to the location specified. A copy will be archived for the Investigator Site File.
! Only participants enrolled in the study may receive study interventions and only authorized site 
staff may supply or administer it. All study interventions must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area, in accordance with the 
labeled storage conditions, and with access limited to the Investigator and authorized site staff.
! Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
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! Study interventions accountability records at the study site will include the following:
o Confirmation of receipt, in good condition and in the defined temperature range
o The inventory provided for the clinical study and prepared at the site
o The dose(s) each participant used during the study
o The disposition (including return, if applicable) of any unused study intervention(s)
o Dates, quantities, batch numbers, container numbers, expiry dates, formulations for study 
interventions prepared at the site, and the participant numbers.
! The Investigator site will maintain records, which adequately document that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled.
! Unused study intervention(s) must not be discarded or used for any purpose other than the 
current study. No study intervention that is dispensed to a participant may be re-dispensed to a 
different participant.
! A Study Monitor will periodically collect the study interventions accountability forms.
! Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
6.2.1
Avelumab
Avelumab is formulated as a 20.0 mg/mL solution and is supplied by the Sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal. 
Avelumab must be stored at 2°C to 8°C until use, with a temperature log maintained daily. All 
medication boxes supplied to each study site must be stored carefully, safely, and separately from 
other drugs.
Avelumab stored at room temperature (23°C to 27°C) or at elevated temperatures (38°C to 42°C) 
for extended periods is subject to degradation. Avelumab must not be frozen. Rough shaking of 
avelumab must be avoided.
For application in this study, avelumab must be diluted with 0.9% saline solution (sodium chloride 
injection) or as indicated in the Pharmacy Manual. Detailed information on infusion bags and 
medical devices to be used for the preparation of the dilutions and subsequent administration will 
be provided in the Pharmacy Manual.
Avelumab must not be used for any purpose other than this study. The administration of avelumab 
provided for the purpose of this study to anyone who has not been enrolled is not covered by the 
study insurance.
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Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration. Storage, handling, preparation, 
and disposal of study interventions should be according to local institutional guidelines.
6.2.2
M6620
M6620 will be supplied as a 20 mg/mL sterile solution provided in 20% betadex sulfobutyl ether 
sodium (w/v) and 86 mM acetate buffer to be diluted in 5% dextrose solution in water before 
intravenous infusion.
Additional instructions for the preparation, handling, storage, and disposal of M6620 will be 
provided in the Manual of Procedure.
6.2.3
Carboplatin
Carboplatin will be sourced from the local hospital pharmacy or central pharmacy.
Refer to the SmPC or Package Insert for additional instructions for preparation, handling, storage, 
and disposal of carboplatin.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
! After confirmation of a participant’s eligibility, the Interactive Web Response System (IWRS)
will be used to assign unique participant numbers.
! After confirmation of a participant’s eligibility for Part B of the study and prior to study 
intervention administration in Part B, participants will be centrally allocated to either study 
intervention (carboplatin + M6620 + avelumab) or SoC treatment in a 1:1 ratio, stratified by 
BRCA status, using IWRS and per a computer-generated randomization list. The Investigator 
should choose and document the potential SoC treatment option for the individual participant 
prior to randomization.
! Before the study is initiated, the telephone number and call-in directions for the IWRS and/or 
the log-in information and directions for the IWRS will be provided to each site. The site will 
contact the IWRS prior to starting study intervention administration for each participant. The 
site will record the study intervention assignment in the applicable electronic case report form 
(eCRF).
6.3.2
Blinding
This is an open-label study. Therefore, study interventions are not blinded. However, any 
aggregate summary of data, if required, will be provided only in a blinded way during the study, 
to limit bias in the conduct of the study.
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6.4
Study Intervention Compliance
In this study, participants will receive study interventions at the investigational site. Well-trained 
medical staff will monitor and perform the administration of study interventions. The information 
of each study intervention administration including the date, time, and dose of study intervention 
will be recorded on the eCRF. The Investigator will ensure that the information entered into the 
eCRF regarding study intervention administration is accurate for each participant. Any reason for 
noncompliance should be documented.
Noncompliance is defined as a participant missing > 1 consecutive cycle of study intervention for 
nonmedical reasons and barring any extenuating circumstances in the opinion of the Investigator. 
If 1 cycle was missed and the interval between the subsequent treatment cycle and the last 
administered treatment cycle is longer than 4 weeks for nonmedical reasons, the criteria of 
insufficient compliance are met as well. Continuation of treatment should be discussed with the 
Medical Monitor under consideration of scientific integrity of the data, potential benefits and risks 
of study interventions and any alternative options.
Noncompliance may lead to discontinuation of study interventions as described in Section 7.1. In 
case of overdose, see Section 8.4. Noncompliant participants may be replaced.
6.5
Concomitant Therapy
Record in the eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Rescue Medicine
Rescue medications may be administered due to adverse reactions or emergency situations.
Immediate access to an intensive care unit or equivalent environment and appropriate medical 
therapy (including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen) must be available for use in the treatment of infusion-related reactions. 
If hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. Participants should be instructed to report any delayed reactions to the 
Investigator immediately. In addition, all hypersensitivity reactions are to be reported in a timely 
manner.
6.5.2
Permitted Medicines
Any medicines that are considered necessary to protect the participant’s welfare in emergencies 
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
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Administration of steroids through a route known to result in a minimal systemic exposure (topical, 
intranasal, intro-ocular, or inhalation) or as short-term premedication for study interventions are 
acceptable.
6.5.2.1
Prophylactic Medications and Treatments
Table 9 lists the prophylactic medications that should be administered prior to the administrations 
of avelumab and/or M6620.
Table 9
Prophylactic Medications Administered Prior to Avelumab and/or 
M6620
Avelumab
M6620
Comment
Antihistamine
X
X
e.g., either 10 mg of chlorphenamine or 25 mg of 
diphenhydramine iv approximately 30 to 
60 minutes before the infusions, or alternative 
drugs as per local guidelines
Corticosteroids
X
100 mg to 200 mg hydrocortisone iv
approximately 60 minutes (± 15 minutes) before 
M6620 infusion
Acetaminophen (paracetamol)
X
500-650 mg approximately 30 to 60 minutes 
before the infusions.
iv=intravenous.
For avelumab, premedication is mandatory prior to the first 4 doses, and thereafter is based upon 
clinical judgment and presence/severity of prior infusion reactions. Standard prophylactic 
premedication with corticosteroids is not recommended; however, prophylactic steroids to prevent 
recurrence of infusion-related reaction are not prohibited, based on the Investigator’s clinical 
judgment.
Premedication with a corticosteroid and an antihistamine should be given to participants who have 
developed acute hypersensitivity or pruritus with M6620 infusion and who continue to receive 
treatment with M6620.
For carboplatin and other SoC treatments, premedications (e.g., antiemetics, corticosteroids, etc.) 
should be administered according to the local institutional treatment standards.
Premedications and their regimens may be modified based on local treatment standards and 
guidelines as appropriate.
6.5.3
Prohibited Medicines
Prohibited medicines are as listed in the exclusion criteria (see Section 5.2).
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The following treatments must not be administered during the study:
1. Immunotherapy or immunosuppressive drugs (i.e., chemotherapy other than assigned study 
intervention or systemic corticosteroids) except: 
a.
When required for the treatment of irAEs, infusion-related reactions, or 
hypersensitivity to any of the study interventions
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent
c.
Systemic corticosteroids for management of participants with allergy to CT 
intravenous radiographic contrast media.
2. Administration of a live vaccine within 30 days prior to study intervention.
3. Growth factors (e.g., granulocyte colony stimulating factor or granulocyte macrophage 
colony stimulating factor). Exception: Growth factors are allowed for treatment of study
intervention-related myelosuppression and for prophylaxis of repeat myelosuppression 
after initial occurrence.
4. Hematopoietic growth factors within 14 days before the first dose of study intervention. 
During Cycle 1 in the Part A, hematopoietic growth factors may not be used 
prophylactically. These may be used to specifically address participant symptoms. 
5. Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to 
potentially interfere with major organ function (e.g., hypericin).
6. Strong CYP3A inhibitors or inducers as listed in Appendix 5 from 14 days before the start 
of study intervention until 7 days after discontinuation of M6620.
If a participant receives prohibited medication that is considered medically necessary, 
the participant may be withdrawn from the study at the discretion of the Investigator in case 
potential risks of continuation of allocated treatment are deemed to outweigh potential benefits 
(see Section 7).
The Investigator should refer to the carboplatin SmPC or Package Insert for guidance on prohibited 
mediations during treatment. 
6.5.4
Other Interventions
The following nondrug therapy must not be administered during the study (and within 28 days 
before the start of study intervention):
! Radiotherapy, with the exception of palliative short course, limited field (i.e., ≤10 fractions and 
≤30% bone marrow involvement or per institutional standard) radiotherapy, which may be 
administered during the study. However, as M6620 and other DDRi are expected to synergize 
with radiotherapy both on the efficacy and the safety end, M6620 dosing must be suspended at 
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least 5 days prior to the start of radiotherapy and must not be resumed until at least 5 days after 
the last radiotherapy fraction. Note: The assessment of PD will be made according to 
RECIST v1.1 (Eisenhauer 2009) and not based on the necessity for palliative radiotherapy.
6.6
Dose Selection and Modification
An overview of the intended study interventions dose and timing of treatments is provided in 
Table 10. Participants will receive carboplatin + M6620 + avelumab or SoC as per the initial 
treatment assignment until the criteria are met as outlined in Section 4.4 (End of Study Definition) 
and Section 6.7 (Study Interventions After the End of the Study).
Table 10
Overview of Intended Study Interventions Dose and Timing of 
Treatments
Study Intervention
Administration Days for 
Each Cycle
Dose 
Administration
Carboplatin
On Day 1 of each Q3W cycle 
for a maximum of 6 cycles
AUC 5 (for 6 cycles)
Carboplatin will be 
administered before 
avelumab. 
(Guidance on 
premedication is given in 
Section 6.5.2.)
Avelumab
On Day 1 of each Q3W cycle 
1600 mg Q3W in 
combination with 
carboplatin + M6620 for up 
to 6 cycles
800 mg Q2W as 
monotherapy following 
discontinuation of 
carboplatin + M6620 until 
PD or discontinuation after 
minimum 12 months of 
maintenance after a 
confirmed CR per 
RECIST v1.1
Avelumab will be 
administered after 
carboplatin following flush 
of the iv line. 
(Guidance on 
premedication is given in 
Section 6.5.2.)
M6620
On Day 2 of a Q3W cycle for a 
maximum of 6 cycles (only 
with prior carboplatin 
administration)
Starting dose: 90 mg/m2
(RP2D) of the doublet 
carboplatin + M6620
De-escalated dose (if 
required) to 60 mg/m2 or 
40 mg/m2
(Guidance on 
premedication is given in 
Section 6.5.2.)
AUC=area under the concentration-time curve; iv=intravenous; Q2W=every 2 weeks; Q3W=every 3 weeks; 
PD=progressive disease; RP2D=recommended Phase II dose.
No intraparticipant dose modifications of avelumab will be allowed during this study. 
Modifications of the infusion rate due to infusion-related reactions, as well as for other reasons, 
are permitted as described in Section 6.11.1.
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In the case of occurrence of an AE attributed to M6620, treatment may be interrupted and may 
resume when all toxicities have returned to Grade 2 or less, at the discretion of the Investigator. In 
case a dose reduction is necessary, M6620 will be administered as described in Section 6.11.2.
No dose modifications of carboplatin are allowed prior to occurrence of a DLT. In case a dose 
reduction is necessary, carboplatin will be administered as described in Section 6.11.3.
Justification for dose is presented in Section 4.3.
As described in Appendix 2, the SMC will review the safety data on a regular basis throughout 
this clinical study. For the Safety Run-in Period (Part A), the SMC will regularly review the safety 
of participants enrolled in this study (at least after each applicable dose level), will decide on 
relevant DLTs based on criteria defined in the protocol (see Section 6.6.1) and by consensus on 
dose de-escalation, or suspension of enrollment and/or recommendation of the safe dose of 
carboplatin + M6620 in combination with avelumab. 
6.6.1
Definition of Dose-limiting Toxicity
A DLT is specifically defined as any death not clearly due to the underlying disease or extraneous 
causes or any Grade ≥3 nonhematologic or Grade ≥4 hematologic toxicity that is possibly, 
probably, or definitely related to any of the study interventions (carboplatin, M6620, or avelumab) 
or the combination (as assessed by the Investigator and/or Sponsor) that occurs during the 3-week 
DLT observation period, except for any of the following:
! Grade 3 infusion-related reaction resolving within 6 hours from the end of infusion and 
controlled with medical management.
! Transient (≤6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.
! Transient (≤72 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤1 with medical management.
! Grade 3 diarrhea, Grade 3 skin toxicity, or Grade 3 liver function test increase (ALT or AST) 
that resolves to Grade ≤1 in less than 3 days after medical management (e.g.,
immunosuppressant or antidiarrheal treatment) has been initiated. EXCEPTION: Grade 3 liver 
function test increases that are assessed as irAEs will still be considered a DLT.
! Single laboratory values out of normal range that, according to the Investigator, do not have 
any clinical correlate, and resolve to Grade ≤1 within 7 days with adequate medical 
management.
! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor that resolve to Grade ≤2 within 3 days.
! Neutropenia (Grade 3 or 4) less than 7 days not associated with any infection (clinically or 
microbiologically). NOTE: Grade 3 or 4 neutropenia with clinical signs/symptoms (e.g., febrile 
neutropenia) is a DLT.
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! Grade 3 thrombocytopenia for less than 7 days without clinically significant bleeding and not 
requiring platelet transfusion. 
! Symptomatic thyroid dysfunction that is manageable with adequate treatment and resolves to 
Grade ≤2 within 6 days.
6.7
Study Intervention Beyond Progression
6.7.1
Treatment Beyond Initial Progression
Participants will receive study interventions as outlined in the SoA with avelumab administered 
until disease progression. Study interventions may continue past the initial determination of 
disease progression according to RECIST v1.1 as long as the following criteria are met:
! Participant was allocated to receive avelumab, and treatment with avelumab is ongoing
! No new unacceptable treatment or disease-related toxicity
! Tolerance of study interventions
! Stable ECOG PS
! Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases).
A radiographic assessment should be performed within 4 to 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the participant is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with study 
intervention(s).
6.7.2
Treatment Beyond Confirmed Progression
After confirmed PD, if the Investigator feels that the participant continues to achieve clinical 
benefit by continuing treatment with avelumab, with or without carboplatin and M6620, the 
participant should remain on the study and continue to receive monitoring according to the SoA. 
The decision to continue treatment beyond confirmed PD should be discussed with the Medical 
Monitor and documented in the study records.
Participants receiving avelumab who continue beyond progression will be evaluated for further 
tumor response as per the protocol schedule. Treatment should be discontinued permanently upon 
documentation of further, unequivocal disease progression unless there are no alternative 
therapeutic options and the benefit-risk assessment is favorable in consultation between the 
Investigator and the Medical Monitor. In case of continuation of treatment beyond PD, treatment 
will be discontinued once any other criteria for withdrawal are met (see Section 7.1).
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6.8
Continuation of Study Intervention After Local Treatment of 
Disease Progression
If disease progression is due to brain metastasis, participants may continue study interventions 
after the local treatment of the brain lesions provided that the above criteria are met in addition to 
the following:
! Tumor assessment showing disease progression has been performed and was documented 
according to RECIST v1.1 prior to the procedure.
! Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior to 
re-initiation of study interventions. 
! There are no ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).
! Participants must be either off steroids or on a stable or decreasing dose of ≤10 mg daily 
prednisone (or equivalent).
! Benefit-risk assessment to continue study intervention is favorable under consideration of any 
alternative treatment options as assessed by the Investigator.
In addition, if disease progression is mainly due to a metastatic lesion that in the opinion of the 
Investigator may be surgically removed, participants may continue study interventions after the 
local treatment of such a lesion, provided that:
! Tumor assessment showing disease progression has been performed and was documented 
according to RECIST v1.1 prior to the procedure.
! It has been at least 2 weeks and the participant has fully recovered from the surgery.
! Benefit-risk assessment to continue study intervention is favorable under consideration of any 
alternative treatment options as assessed by the Investigator.
6.9
Study Intervention After the End of the Study
After a participant has completed the study or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the investigational site’s SoC, generally accepted 
medical practice, and depending on the participant’s individual medical needs. The Sponsor will 
not provide any additional care to participants who have discontinued the study because such care 
should not differ from what is normally expected for participants with advanced malignancies.
Upon withdrawal from the study, participants may receive whatever care they and their physicians 
agree upon.
Survival follow-up will continue for participants until up to 1 year after the last participant has 
received the last dose or the last participant dies, whichever comes first. The Sponsor may 
terminate the study at any time and there may be allowance for participants to enter a rollover 
study, or other mechanism for avelumab access for Part A or Part B participants if randomized to 
that treatment, as appropriate.
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6.10
Special Precautions
6.10.1
Avelumab
As a routine precaution, participants enrolled in this study must be observed for 1 hour post 
infusion for the first 4 infusions, and then according to clinical signs and symptoms, in an area 
with resuscitation equipment and emergency agents. At all times during investigational treatment, 
immediate emergency treatment of an infusion-related reaction or a severe hypersensitivity 
reaction according to institutional standards must be assured. Treatment for possible 
hypersensitivity reactions (e.g., dexamethasone 10 mg and epinephrine in a 1:1000 dilution or 
equivalents) should always be available along with equipment for assisted ventilation.
Prophylactic medications and treatments are outlined in Section 6.5.2. The treatment 
recommendations for infusion-related reactions are outlined in Section 6.11. 
Investigators should also monitor participants closely for potential irAEs, which may occur at any 
time during treatment. Such events include, but are not limited to, pneumonitis, hepatitis, colitis, 
endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes 
mellitus), myocarditis, myositis, and rash. See Section 6.11 for details on the management of 
irAEs.
If a hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. Participants should be instructed to report any delayed reactions to the 
Investigator immediately.
6.10.2
M6620
To minimize the possibility of phlebitis, M6620 should be administered through a large-bore 
catheter into a large-caliber peripheral vein or central line if clinically indicated. The intravenous
infusion site should be monitored closely for the development of erythema, induration, purulence, 
tenderness, or warmth.
If any participant develops phlebitis, or signs or symptoms of inflammation that may progress to 
phlebitis or that the participant cannot tolerate, standard measures should be employed to 
ameliorate these symptoms (including removal of the infusion catheter and resumption of infusion 
through a different vein). If standard procedures to limit symptoms of injection site reaction, or 
pruritus or acute hypersensitivity are insufficient, then the infusion time may be extended beyond 
60 minutes, but no more than 90 minutes.
Based on the observation of acute hypersensitivity in 3 participants at various doses of M6620 and 
of pruritus in 2 participants at 480 mg/m2 of M6620, premedication with a corticosteroid and an 
antihistamine may be considered for all participants receiving M6620 (as prophylaxis against 
possible acute hypersensitivity). In addition, corticosteroids and antihistamine should be used for 
treatment of participants who develop acute hypersensitivity or pruritus after M6620 infusion, and 
should be used prophylactically as premedication for all participants who develop acute 
hypersensitivity or pruritus with M6620 infusion and who continue to receive treatment with 
M6620 (see Section 6.5.2).
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6.10.3
Carboplatin
Refer to the carboplatin SmPC or Package Insert for information regarding precautions.
6.10.4
Standard of Care Treatment
Refer to the respective SmPCs or Package Inserts for information regarding precautions.
6.11
Management of Adverse Events of Interest
6.11.1
Avelumab
The following adverse drug reactions (ADRs) (defined as an AE that is thought to potentially be 
related to study intervention) require permanent treatment discontinuation or treatment 
modification of avelumab:
! Any Grade 4 ADRs: permanently discontinue avelumab except for laboratory values out of 
normal range that do not have any clinical correlate.
! Any Grade 3 ADRs: 
o Withhold avelumab except for laboratory values out of normal range that do not have any 
clinical correlate.
o Permanently discontinue avelumab if toxicity does not resolve to Grade ≤1 or baseline 
within 12 weeks of last administration or if the same Grade 3 toxicity recurs (consider 
consult with the Medical Monitor before permanently discontinuing the treatment).
If dosing is delayed more than 4 weeks, treatment may be resumed after consultation with the 
study Medical Monitor. Any delay in dosing in excess of 12 weeks due to ADRs is not permitted.
Infusion-related reactions and irAEs should be handled according to the following guidelines (see 
Appendix 6) and consistent with the 2018 ASCO guidelines.
Infusion-related Reactions
To mitigate infusion-related reactions, participants must be premedicated as described in 
Section 6.5.2.
Management of infusion-related reactions should follow the guidelines presented in Table 11.
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Table 11
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated with Avelumab
NCI-CTCAE Grade
Treatment Modification for Avelumab
Grade 1 – mild
!
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
!
Decrease the avelumab infusion rate by 50% 
and monitor closely for any worsening.
Grade 2 – moderate
!
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, iv 
fluids); prophylactic medications indicated for 
# 24 hours.
!
Temporarily discontinue avelumab infusion.
!
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity and
monitor closely for any worsening.
Grade 3 or Grade 4 – severe or life-threatening
!
Grade 3: Prolonged (e.g., not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.
!
Grade 4: Life-threatening consequences; 
urgent intervention indicated.
!
Stop the avelumab infusion immediately and 
disconnect infusion tubing from the participant.
!
Participants must be withdrawn immediately 
from avelumab treatment and must not receive 
any further avelumab treatment.
CTCAE=Common Terminology Criteria for Adverse Events; iv=intravenous; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Immune-related Adverse Events
Because inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs 
is mainly dependent upon severity (NCI-CTCAE grade):
! Grade 1 to 2: treat symptomatically or with moderate dose steroids and increase the frequency 
of monitoring
! Grade 1 to 2 (persistent): manage similar to high-grade AE (Grade 3 to 4)
! Grade 3 to 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow the guidelines presented in Appendix 6 (Management of irAEs).
6.11.2
M6620
In the case of occurrence of an AE attributed to M6620, treatment may be interrupted and may 
resume when all toxicities have returned to Grade 2 or less, at the discretion of the Investigator.
Except for participants in Part A during the DLT observation period, doses of M6620 may be 
reduced after occurrence of a related AE using the following guidelines:
! For Grade 4 hematologic toxicity: the dose of M6620 will be reduced by 25%
! For Grade 3 nonhematologic toxicity: the dose of M6620 will be reduced by 25%
! For Grade 4 nonhematologic toxicity: the dose of M6620 will be reduced by 50%.
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Guidelines for dose modification for toxicity are provided below. The final dose reduction or delay 
for each participant may be determined by the Investigator and Sponsor. However, these guidelines 
provide the minimum dose reduction or delay criteria. Additionally, if a participant who is 
responding to treatment experiences toxicity even after 2 dose reductions, the participant may 
continue to receive treatment if in the judgment of the Investigator it is in the best interest of the 
participant. In this case the dose of M6620 will further be reduced by at least 25%.
! In case of M6620 Grade 3 or higher toxicity (excluding fatigue or nausea/vomiting/diarrhea 
adequately managed by supportive care), treatment will be interrupted and may be resumed 
when all toxicities have returned to Grade 2 or lower, at the discretion of the Investigator.
! For the following hematologic toxicities, once the toxicity has returned to Grade 2 or lower, 
dosing can be resumed with 1 dose level reduction (Table 12). If, after 1 dose level reduction, 
any of the below drug-related hematologic toxicities are subsequently observed, then dosing 
may be resumed with 2 dose level reductions (Table 12):
! Grade 4 thrombocytopenia
! Febrile neutropenia (growth factor support, per site protocol, may be used in lieu of dose 
reduction) except during the DLT assessment period prior to occurrence of a DLT. Once a 
DLT has occurred, it is acceptable to use growth factor support even during the DLT period.
! Grade 4 neutropenia lasting more than 7 days.
! If any of the drug-related toxicity listed below is subsequently observed, the M6620 dose will 
be reduced by 1 dose level (Table 12).
! Grade 3 nonhematologic toxicity (except for fatigue or nausea, vomiting, or diarrhea 
adequately controlled by medication). For infusion reactions, hypersensitivity, or allergic 
reactions related or possibly related to M6620, see Section 6.10.2 for additional guidelines 
for management.
! Any Grade 2 or lower nonhematologic toxicity requiring dose delay of more than 2 weeks.
! For Grade 4 nonhematologic toxicity, treatment will be interrupted and may be resumed with 
2 dose level reductions (Table 12) when toxicity has returned to Grade 2 or lower.
If any toxicity not described above results in a delay in dosing during any part of the study and the 
participant may be benefitting from therapy, then the doses of M6620 may be reduced by 1 dose 
level at the discretion of the Investigator.
Table 12
Guidelines for M6620 Dose Modification for Toxicity in Combination 
with Avelumab and Carboplatin
Dose Level
M6620
(mg/m2)
Carboplatin
(mg∙min/mL)
1
90
AUC 5
-1
60
AUC 5
-2
40
AUC 5
AUC=area under the concentration-time curve.
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6.11.3
Carboplatin
No dose modifications of carboplatin are allowed prior to occurrence of a DLT. 
See Table 12 for dose level modification guidelines for toxicity when administering carboplatin 
with M6620 + avelumab.
6.11.4
Standard of Care Treatment
Sites should refer to institutional standards for management of ADRs for SoC platinum 
chemotherapy.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Interventions
Participants must be withdrawn from study interventions if any of the following occurs:
! Participants meeting the definition of confirmed PD while on treatment based on RECIST v1.1. 
Participants who experience PD may continue treatment with study interventions under 
conditions described in Section 6.7 if the Investigator believes the participant will experience 
clinical benefit from the treatment and there is no unacceptable toxicity resulting from the 
treatment. Such participants will be withdrawn from the treatment if any other criteria for 
withdrawal are met or if alternative treatment options are available and indicated.
o In case of premature withdrawal from the study interventions for reasons other than PD, 
participants will be asked to attend scheduled visits, including tumor assessment and other 
assessments as planned, until confirmed PD, end of study, or death.
! Significant clinical deterioration (clinical progression), defined as new symptoms that are 
deemed by the Investigator to be clinically significant or significant worsening of existing 
symptoms.
! Unacceptable toxicity.
! Withdrawal of consent from further treatment or from further study participation. In case of 
selective withdrawal from study intervention, other study-related procedures and assessments 
should be continued as planned.
! Occurrence of an exclusion criterion, which is clinically relevant and affects the participant’s 
safety, if study intervention discontinuation is considered necessary by the Investigator and/or 
Sponsor.
! Therapeutic failure requiring urgent additional drug (if applicable).
! Occurrence of any Grade 4 ADRs (defined as an AE that is thought to potentially be related to 
study interventions) (see Section 6.11).
! Occurrence of AEs resulting in the discontinuation of the study interventions being desired or 
considered necessary by the Investigator and/or the participant.
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! Occurrence of irAEs requiring discontinuation of study interventions as described in
Appendix 6.
! Occurrence of pregnancy.
! Use of a prohibited concomitant drug, as defined in Section 6.5.3, where the predefined 
consequence is withdrawal from the study intervention if considered necessary by the 
Investigator or the Sponsor.
! Noncompliance if the benefit-risk assessment for continuation of treatment is negative 
according to Investigator assessment.
! Participation in another interventional clinical study.
For study group assigned to carboplatin + M6620 + avelumab, if confirmed CR by RECIST v1.1 
followed by minimum 12 months of maintenance therapy then may discontinue treatment if 
participant and Investigator agree.
Investigator should consult with Medical Monitor if early discontinuation of 1 of the 3 drugs in 
the study intervention to discuss plan for completing the 6 cycles as per the following options;
!
If participant discontinues carboplatin early for any reason, then must also discontinue 
M6620 and proceed into the avelumab maintenance. 
!
If participant discontinues M6620 early for any reason, but clinically can continue to 
receive carboplatin, then may complete the 6 cycles of treatment and proceed into the 
avelumab maintenance. 
!
If participant discontinues avelumab early for any reason prior to completing the 6 cycles, 
but clinically can continue carboplatin + M6620 or carboplatin alone to complete the 
6 cycles and then proceed to End of Treatment visit. 
Participants who prematurely discontinue treatment in this study or who are withdrawn from the 
study for any reason will be asked to return to the clinical site for an End of Treatment Visit within 
7 days, and Safety Follow-up Visits at 30 days (in office) and 90 days (phone call) after their last 
dose of study intervention. As applicable, participants who have no evidence of PD at 
discontinuation, will also be asked to return for follow-up tumor scans according to the SoA
(Section 1.3). Participants will be followed every 12 weeks for survival and documentation of 
anticancer treatment, for which participants may come to the study site or may be contacted by 
phone.
The SoA (Section 1.3) specifies the data to collect at study intervention discontinuation and follow-
up, and any additional evaluations that need to be completed.
7.1.1
Temporary Discontinuation
See Section 6.11 for instructions for temporary discontinuation of study interventions in response 
to Grade 2 infusion-related reactions or toxicity events. See Section 6.5 for temporary 
discontinuation due to administration of prohibited medicines or interventions.
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Instructions for temporary discontinuation of study interventions in the management of irAEs are 
presented in Appendix 6 (Management of irAEs).
7.2
Participant Discontinuation/Withdrawal from the Study
! A participant may withdraw from the study at any time, at his/her own request (i.e., withdrawal 
of consent), and without giving a reason. Withdrawal of consent will be considered withdrawal 
from the study unless the participant agrees to participate in further study-related assessments 
and/or agrees to be followed for survival, which may include verification of medical records. 
Participants should be explicitly asked at the time of withdrawal of consent if they would allow 
further study-related assessments, especially tumor assessment, safety-related assessments, 
documentation of subsequent anticancer therapy, or collection of survival information including 
verification of medical/public records or contact of the participant’s primary physician or family 
as permitted by local regulations. These responses should accordingly be captured in the eCRF.
! The participant may be withdrawn by the Investigator due to participation in another clinical 
study; however, participants will continue to be followed for survival and documentation of 
anticancer treatment.
! The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons.
! The SoA specifies the data to collect at study discontinuation and follow-up, and any additional 
evaluations that need to be completed. In case of participant withdrawal from the study, the 
appropriate End of Study page must be completed.
! If a participant fails to attend scheduled study assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
! In Part A, if a participant is withdrawn prior to the end of the DLT observation period (for any 
reason except for a DLT), the participant may be replaced.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
! The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study.
! Before a participant is deemed “lost to follow-up,” the Investigator or designee must make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be documented 
in the participant’s medical record.
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! Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.
8
Study Assessments and Procedures
! Study assessments and procedures and their timing are summarized in the SoA (Section 1.3).
! No protocol waivers or exemptions are allowed.
! Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.
! Adherence to the study design requirements, including those specified in the SoA (Section 1.3), 
is essential and required for study conduct.
! All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for screening 
failure.
! Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2.
! Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA (Section 1.3).
! Order of Procedures:
o Patient-reported outcomes assessments should be completed by the participant prior to a 
health care intervention of any nature, regardless of whether it is study-related. A protocol 
deviation occurs only when study-related interventions occur prior to PRO assessments, 
other than vital signs, demographics, and clinical history information.
o Electrocardiogram assessments should be performed prior to blood sample collection, such 
that the blood sample is collected at the nominal time. However, at the PK time points where 
the acceptable window of sample collection is within 5 minutes, the ECG should be 
performed 10 minutes after sample collection to allow participants to recover to normal heart 
rate. 
8.1
Efficacy Assessments and Procedures
8.1.1
Tumor Response Assessment
Computed tomography or magnetic resonance imaging (MRI) scans will be performed and 
collected until confirmed PD is assessed by the Investigator according to RECIST v1.1
(Eisenhauer 2009) or until start of new anticancer therapy in case of continuation of avelumab 
beyond PD, according to the SoA (Section 1.3). 
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For participants receiving avelumab, a subsequent scan 4 to 6 weeks after the initial assessment of 
PD should be collected if clinically feasible to confirm PD. 
Radiographic images and physical findings (physical assessments) will be used by the Investigator 
for the local determination of PD and participant’s treatment decisions. 
For each participant, tumor response assessment will be performed by CT scan or MRI (if MRI is 
used, chest CT is mandatory) imaging of the chest/abdomen/pelvis (plus other regions as 
specifically required) and other established assessments of tumor burden if CT/MRI imaging is 
insufficient for the individual participant. All scans performed at Screening and other imaging 
performed as clinically required (other supportive imaging) need to be repeated at subsequent 
visits. In general, lesions detected at Screening need to be followed using the same imaging 
methodology and preferably the same imaging equipment at subsequent tumor evaluation visits.
For each participant, the Investigator will designate 1 or more of the following measures of tumor 
status to follow for determining response: CT or MRI images of primary and/or metastatic tumor 
masses, physical examination findings, and the results of other assessments. All available images 
collected during the study period will be considered. The most appropriate measures to evaluate 
the tumor status of a participant should be used. The measure(s) to be chosen for sequential 
evaluation during the study must correspond to the measures used to document the progressive 
tumor status that qualifies the participant for enrollment. The tumor response assessment will be 
assessed and listed according to the SoA (Section 1.3).
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
disease status. Investigator’s assessment of objective tumor response to treatment will be 
performed according to RECIST v1.1 (all measurements should be recorded in metric notation, as 
described in RECIST v1.1).
! At Baseline, tumor lesions will be categorized in target and nontarget lesions as described in 
RECIST v1.1.
! Results for these evaluations will be recorded with as much specificity as possible so that 
pretreatment and post-treatment results will provide the best opportunity for evaluating tumor 
response. 
! Any CR or PR should be confirmed, preferably at the next subsequent scheduled imaging
interval, but no sooner than 6 weeks after the initial documentation of CR or PR. Confirmation 
of PR can be confirmed at an assessment later than the next assessment after the initial 
documentation of PR.
! The Investigator may perform scans in addition to a scheduled study scan for medical reasons 
or if the Investigator suspects PD. Participants who withdraw from the investigational treatment 
for clinical or symptomatic deterioration before objective documentation of PD or who 
discontinue from investigational treatment for reasons other than objective PD will be requested 
to continue appropriate imaging according to the study schedule until determination of 
confirmed PD or discontinuation of the study, whichever occurs earlier. Every effort should be 
made to confirm a clinical diagnosis of PD by imaging.
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8.1.2
Response Evaluation Based on CA-125 According to 
Gynecologic Cancer Intergroup Recommendations
Tumor response evaluation based on cancer antigen 125 (CA-125) will be assessed according to 
the SoA (Section 1.3). 
According to the GCIG criteria, response based on CA-125 is defined as at least a 50% reduction 
in CA-125 levels from a pretreatment sample. The response must be confirmed and maintained for 
at least 28 days. Participants can be evaluated according to CA-125 only if they have a pretreatment 
sample that is ≥2 × ULN and within 2 weeks prior to starting treatment (Rustin 2011).
According to the GCIG criteria progression based on CA-125 is defined as progression by 
RECIST v1.1 OR progression by CA-125.
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a
progressive serial elevation of serum CA-125 according to the following criteria:
1. Participants with elevated CA-125 pretreatment and normalization of CA-125 must show
evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 
2 occasions at least 1 week apart, OR
2. Participants with elevated CA-125 before treatment, which never normalizes, must show
evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 occasions at least 1 
week apart, OR
3. Participants with CA-125 in the reference range before treatment must show evidence of
CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 2 occasions 
at least 1 week apart.
CA-125 progression will be assigned the date of the first measurement that meets the criteria as 
noted. Participants are not evaluable by CA-125 if there has been medical and/or surgical
interference with their peritoneum or pleura (e.g., paracentesis) during the previous 28 days.
A Participant may be declared to have PD on the basis of either the objective RECIST v1.1 criteria
or the CA-125 criteria. The date of progression will be the date of the earlier of the 2 events if both 
are documented.
8.1.3
Survival Follow-up
Participants without PD according to RECIST v1.1 at the End of Treatment Visit will be followed 
up for disease progression (CT/MRI scans according to the schedule indicated in the SoA 
[Section 1.3], using the same procedures and review as while on treatment) until PD. In the case 
of PD with discontinuation of treatment, any subsequent local tumor assessments should be 
documented. Any subsequent anticancer therapies and the date of any response and subsequent 
progression should be captured in the eCRF.
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Participants will be followed every 12 weeks (± 1 week) for survival (including assessment of any 
further antitumor therapy). The survival follow-up will continue until 1 year after the last 
participant receives the last dose of study intervention, or the last participant dies, whichever 
occurs first. Under some circumstances, participants may not be followed for 1 year for survival 
in this study; e.g., participants may be offered to enroll into a rollover study, or the Sponsor may 
terminate the study early.
8.1.4
Patient-reported Outcomes
Patient-reported outcomes will be distributed in paper form, accompanied by the instructions on 
how to complete them, exclusively for Part B participants and according to the SoA (Section 1.3).
If the participant is illiterate, blind, or too ill to complete PRO measures, the study staff (e.g., Study 
Coordinator, Investigator, or Subinvestigator) may obtain the participant’s responses by reading 
aloud each question followed by the corresponding response categories and recording the 
participant’s response. No help should be provided to the participant by any person other than the 
designated study staff. The designated study staff should not influence the participant’s responses 
by any means, such as commenting, agreeing, or disagreeing with responses, either verbally or 
nonverbally. The designated study staff cannot translate the question into simpler language, and 
questions must be read verbatim. Any content may be repeated and/or read more slowly for 
clarification upon participant request. These instances must be documented as notes to file and 
included in the study site file.
The baseline assessments should be completed at Screening; if this does not occur, they can be 
done at Visit 1 (Day 1).
Whenever possible, the PRO assessments should be completed by the participant prior to a health 
care intervention of any nature, regardless of whether it is study-related or not. This sequencing is 
important to reduce measurement bias as the participant’s assessment should reflect the 
participant’s impressions up to a given visit; any intervention administered on that visit would be 
captured in the subsequent assessment. Any intervention on a given visit may bias the participant’s 
responses positively or negatively and may no longer be an accurate reflection of the participant’s 
impressions leading up to that visit. A protocol deviation occurs only when study-related 
interventions are done prior to PRO assessments, other than vital signs, demographics and clinical 
history information.
Data will be collected by the contract research organization (CRO) and housed in a database. 
Analysis of the questionnaires will be described in the Integrated Analysis Plan (IAP).
8.1.4.1
EORTC QLQ-30
The EORTC QLQ-C30 is a cancer-specific health-related quality-of-life questionnaire that has
been widely used in clinical studies and investigations using PROs for individual participant 
management (Fayers 2001). It includes 5 function domains (physical, emotional, social, role, 
cognitive), 8 symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, 
and appetite loss), as well as global health/quality-of-life and financial impact. Participants 
respond on a 4-point scale from “not at all” to “very much” for most items. Most items use a “past
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week” recall period. Raw scores can be linearly converted to a 0–100 scale with higher scores 
reflecting higher levels of function and higher levels of symptom burden. A subset of items from 
the QLQ-C30 will be used in this study; namely, fatigue (3 items), appetite loss (1 item), overall 
quality of life (QoL) (1 item), and physical function (5 items).
8.1.4.2
EORTC QLQ-OV28
The EORTC QLQ-OV28 is a 28-item PRO questionnaire created to measure the cardinal 
symptoms of ovarian cancer (Greimel 2003). Items measure pain, bloating, bowel habit, flatulence, 
early satiety, dyspepsia, neuropathy, sensory problems, and frequent urination. Each of these items 
is rated on a 4-point scale from “not at all” to “very much,” using the past week as the recall period. 
The QLQ-OV28 is scored similarly to the QLQ-C30, with raw scores linearly transformed to a 
0-100 scale, with higher scores higher levels of symptom burden. A subset of items from the 
QLQ-OV28 will be used in this study; namely, pain (1 item), bloating (1 item), early satiety 
(1 item), indigestion (1 item), and urinary frequency (1 item).
8.1.4.3
Patient Global Impression of Severity
The Patient Global Impression of Severity (PGIS) is a single, global item assessing the 
participant’s perception of overall symptom severity (Yalcin 2003; Tinchello 2013). The PGIS 
provides a method for classifying participants as having improved, declined, or not having changed 
for use in exploratory and psychometric analysis, and to evaluate the sensitivity and responsiveness 
of individual symptom items and interpret scores on the PRO instruments. 
8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, ECGs, 
and laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. 
Assessments are performed at each visit prior to administration of any medications. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information). Due to the combined 
administration of treatments in this study, it is important that the Investigator carefully review and 
attempt to differentiate causality of AEs (for carboplatin, M6620, or avelumab) to ensure 
appropriate toxicity treatment recommendations.
8.2.1
Physical Examinations
! A complete physical examination will include, at a minimum, assessments of general 
appearance and dermatological, pulmonary, cardiovascular, gastrointestinal, genitourinary, 
lymphatic, neurologic and musculoskeletal systems, head/neck, extremities, eyes, ears, nose, 
throat, and cognitive status. Height (at Screening) and weight will also be measured and 
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recorded according to the SoA (Section 1.3). If Screening physical examination is done within 
3 days of Visit 1 (Day 1), it does not have to be repeated at Visit 1.
! A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen) and should be a focused physical 
examination with attention paid to irAEs. 
! Investigators should pay special attention to clinical signs related to previous serious illnesses.
All newly diagnosed or worsening conditions, signs, and symptoms observed from Screening, 
whether related to study intervention or not, are to be reported as AEs.
! The ECOG PS will be documented during Screening and at each visit according to the SoA 
(Section 1.3) and document in the eCRF. If the Screening ECOG PS was performed within 
3 days prior to Day 1, it does not have to be repeated at Day 1.
8.2.2
Vital Signs
! Oral or tympanic temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
! Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
! Blood pressure and pulse measurements should be preceded by at least 5 minutes of seated rest
for the participant in a quiet setting without distractions (e.g., television, cell phones).
! Vital signs (to be taken before blood collection for laboratory tests; see SoA in Section 1.3) will 
consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure readings 
will be recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded on the eCRF.
8.2.3
Electrocardiograms
Scheduled 12-lead electrocardiograms (ECGs) will be recorded after the participant has been in a 
supine position breathing quietly for 5 minutes.
Electrocardiogram assessments should be performed prior to blood sample collection, such that 
the blood sample is collected at the nominal time. However, at the PK time points where the 
acceptable window of sample collection is within 5 minutes, the ECG should be performed 
10 minutes after sample collection to allow participants to recover to normal heart rate. 
! Triplicate or single 12-lead ECG will be obtained as outlined in the SoA (Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. See Section 7 (Discontinuation of Study Intervention and Participant/ Withdrawal) 
for QTc withdrawal criteria and any additional QTc readings that may be necessary.
! At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes.
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! ECG recordings will be obtained after the participant has been in a supine position breathing 
quietly for 5 minutes. The ECG results will be used to evaluate the heart rate, atrial ventricular 
conduction, QR and QT intervals, and possible arrhythmias.
! All participants require a single ECG measurement at Screening.
! On-treatment ECGs will be performed predose (within 4 hours) on Day 1 (before avelumab and 
carboplatin administration) and on Day 2 (before M6620 administration) of Cycles 1 and 2. On 
those days, 3 consecutive 12-lead ECGs (triplicate) will be performed at each PK time point for 
M6620, approximately 2 minutes apart to determine mean QTc (average of triplicates) with 
digital upload for centralized analysis.
! PK-matched digital ECGs will be collected to evaluate if there is any relationship between 
treatment exposure and cardiovascular toxicity (e.g., QTc prolongation). These will be 
performed in triplicate in order to reduce the variability and improve the reliability of the 
measured QTc intervals.
! If a participant experiences a cardiac or neurologic AE (specifically syncope, dizziness, 
seizures, or stroke), triplicate ECGs should be obtained at the time of the event. If the mean 
QTc is prolonged (> 500 msec), the ECGs should be re-evaluated by a qualified person at the 
study site for confirmation and repeated as clinically indicated. Additional triplicate ECGs may 
be performed as clinically indicated.
8.2.4
Clinical Safety Laboratory Assessments
! Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 7, 
at the time points listed in the SoA (Section 1.3). All samples should be clearly identified. 
! Thyroid-stimulating hormone, thyroxine, and urinalysis will be assessed at the time points 
defined in the SoA (Section 1.3). If confirmation of a participant’s postmenopausal status is 
necessary, measurement of follicle-stimulating hormone (FSH) levels will also be performed at 
Screening.
! For WOCBP, serum and urine β-human chorionic gonadotropin pregnancy tests will be 
performed as indicated in the SoA (Section 1.3).
! Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations.
! The tests will be performed by the local laboratory.
! The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
interventions. Any changes to the ranges during the study must be forwarded to the Sponsor or 
designated organization.
! The Investigator must review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
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8.2.5
Safety and Data Monitoring Committees 
A Safety Monitoring Committee (SMC) consists of permanent members from the Sponsor and/or 
CRO (clinical development lead, medical responsible, biostatistician, and global patient safety 
representative), the Coordinating Investigator, and other optional members with expertise in 
relevant areas (e.g., immune-oncology, DDR, clinical pharmacology) as well as treating 
Investigators, as required.
For the Safety Run-in Period (Part A), the SMC will regularly review the safety of participants 
enrolled in this study (at least after each applicable dose level) and will decide on relevant DLTs
based on criteria defined in this protocol and by consensus on dose de-escalation, or suspension of 
enrollment and/or recommendation of the safe dose of M6620 in combination with carboplatin and 
avelumab.
In the absence of prior human experience with the triplet combination investigated here, a 
conservative approach (i.e., toxicities are assessed as related to combination treatment unless the 
opposite is proven) will be adopted in ascribing the relevance of the treatment-related toxicity to 
study interventions (carboplatin, M6620, avelumab). Treatment-related AEs will be ascribed as 
related to the individual study interventions or their combination, except where a clear relationship 
to the underlying disease or recognized co-morbidities is evident.
The SMC decision to de-escalate to the next dose level will be guided by the following rules:
! Assessment of individual DLTs according to criteria outlined in Section 6.6.1.
! If 1 DLT is observed among the first 3 participants of the Safety Run-in cohort, an additional 
3 participants will be enrolled and treated.
! At any time if ≥2 DLTs are observed, treatment with the corresponding dose will be stopped 
and the next dose level will be considered as shown in the Part A Schema (Section 1.2).
! Should a M6620 dose lower than 40 mg/m2 be required or at any other time, the SMC may 
recommend another dose level or to stop the study.
The specific working procedures will be described in an SMC Charter, which will be established 
prior to the start of recruitment.
For Part B, a data monitoring committee (DMC) will be constituted by Sponsor members 
independent from the project team and if needed may include external medical expert to regularly 
review the data in Part B of the study to ensure safety of the participants as well validity and 
integrity of the study. The participants, data reporting details and specific working procedures will 
be defined in the DMC charter prior to start of enrollment in Part B.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a Serious Adverse Event (SAE) are in Appendix 8.
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8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until the 90-day Safety Follow-up Phone Call.
After the 30-day Safety Follow-up Visit, all SAEs, AESIs, and treatment-related nonserious AEs 
need to be documented until the 90-day Safety Follow-up Phone Call. Participants with an ongoing 
SAE at the 90-day Safety Follow-up Phone Call must be followed by the Investigator until 
stabilization or until the outcome is known, unless the participant is documented as “lost to 
follow-up.” 
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 8, whenever it occurs, irrespective of the time elapsed since the last administration of 
study interventions.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 8.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator.
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate SAE Report Form 
as specified in Appendix 8.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
AEs are recorded and assessed continuously throughout the study, as specified in Section 8.3.1
(Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) and are assessed for their outcome at the 30-day Safety Follow-up Visit and 90-day 
Safety Follow-up Phone Call. All SAEs (related and unrelated to study intervention), nonserious 
AEs classified as related to interventions by the Investigator, and AESIs that are ongoing at the 
90-day Safety Follow-up Phone Call must be monitored and followed up by the Investigator until 
stabilization or until the outcome is known, unless the participant is documented as “lost to 
follow-up.” Reasonable attempts to obtain this information must be made and documented. 
It is also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. Further information on follow-up procedures 
is given in Appendix 8.
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8.3.3.1
Monitoring of Specific Adverse Events
Infusion-related reactions, including drug hypersensitivity reactions and immune-related adverse 
reaction(s) (immune-related pneumonitis, immune-related colitis, immune-related hepatitis), 
immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, new-onset type I 
diabetes mellitus, pituitary disorders), immune-related nephritis and renal dysfunction, and other 
irAEs (myositis, myocarditis, Guillain-Barré syndrome, uveitis) have been identified as AESIs for 
avelumab (see Section 6.11 and Appendix 6).
Any AE that is suspected to be a potential immune-related adverse reaction or infusion-related 
reaction will be considered an AESI. These AESIs do not require expedited reporting unless they 
are serious. Should the AESI be serious, an SAE Report Form should be completed, and the 
reporting process for SAEs should be followed.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) that approved the study.
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), 
the Sponsor/designee will inform the Investigator of findings that could adversely affect the safety 
of participants, impact the conduct of the study or alter the IEC’s/IRB’s approval/favorable opinion 
to continue the study. In line with respective regulations, the Sponsor/designee will inform the 
Investigator of AEs that are both serious and unexpected and considered to be related to the 
administered product (“suspected unexpected serious adverse reactions” or SUSARs). The 
Investigator should place copies of Safety Reports in the Investigator Site File. National 
regulations regarding Safety Report notifications to Investigators will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
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8.3.5
Pregnancy
Only pregnancies the Investigator considers to be related to the study intervention (e.g., resulting 
from a drug interaction with a contraceptive method) are AEs. However, all pregnancies with an 
estimated conception date during the period defined in Section 8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and Serious Adverse Event Information) must be recorded in the AE 
page/section of the eCRF for pregnancies in female participants. The Investigator must notify the 
Sponsor/designee in an expedited manner of any pregnancy using the Pregnancy Report Form, 
which must be transmitted by the same process specified for SAE reporting in Appendix 8, section 
on Reporting Serious Adverse Events, Adverse Events of Special Interest, and DLTs.
Investigators must actively follow-up, document, and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. Any abnormal outcome (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) must be reported in an expedited manner, as specified in 
Section 8.3.1, while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay and 
the participant must be followed as indicated above.
8.4
Treatment of Overdose
For this study, any dose of avelumab greater than 10% above the planned dose for a particular 
administration will be considered an overdose.
For this study, any dose of M6620 greater than 10% above the dose identified in Part A (starting 
with RP2D of the doublet [90 mg/m2]) within a 24-hour time period will be considered an 
overdose.
For this study, any dose of carboplatin greater than 10% above the planned dose for a particular 
administration within a 24-hour time period will be considered an overdose.
For this study, any dose of SoC chemotherapy greater than 10% above the planned dose for a 
particular administration within a 24-hour time period will be considered an overdose.
Even if it is not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to the Sponsor’s Global Patient Safety Department in an expedited manner. Overdoses are reported 
on a SAE Report Form, following the procedure in Appendix 8, section on Reporting Serious 
Adverse Events, Adverse Events of Special Interest, and DLTs.
The Sponsor does not recommend specific treatment for an overdose. There are no known 
symptoms of avelumab overdose to date. Based on available clinical data, overdose of M6620 may
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increase severity and/or toxicity of carboplatin therapy. The Investigator should use his or her 
clinical judgment when treating an overdose of the study interventions.
8.5
Pharmacokinetics
The following PK parameters will be calculated for M6620, when appropriate (Table 13).
Table 13
Pharmacokinetics Parameters
Symbol
Definition
AUC0-t
The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last 
sampling time (tlast) at which the concentration is at or above the lower limit of quantification. 
Calculated using the mixed log linear trapezoidal rule (linear up, log down).
AUC0-∞
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the 
concentration at tlast, as estimated using the linear regression from λz determination. 
AUC0-∞=AUC0-t+Clast pred/ λz
AUCτ
The area under the concentration-time curve (AUC) over the dosing interval from T1=0 h to T2=τ h. 
Calculated using the mixed log linear trapezoidal rule (linear up, log down). For single dose, AUCτ 
is calculated as a partial area with the defined time range. In multiple dose profiles AUC∃is 
calculated at steady state from 1 predose time point to the dosing interval time. In cases where the 
actual observation time is not equal to the scheduled observation time AUC∃will be calculated 
based on the estimated concentration at τ hours, and not the concentration at the actual 
observation time.
λz
Terminal first order (elimination) rate constant. Determined from the terminal slope of the 
log-transformed concentration curve using linear regression on terminal data points of the curve
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration during a complete dosing interval
tmax
The time to reach the maximum observed concentration collected during a dosing interval (unless 
otherwise defined, take the 1st occurrence in case of multiple/identical Cmax values)
t1/2
Apparent terminal half-life. t1/2  = ln (2)/λz
! Pharmacokinetics of avelumab for all the participants will be assessed using a sparse sampling 
approach. Serum concentrations from sparse PK sampling for avelumab will allow population 
PK analyses. The population PK report will be a separate document and will not be included in 
the clinical study report (CSR).
! Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of M6620, as specified in the SoA (Section 1.3). The actual date and time 
(24-hour clock time) of each sample will be recorded.
! The quantification of M6620 in plasma will be performed using a validated analytical method. 
Concentrations will be used to evaluate the PK of M6620. The M6620 plasma samples may 
also be used for evaluations of metabolites of M6620, for further evaluation of the bioanalytical 
method, and for analyses that provide information on the metabolic pathways used by or 
affected by M6620.
! Whole blood samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of avelumab, as specified in the SoA (Section 1.3). The actual date and time 
(24-hour clock time) of each sample will be recorded.
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! The quantification of avelumab in serum will be performed using a validated immunoassay 
method. Concentrations will be used to evaluate the PK of avelumab.
! Remaining samples collected for analysis of avelumab serum concentration may also be used 
to evaluate immunogenicity and safety or efficacy aspects related to concerns arising during or 
after the study.
! Details on processes for collection, processing, handling, storage and shipment of these samples 
will be provided in the Laboratory Manual. The Sponsor will store the samples in a secure 
storage space with adequate measures to protect confidentiality. Retention time and possible 
analyses of samples after the end of study are specified in the respective ICF.
! The PK sampling schedule may be modified upon agreement of the clinical pharmacologist and 
Investigators to optimize the sampling time for M6620 disposition but will not increase the total 
number of PK blood draws. All efforts will be made to obtain the PK samples at the exact 
nominal time relative to dosing. The exact sampling time should be recorded. Acceptable PK 
sampling windows are presented in Table 14. However, only cases in which no sample is 
collected are considered as protocol deviations. 
Table 14
Acceptable Pharmacokinetic Sampling Windows
Sampling Time
Time from Scheduled Sampling Allowed
Before BOI
- 120 minutes 
EOI
± 5 minutes for M6620, ± 15 minutes for avelumab
0.5 to 2 hours after EOI
± 5 minutes
> 2 and ≤7 hours after EOI
± 20 minutes
> 7 and ≤23 hours after EOI
± 60 minutes
> 23 hours after EOI
± 120 minutes
BOI=beginning of infusion, EOI=end of infusion.
! For participants undergoing paired tumor biopsies on Day 2 of Cycle 1 or Cycle 2, blood 
samples for M6620 PK at 1, 2, and/or 3 hours may be optional only if they cannot be feasibly 
collected. At minimum, a blood sample should be collected for M6620 PK as close to the time 
of post-M6620 biopsy as is feasible, and the time recorded.
! No PK sampling will be performed for participants receiving treatment with SoC.
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8.9
Medical Resource Utilization and Health Economics
Not applicable.
8.10
Immunogenicity Assessments
! Whole blood samples of approximately 3.5 mL will be collected for detection of antibodies 
against avelumab in serum, as specified in the SoA. Samples will be collected prior to any 
avelumab administration on the same Study Day.
! The detection of antibodies to avelumab will be performed using a validated assay method with 
tiered testing of screening, confirmatory, and titration. Confirmed positive antibodies may be 
tested for the presence of neutralizing antibodies and may be further characterized. 
! Details on processes for collection and shipment of these samples are in the Laboratory Manual. 
The Sponsor will store the samples in a secure storage space with adequate measures to protect 
confidentiality. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICF.
9
Statistical Considerations
All analyses will be described in detail in the IAP.
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9.1
Statistical Hypotheses
No formal statistical hypothesis will be tested, as the study is designed to be exploratory.
9.2
Sample Size Determination
Part A
During Part A of the study, approximately 3 to 18 participants are expected to be enrolled to 
evaluate the safe dose for the triplet combination (modified 3 + 3 design, but only dose reductions 
will be considered if necessary). 
Part B
After confirmation of the safe target dose, approximately 72 participants will be randomly assigned 
to 1 of 2 treatment groups in Part B of the study (36 participants per arm; 1:1 randomization,
stratified by BRCA status). The median time for PFS in participants who have received treatment 
with platinum-containing chemotherapy after failure to PARPi maintenance treatment has been 
reported to be approximately 6 months (Ang 2013), depending on prior lines of treatment and 
platinum-free interval.
A sample size of 36 participants in each treatment group is chosen based on the following 
assumptions: Based on 50 events for PFS, the probability to observe a hazard ratio (HR) of 0.6 or 
lower is 74% under the assumption of a true HR of 0.5; whereas, if the true HR is 0.75 (a 
nonrelevant effect regarding further development of this combination therapy for such an 
indication), the probability to observe a HR of 0.6 or lower is 21.5%, and if there is no effect (i.e.,
if the true HR = 1), the probability for an observed HR of 0.6 is 3.5%.
It is assumed that the accrual period will be approximately 12 months, followed by a follow-up 
period of 15 months (assuming median PFS time of 12 months in the triplet combination arm and 
6 months in the SoC arm). The predicted drop-out rate (participants without any information about 
PFS event) is 10% in total.
9.3
Populations for Analyses
The analysis populations are specified in Table 16. The final decision to exclude participants from 
any analysis population will be made during a blinded data review meeting prior to database lock.
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Table 16
Population Analysis Sets
Analysis 
Population
Description
Enrolled
(Parts A + B)
All participants who provided informed consent
DLT Analysis Set
(Part A only)
All evaluable participants with data used for implementing the dose-escalation schedule. 
These participants will have received at least 1 study intervention administration of each 
avelumab, M6620, and/or chemotherapy in the DLT evaluation period or should have 
stopped treatment because of DLTs in the DLT evaluation period
FAS (Full Analysis 
Set)
(Part B only)
All participants who were randomized. Participants will be classified according to the 
treatment assigned at randomization as per the intent-to-treat principle.
SAF Analysis Set
(Parts A + B)
All participants who receive at least 1 dose of any study intervention.
The SAF Analysis Set will be also used for the efficacy analyses of Part A.
QoL Analysis Set
The QoL Analysis Set will include all randomized participants who complete PRO 
assessments at Baseline.
PK Analysis Sets
PK Analysis Set Avelumab
All participants who receive at least 1 dose of avelumab, have no clinically important 
protocol deviations or important events affecting PK, and provide at least 1 measurable 
postdose concentration. Participants will be analyzed per the actual study intervention 
they received. All PK analyses for avelumab will be based on this analysis set.
PK Analysis Set M6620
All participants who receive at least one dose of M6620, have no clinically important 
protocol deviations or important events affecting PK, and provide at least 1 measurable 
postdose concentration. Participants will be analyzed according to the actual treatment 
they received. All PK analyses for M6620 will be based on this analysis set.
Immunogenicity 
Analysis Set
All participants who have received at least 1 dose of avelumab and M6620 and have at 
least 1 valid ADA result.
ADA=antidrug antibody; 
; DLT=dose-limiting toxicity; 
DNA=deoxyribose nucleic acid; 
; PK=pharmacokinetic; 
PRO=patient-reported outcomes; QoL=quality of life; SAF=Safety.
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9.4
Statistical Analyses
There is no formal significance level for this study, and all analyses are considered descriptive.
In general, continuous variables will be summarized using number of participants (n); mean, 
standard deviation; median; 25th percentile to 75th percentile (Q1 to Q3); minimum; and maximum. 
If there are fewer than 5 observations available, only the mean and the observed data will be given.
Categorical variables will be summarized using frequency counts and percentages.
The calculation of proportions will be based on the number of participants in the analysis set of 
interest, unless otherwise specified in the IAP.
Only tumor assessments performed before the start of any further anticancer treatment will be 
considered in the assessment of BOR. Clinical deterioration will not be considered as 
documented PD. 
Baseline
In general, the last nonmissing measurement prior to the first study intervention will serve as the 
baseline measurement. If no such a value is available, the last measurement prior to the first study 
intervention administration will be used as the baseline measurement with the exception of 
pre-randomization assessments used for the derivation of efficacy endpoints (e.g., tumor 
assessment at Baseline, which will be set to missing, if not done prior to randomization).
The last available assessment prior to the start of study intervention is defined as “baseline” value 
or “baseline” assessment for safety.
On Treatment
The on-treatment period is defined as the time from the first dose of study intervention through 
minimum (30 days + last dose of study intervention, start day of new anticancer therapy – 1 day), 
unless otherwise stated.
9.4.1
Efficacy Analyses
Analysis of Primary Endpoint (Part B: Randomized-controlled Period)
The PFS time is defined as the time (in months) from the date of randomization to the date of the 
first documentation of objective PD as per RECIST v1.1, as assessed by the Investigator, or death 
due to any cause, whichever occurs first.
The HR (including 95% confidence interval) will be calculated by Cox’s proportional hazards 
model (Table 17). A stratified analysis by BRCA status will be performed if sufficient number of 
participants in each stratum is available. The Full Analysis Set will be used for all efficacy analyses
in Part B.
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The PFS data will be censored on the date of the last adequate tumor assessment in the following 
cases: 
! For participants who do not have an event (PD or death)
! For participants who start a new anticancer therapy prior to an event
! For participants with an event after 2 or more missing tumor assessments.
Participants who do not have a baseline tumor assessment or who do not have any postbaseline 
tumor assessments will be censored on the date of randomization, unless death occurred on or 
before the time of the second planned tumor assessment, in which case the death will be considered 
an event.
Subgroup analyses (for PD-L1 expression levels for instance) may be performed. Details will be 
available in the Integrated Analysis Plan.
Table 17
Statistical Analysis Methods for Efficacy Endpoints, Part B
Endpoint
Statistical Analysis Methods
Primary
Cox’s proportional hazards model – Full Analysis Set
Secondary
Descriptive statistics:
!
Continuous variables: number of participants; mean, standard deviation; median, 
Q1 to Q3, minimum, and maximum
!
Categorical variables: frequency counts and percentages
Q1=25th percentile; Q3=75th percentile.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.
Safety analyses will include the examination of vital signs, 12-lead ECGs, physical examination 
findings, and clinical laboratory tests (including hematology, blood chemistry, and urinalysis), and 
AEs. All safety parameters will be summarized using descriptive statistics (Table 18).
Table 18
Statistical Analysis Methods for Safety Endpoints
Endpoint
Statistical Analysis Methods
Secondary
Descriptive statistics:
!
Continuous variables: number of participants; mean, standard deviation; median, 
Q1 to Q3, minimum, and maximum
!
Categorical variables: frequency counts and percentages
Q1=25th percentile; Q3=75th percentile.
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9.4.2.1
Adverse Events
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Severity of AEs will be graded using the NCI-CTCAE toxicity grading scale. 
Treatment-emergent adverse events (TEAEs) are defined as events with onset dates occurring on 
treatment, or events which worsen on-treatment (see Appendix 8, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting).
The frequency of participants experiencing TEAEs, regardless of relatedness to study 
interventions, will be summarized by system organ class and preferred term for each treatment 
arm. Similar summaries will also be provided for serious TEAEs, TEAEs leading to permanent 
discontinuation of study interventions, TEAEs by maximum severity, TEAEs related to study 
intervention, TEAEs with fatal outcome, and treatment-emergent AESIs, such as irAEs. A listing 
of AEs meeting DLT definition will be provided. 
9.4.2.2
Laboratory Values 
Laboratory results will be classified by grade according to NCI-CTCAE. The worst on-treatment 
grades for chemistry and hematology laboratory results will be summarized. Shifts in toxicity 
grading from Baseline to highest grade during the on-treatment period will be displayed. For 
laboratory tests without an NCI-CTCAE grade definition, results will be presented categorically 
(e.g., below, within, or above normal limits). 
9.4.3
Other Analyses
9.4.3.1
Baseline Characteristics
Analyses of participant disposition, treatment/study discontinuations, demographics, and other 
baseline characteristics will be described in the IAP. 
PK, immunogenicity, PD, and biomarker exploratory analyses will be specified in the Integrated 
Analysis Plan finalized before database lock. Integrated analyses across studies, such as the 
population PK analysis and pharmacodynamic analyses will be presented separately from the main 
clinical study report (CSR).
9.4.3.2
Estimation of Individual PK Parameters
Pharmacokinetic parameters for M6620 will be calculated by the PK/
 Data Processing Group 
of QPD, Merck, Darmstadt, Germany, or by a CRO selected by the Sponsor, using standard 
noncompartmental methods and the actual administered dose. Pharmacokinetic parameters will be 
calculated using the actual elapsed time since dosing, given with a precision of 14 significant digits 
or the Statistical Analysis System (SAS®) format Best12. When the actual sampling time is 
missing, calculations will be performed using the scheduled time. Otherwise, there will be no 
further imputation of missing data. 
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Noncompartmental computation of PK parameters will be performed using the computer program 
Phoenix® WinNonlin® version 6.3, or higher (Certara, L.P., 1699 S Hanley Road, St Louis, MO 
63144, USA). 
The statistical software SAS® (SAS-Institute, Cary, NC, USA, Windows version 9.1 or higher) 
may be used to produce tables, listings, and figures and in the calculation of PK parameters if 
appropriate.
Pharmacokinetic parameters to be calculated are presented in Section 8.5. The calculation of the 
AUCs will be performed using the mixed log-linear trapezoidal method (linear up, log down). 
Extrapolated areas will always be computed using the predicted last concentration that is estimated 
using the linear regression from terminal rate constant determination. Pharmacokinetics of 
avelumab for all participants will be assessed using a sparse sampling approach. Plasma 
concentrations from sparse PK sampling for avelumab will allow population PK analyses. The 
population PK report will be a separate document and not be included in the CSR.
Pharmacokinetic concentrations below the lower limit of quantification (LLOQ) are taken as zero 
for descriptive statistics for M6620 and avelumab. M6620 PK concentrations below LLOQ, which 
are before the last quantifiable data point, will be taken as zero for calculating the AUC. The PK 
parameters will be summarized using descriptive statistics. Individual as well as mean 
concentration-time plots will be depicted.
9.4.3.3
Immunogenicity Analysis
Participants will be categorized based on the onset and duration of the ADA response. Tables will 
be prepared for incidence and listings will be prepared for characterization of the ADA response 
and potential association with PK, safety, and efficacy.
9.4.4
Sequence of Analyses
This is an exploratory study. Available data will be evaluated during the study by the SMC during 
part A and the DMC during part B.
No formal interim analyses are planned; however, unplanned interim analyses may be performed.
The SMC and DMC will be formed to review the safety data on a regular basis throughout this 
clinical study and is described in Section 8.2.5. For Part B, no formal statistical stopping rule will 
be used for the DMC. Refer to the DMC Charter for additional details.
The main analysis will be performed approximately 15 months after the last participant’s first visit.
The analyses will be performed based on the IAP, which will be finalized prior to database lock.
10
References 
Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-
controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-
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sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 
2012 Jun 10;30:2039-45. doi: 10.1200/JCO.2012.42.0505. Epub 2012 Apr 23.
Ang JE, Gourley C, Powell CB, et al. Efficacy of chemotherapy in BRCA1/2 mutation carrier 
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11
Appendices
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Appendix 1
Abbreviations
ADA
Antidrug antibody
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATR
Ataxia telangiectasia and Rad3-related
ATRi
Ataxia telangiectasia and Rad3-related inhibitor
AUC
Area under the concentration-time curve
BOI
Beginning of infusion
BOR
Best overall response
BRCA
Breast cancer gene (BRCA1, BRCA2) 
CA-125
Cancer antigen 125
Chk1
Checkpoint kinase 1
CR
Complete response
CRO
Contract research organization
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor deoxyribose nucleic acids
CYP3A4
Cytochrome P450 3A4
DDR
DNA damage response
DDRi
DNA damage response inhibitor
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
dsDNA
Double-stranded DNA
ECG
Electrocardiogram
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ECOG PS
Eastern Cooperative Oncology Group Performance Status
(e)CRF
(Electronic) Case Report Form
EOI
End of infusion
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core-30
EORTC QLQ-OV28
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire – Ovarian Cancer
FFPE
Formalin-fixed, paraffin-embedded
FSH
Follicle-stimulating hormone
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HR
Hazard ratio
HRD
Homologous recombination deficiency
IAP
Integrated Analysis Plan
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
irAE
Immune-related adverse event
IRB
Institutional Review Board
iv
Intravenous
IWRS
Interactive Web Response System
LLOQ
Lower limit of quantification
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
OS
Overall survival
PARP
Poly (ADP-ribose) polymerase
PARPi
Poly (ADP-ribose) polymerase inhibitor
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
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PD-1
Programmed death 1
PD-L1
Programmed death ligand 1
PFS
Progression-free survival
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetic(s)
PR
Partial response
PRO
Patient-reported outcomes
QoL
Quality of life
RECIST v1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RP2D
Recommended Phase II dose
SAS
Statistical Analysis System
SAE
Serious adverse event
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SoC
Standard of care
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TIL
Tumor-infiltrating lymphocyte
TO
Target occupancy
ULN
Upper limit of normal
WOCBP
Woman of childbearing potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
! The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions on the study.
! Participants must be informed that their participation is voluntary.
! Participants or their legally-authorized representative (defined as an individual or judicial or 
other body authorized under applicable law to consent on behalf of a prospective participant to 
the participant’s participation in the procedure[s] involved in the research) will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50; local 
regulations; ICH guidelines; Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable; and the IRB/IEC or study center.
! The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
! If the ICF is updated during their participation in the study, participants must be reconsented to 
the most current, approved version.
! A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.
! The original signed and dated consent will remain at the Investigator’s site and must be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes.
! As this study includes optional 
 examinations, including collection and 
storage of biological samples, a separate 
 ICF will be required. At selected 
sites, optional blood samples for immune cell subset by flow cytometry analyses will be 
collected under a separate required ICF.
! Participants who are rescreened are required to sign a new ICF.
Data Protection
! The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the identifier 
only; participant names or any identifiable information will not be transferred.
! The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant.
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! The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality.
! The Investigator will complete the participant registration form using IWRS (see Section 6.3.1). 
At Screening, the participant will receive a screening identification number. If the participant 
meets all inclusion criteria and does not meet any of the exclusion criteria, the participant will 
be registered by IWRS.
Study Administrative
The Sponsor of this clinical study is EMD Serono Research & Development Institute, Inc. (EMD 
Serono R&D), Billerica, MA, in the United States, and Merck KGaA, Darmstadt, Germany, for 
sites outside the United States.
The study will be conducted at approximately 35 study sites in the European Union and the United 
States. Approximately 24 sites will be in the United States. Sites will be a mixture of academic 
centers and inpatient clinics.
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the CSR.
The study will appear in the following clinical studies registries: ClinicalTrials.gov, EudraCT, and 
all other required registries.
An SMC in Part A and a DMC in Part B will review the safety data on a regular basis throughout 
this clinical study (see Section 8.2.5). 
The Sponsor will coordinate the study and will utilize the support of CROs (e.g.,
), for some 
activities of the study. The Sponsor will perform oversight of the activities performed by the CROs. 
Monitoring and data management will be performed by 
 and the Sponsor will be 
responsible for regulatory submission.
The Clinical Trial Supplies department of the Sponsor will supply the study interventions of 
avelumab and M6620. The study interventions will be packaged, labeled, and distributed by a 
designated contract manufacturing organization.
Safety laboratory assessments will be performed locally by each investigational site. 
Pharmacokinetics and exploratory biomarker analyses will be performed under the responsibility 
and/or supervision of the Sponsor.
The Sponsor’s Global Patient Safety Department, Merck KGaA, Darmstadt, Germany, or its 
designated representative will supervise drug safety and the timely reporting of AEs and SAEs.
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Quality assurance of the study conduct will be performed by the Sponsor’s Development Quality 
Assurance Department, Merck KGaA, Darmstadt, Germany.
A CRO (e.g., 
) will write the study IAP, perform the statistical analyses, and will provide 
the outputs from the statistical analyses; the Sponsor will provide oversight.
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Study Leader.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
o Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
o Applicable ICH GCP Guidelines
o Applicable laws and regulations
! The Investigator must submit the protocol, protocol amendments (if applicable), ICF, IB, and 
other relevant documents (e.g., advertisements) to an IRB/IEC and the IRB/IEC must review 
and approve them before the study is initiated.
! Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be
submitted to the appropriate Health Authorities.
! The Investigator will be responsible for the following:
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.
o Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures
o Providing oversight of the study conduct at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
! The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
! The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
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participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable).
! The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators.
! When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor physician. This includes provision of a 24-hour contact number at a call center, 
whereby the health care providers will be given access to the appropriate Sponsor physician to 
assist with the medical emergency and to provide support for the potential unblinding of the 
participant concerned.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
Clinical Study Report
After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator.
Publication
! The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
! The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a Coordinating 
Investigator will be designated by agreement.
! Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
Posting of data on Clintrials.gov, EudraCT, and all other required registries is planned and will 
occur 12 months after the last clinic visit of the final study participant or another appropriate date 
to meet applicable requirements.
Data Quality Assurance
! All participant study data will be recorded on printed or electronic CRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
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verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the Manual of Operations.
! For PRO data (e.g., QoL and pain assessments), ePRO will be used.
! The Investigator must maintain accurate documentation (source data) that supports the 
information in the eCRF.
! The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data.
! The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. PDF files of the eCRFs will be 
provided to the Investigators at study completion.
! Study monitors will perform ongoing source data verification to confirm that data in the eCRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
! Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be destroyed 
during the retention period without the Sponsor’s written approval. No records may be 
transferred to another location or party without the Sponsor’s written notification.
Source Documents
! Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
! The Investigator must keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file must identify each participant, contain the 
following demographic and medical information for the participant, and should be as complete 
as possible:
o Participant’s full name, date of birth, sex, height, and weight
o Medical history and concomitant diseases
o Prior and concomitant therapies (including changes during the study)
o Study identifier (i.e., the Sponsor’s study number) and participant’s study number.
o Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site
o Any medical examinations and clinical findings predefined in the protocol
o All AEs
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! Date that the participant left the study, including any reason for early withdrawal from the study 
or study intervention, if applicable.
! All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed and dated by the Investigator. 
! Data recorded on printed or electronic CRFs that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
! The Study Monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator, countersigned by the Study Monitor,
and kept in the study file.
! Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures
that no destruction of medical records is performed without the Sponsor’s written approval.
! Definition of what constitutes source data is found in the eCRF guidelines.
Study and Site Closure
! The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a site closure visit has 
been completed.
! The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
! Reasons for the early closure of a study site by the Sponsor or Investigator may include:
o Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines.
o Inadequate recruitment of participants by the Investigator.
o Discontinuation of further development of the Sponsor’s compound.
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Appendix 3
Contraception
Woman of Childbearing Potential (WOCBP)
A woman is of childbearing potential (i.e., fertile), following menarche and until either:
1)
becoming postmenopausal; or,
2)
is permanently sterile by means of a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy.
Postmenopausal is defined as no menses for 12 months without an alternative medical cause. A 
high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
Highly Effective Contraceptive Methods
Highly effective methods are those with a failure rate of less than 1% per year when used 
consistently and correctly.
These methods are further classified into user-independent and user-dependent methods.
Because user-independent methods do not depend on the participant’s ability to use them 
consistently and correctly, they are preferred when contraception is introduced as a condition 
for study participation.
Caution should be taken for hormonal contraception, as it may be susceptible to interaction with 
the study intervention(s), which may reduce the efficacy of the contraception method. In this 
case, a second highly effective method of contraception should be used during the treatment 
period and for at least 6 months after the last dose of carboplatin, M6620, or the defined SoC 
combination treatments, or at least 60 days after the last dose of maintenance with avelumab or 
bevacizumab, whichever is later.
User-Dependent
! Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
! Oral
! Intravaginal
! Transdermal
! Progestogen-only hormonal contraception associated with inhibition of ovulation
! Oral
! Injectable
User-Independent
! Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation
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! Intrauterine device (IUD)
! Intrauterine hormone-releasing system (IUS)
! Bilateral tubal occlusion
! Vasectomized partner: This is a highly effective contraception method only if the partner is 
the sole sexual partner of the WOCBP and he has received medical assessment of the surgical 
success.
! Sexual abstinence: This is a highly effective method only if the WOCBP refrains from 
heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Acceptable Contraceptive Method
Allowed only under certain situations, as specified in the Clinical Trial Facilitation Group 
recommendations, because they have a failure rate of more than 1% per year and therefore are 
not considered to be highly effective methods.
! Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action
! Male or female condom with or without spermicide
! Cap, diaphragm or sponge with spermicide
! Combination of a male condom with cap, diaphragm or sponge with spermicide (i.e., double 
barrier method)
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Appendix 4
Carboplatin Dosing
Calvert Equation
Carboplatin dose (mg) = Target area under the curve (AUC mg∙min/mL) x (GFR* + 25)
*GFR (glomerular filtration rate) estimated by calculated creatinine clearance (CrCl) using 
Cockcroft-Gault Equation (see below).
Cockcroft-Gault Equation
CrCl male; mL
min = (140 – age) x (weight in kg)
72 x serum creatinine "mg
dL$
; CrCl (female) = 0.85 x CrCl (male)
Maximum Carboplatin Dose Calculation
Consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity 
due to overdosing. The maximum dose is based on a GFR estimate that is capped at 125 mL/min 
for patients with normal renal function.
Based on target AUC (mg min/mL), the maximum dose can be calculated according to the Calvert 
formula as:
Maximum carboplatin dose (mg) = Target AUC (mg∙min/mL) x (125 mL/min + 25)
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg
Additional Considerations
! Overweight or obese patients (BMI ≥25 kg/m2): Consider using an adjusted body weight.
Adjusted body weight (kg) = 
ideal body weight (IBW) + 0.4 x (total body weight [TBW] – IBW)
! Patients with abnormally low serum creatinine (Cr), including elderly or cachectic patients: 
Consider using a minimum Cr of 0.7 mg/dL to avoid overestimation of CrCl.
For more details refer to the following reference:
https://www.nccn.org/professionals/OrderTemplates/PDF/appendix_B.pdf (last updated: 
12 February 2018)
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Appendix 5
List of Selected Cytochrome P450 3A4 Inducers and Inhibitors
In vitro drug metabolism studies suggest that M6620 is a substrate of CYP3A and its systemic 
exposure may be affected by co-medications that are strong CYP3A inhibitors and inducers (listed 
below). Based upon in vitro data, M6620 is not a potent inhibitor or inducer of human CYP 
enzymes in isolated enzyme systems, and its probability to interact with other medications that are 
substrates of CYP metabolism is expected to be low. However, Investigators should use standard 
precautions when prescribing co-medications, as with any novel therapeutic for which there is 
limited clinical experience.
Inhibitors of CYP3A4
Ketoconazole, itraconazole
Ritonavir, indinavir, saquinavir, nelfinavir
Clarithromycin, telithromycin, chloramphenicol
Inducers of CYP3A4
Phenytoin, carbamazepine, topiramate 
Phenobarbital
St John’s Wort (Hypericum perforatum)
Modafinil
Nevirapine 
Rifabutin, rifampicin, rifapentin
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Appendix 6
Management of Immune-related Adverse Events
Table 19
Management of Immune-related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over
Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment (e.g.,
loperamide)
Close monitoring for worsening symptoms
Educate participant to report worsening 
immediately
If worsens:
Treat as Grade 2, 3, or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; iv fluids indicated 
< 24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤1: 
Resume avelumab therapy
If persists > 5 to 7 days or recurs:
Treat as Grade 3 or 4.
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; iv
fluids ≥24 hours; interfering with 
ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1.0 to 2.0 mg/kg/day 
prednisone iv or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade ≤1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids taper 
(for initial Grade 3). 
If worsens, persists > 3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication). Note: infliximab should 
not be used in cases of perforation or 
sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤30% body surface area 
Continue avelumab therapy 
Symptomatic therapy (e.g.,
antihistamines, topical 
steroids) 
If Grade 2 persists > 1 to 2 weeks or 
recurs: 
Withhold avelumab therapy 
Consider skin biopsy 
Consider 0.5 to 1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 3 to 4. 
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Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
If improves to Grade ≤1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding 
avelumab therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily; 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month, and 
then resume avelumab therapy following 
steroids taper 
If not improving after 2 weeks or 
worsening, or for recurrent Grade 2: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
new/worsening hypoxia;
Grade 4: Life-threatening 
Permanently discontinue 
avelumab therapy.
Hospitalize.
Pulmonary and Infectious 
Disease consults.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (e.g., 
infliximab, cyclophosphamide, iv
immunoglobulin, or mycophenolate 
mofetil) 
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Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 × ULN and/or Total bilirubin 
> ULN to 1.5 × ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4. 
Grade 2
AST or ALT > 3.0 to ≤5 × ULN 
and/or total bilirubin > 1.5 to 
≤3 × ULN 
Withhold avelumab therapy
Increase frequency of 
monitoring to every 3 days.
If returns to Grade ≤1:
Resume routine monitoring; resume 
avelumab therapy.
If elevation persists > 5 to 7 days or 
worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT > 5 × ULN and/or total 
bilirubin > 3 × ULN 
Permanently discontinue 
avelumab therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist/
hepatologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted 
If returns to Grade ≤1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily 
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased 1.5 × baseline, 
or creatinine increased > ULN to 
1.5 × ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased 1.5 × baseline 
and ≤6 × ULN, or creatinine 
increased > 1.5 and ≤6 × ULN
Withhold avelumab therapy
Increase frequency of 
monitoring to every 3 days
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 1 month, and 
resume avelumab therapy following steroids 
taper.
If worsens: 
Treat as Grade 4.
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Grade 4
Creatinine increased > 6 × ULN
Permanently discontinue 
avelumab therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and/or new laboratory 
cardiac biomarker elevations (e.g.,
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis. 
Withhold avelumab therapy.
Hospitalize.
In the presence of life-
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced 
heart failure and arrhythmia 
management.
Cardiology consult to 
establish etiology and rule 
out immune-related 
myocarditis. 
Guideline-based supportive 
treatment as per cardiology 
consult. *
Consider myocardial biopsy 
if recommended per 
cardiology consult.
If symptoms improve and immune-related 
etiology is ruled out, restart avelumab 
therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and 
immune-related etiology is suspected or 
confirmed following cardiology consult, 
manage as immune-related myocarditis.
Immune-related myocarditis
Permanently discontinue 
avelumab.
Guideline-based supportive 
treatment as appropriate as 
per cardiology consult. *
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections.
Once improving, taper steroids over at least 
1 month.
If no improvement or worsening, consider 
additional immunosuppressants (e.g., 
azathioprine, cyclosporine A).
*Local guidelines, or e.g., ESC or AHA guidelines 
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
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Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), anti-
thyroid treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate. 
Rule-out secondary endocrinopathies 
(i.e., hypopituitarism/hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), anti-
thyroid treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for type I 
diabetes mellitus) as appropriate. 
Rule-out secondary endocrinopathies 
(i.e., hypopituitarism/hypophysitis)
Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade ≤1 (with 
or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
Withhold avelumab therapy
If secondary thyroid and/or adrenal 
insufficiency is confirmed (i.e., 
subnormal serum free T4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately low 
ACTH):
!
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women) 
!
Hormone replacement as 
appropriate 
!
Perform pituitary MRI and visual 
field examination as indicated
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤1 (with or 
without hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on MRI/CT 
scan is documented. 
Continue hormone 
replacement/suppression 
therapy as appropriate.
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If hypophysitis confirmed:
!
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month
!
Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed 
by corticosteroids taper during at 
least 1 month.
!
Add prophylactic antibiotics for 
opportunistic infections.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider 
restarting avelumab therapy
If irAE is confirmed, treat as 
Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence 
of Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤1: 
Taper steroids over at least 
1 month and resume avelumab 
therapy following steroids taper.
Recurrence of same Grade 3 
irAEs
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤1: 
Taper steroids over at least 
1 month.
Grade 4 
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade ≤1: 
Taper steroids over at least 
1 month
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Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 
12 weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue avelumab 
therapy
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; AHA=American Heart Association; 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine 
kinase MB; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; ESC=European 
Society of Cardiology; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; iv=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI=National Cancer Institute; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of 
normal.
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Appendix 7
Clinical Laboratory Tests
Table 20
Protocol-required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
!
MCV
!
MCH
!
% Reticulocytes
WBC Count with 
Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
RBC Count
Hemoglobin
Hematocrit
Core Clinical 
Chemistry
BUN/total 
urea
Potassium
AST/SGOT
Total bilirubin
Creatinine
Sodium
ALT/SGPT
Magnesium
Glucose 
Chloride
Phosphorus
Alk Phos
Calcium
Included in Full 
Clinical Chemistry
Amylase
Direct bilirubin
LDH
Lipase
Creatine kinase
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 (Discontinuation of Study Intervention) and Appendix 8 (Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting).
Routine 
Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones, macroscopic appearance, bilirubin, color, 
urobilinogen, nitrite, leukocyte esterase] by dipstick
!
Microscopic examination (at Screening and End of Treatment Visit, or if blood or protein is 
abnormal). 
Hemostaseology
aPTT
Prothrombin time/INR
Thyroid Function
TSH and Free T4
Antidrug 
Antibodies
Totality of binding ADA
Other Screening 
Tests
!
FSH (as needed in women of nonchildbearing potential only)
!
Serum and urine βhCG pregnancy test (as needed for women of childbearing potential). 
!
Serology: Hepatitis B screening: HBsAg, HBsAb, HBcAb IgG and IgM.
Hepatitis C screening: HCVAb with reflex to HCV RNA.
ADA=antidrug antibody; ALT=alanine aminotransferase; Alk Phos = alkaline phosphatase; aPTT=activated partial 
thromboplastin time; AST=aspartate aminotransferase; βhCG=β-human chorionic gonadotropin; BUN=blood urea 
nitrogen; CRP=C-reactive protein; FSH=follicle-stimulating hormone; HCV=hepatitis C virus; HBcAb=hepatitis B core 
antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HCVAb=hepatitis C virus 
antibody; IgG=immunoglobulin G; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; MCV=mean corpuscular volume; MCH=mean corpuscular hemoglobin; RBC=red blood cell; 
RNA=ribonucleic acid; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell.
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Appendix 8
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, 
regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, regardless if it is considered related to the medicinal 
product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the NCI-CTCAE, version 5.0 (publication date: 27 November 2017), 
a descriptive terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment.
The 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening 
! Grade 5 or Death 
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (e.g., sudden death, 
unexplained death), the death per se might then be reported as an SAE.
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Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other nonstudy interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the study 
interventions include, but may not be limited to, temporal relationship between the AE and the 
study interventions, known side effects of study interventions, medical history, concomitant 
medication, course of the underlying disease, and study procedures.
Unrelated:
Not reasonably related to the study intervention. The AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the study intervention. The AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(e.g., anemia or increased ALT) must be reported as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. Life-threatening refers to an event in which the participant is at risk of death 
at the time of the event, not an event that hypothetically might have caused death if it was more 
severe.
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered as SAEs when, based 
upon appropriate medical judgment, they may jeopardize the participant or may require medical 
or surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs, AESIs, and DLTs.
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Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (i.e., undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the participant’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the AE reporting period, as defined in Section 8.3.2 (Method of Detecting Adverse 
Events and Serious Adverse Events).
Adverse Events of Special Interest for Safety Monitoring
Any AE that is suspected to be a potential irAE or an infusion-related reaction will be considered 
an AESI.
Other Adverse Events to be Reported Following a Specialized Procedure 
Dose-limiting toxicities are defined in Section 6.6.1.
Recording and Follow-Up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented. If an AE constitutes a DLT, this is documented accordingly.
Specific guidance is in the eCRF Completion and Monitoring Conventions provided by the 
Sponsor.
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Reporting Serious Adverse Events, Adverse Events of Special Interest, and Dose-limiting 
Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form in the eCRF following specific completion 
instructions.
Reporting of SAEs via paper report form is required as a back-up method only in the case of 
electronic data capture (EDC) failure. Names, addresses, and telephone and fax numbers will be 
included on the paper report form. All information reported via paper form must be transcribed 
into the eCRF as soon as the system becomes available.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be completed immediately thereafter in the eCRF. 
Relevant pages from the eCRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report).
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
Adverse Events of Special Interest
Serious AESIs must be reported in an expedited manner as SAEs as outlined above. Nonserious 
AESI are not required to be reported in an expedited manner.
Reporting of nonserious AESIs via paper report form is required as a back-up method only in the 
case of EDC failure. Names, addresses, and telephone and fax numbers will be included on the 
paper report form. All information reported via paper form must be transcribed into the eCRF as 
soon as the system becomes available.
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Dose-limiting Toxicities
Each event meeting the criteria of a DLT, as specified in Section 6.6.1, must be recorded in the 
eCRF within 24 HOURS after becoming aware of the event. Serious DLTs must be reported in an 
expedited manner as SAEs, as outlined above.
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Appendix 10
Protocol Amendment History
The information for the current amendment is on the title page.
Protocol Version
Description of Change
Brief Rationale
Version 1.1-BEL
Table 2 and Table 3 (Schedule of 
Assessments): Added urine pregnancy test 
at Visit 30 Days (± 5) after Last Treatment 
and a notation that urine pregnancy tests 
are to be performed at 30 days after the 
last dose safety follow-up.
To bring the protocol into alignment with the 
CTFG recommendations for contraception 
and pregnancy testing in clinical trials.
Section 5.1 Inclusion Criteria 11b and 
Appendix 3 Contraception: Added that 
contraception for Parts A and B would 
continue for at least 6 months after the last 
dose of carboplatin, M6620, or the defined 
SOC combination treatments, or at least 60 
days after the last dose of maintenance 
with avelumab, whichever is later.
To bring the protocol into alignment with the 
SmPC for carboplatin and defined SoC 
combination treatments, as well as the 
M6620 IB, which specify to continue 
contraception for at least 6 months after the 
last treatment.
Version 1.0
Original Protocol
Not applicable
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Appendix 13
Principal Investigator Signature Page
Study Title:
A Phase Ib Safety Run-in and Randomized Phase II, 
Open-label Study to Evaluate the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of M6620 in 
Combination with Avelumab and Carboplatin in 
Comparison to Standard of Care Therapy in Participants 
with PARPi-resistant Recurrent Ovarian, Primary 
Peritoneal, or Fallopian Tube Cancer
Regulatory Agency Identifying 
Numbers:
EudraCT # 2018-001534-17
US IND # 
Clinical Study Protocol Version:
30 Nov 2018/Version 2.0
Site Number:
I am responsible for the conduct of the study at this site, and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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SAP_001.pdf: 
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Integrated Analysis Plan
Clinical Trial Protocol 
Identification No.
MS201943-0029
Title:
A Phase Ib Safety Run-in and Randomized Phase II, Open-
label Study to Evaluate the Efficacy, Safety, Tolerability, 
and Pharmacokinetics of M6620 in Combination with 
Avelumab and Carboplatin in Comparison to Standard of 
Care Therapy in Participants with PARPi-resistant 
Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube 
Cancer
Trial Phase
Ib/II
Investigational Medicinal 
Product(s)
M6620 in combination avelumab and carboplatin
Clinical Trial Protocol Version
30 November 2018 / Version 2.0
Statistical Analysis Plan Author
Statistical Analysis Plan
Date and Version
27 Nov 2019 / Version 1.0
Statistical Analysis Plan 
Reviewers
, 
 
, Merck KGaA
, 
, Merck KGaA
, 
, EMD Serono
, 
, Merck KGaA
, 
, EMD Serono
, 
, Merck KGaA
, 
, Merck KGaA
, 
, 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2019 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Approval Page
Integrated Analysis Plan: MS201943-0029
A Phase Ib Safety Run-in and Randomized Phase II, Open-label Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics of M6620 in Combination with Avelumab and 
Carboplatin in Comparison to Standard of Care Therapy in Participants with PARPi-resistant 
Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Approval of the IAP by all Merck Data Analysis Responsible is documented within ELDORADO
via eSignature. With the approval within Eldorado, the Merck responsible for each of the analysis 
also takes responsibility that all reviewers’ comments are addressed adequately.
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1
Table of Contents
Integrated Analysis Plan ....................................................Error! Bookmark not defined.
Approval Page
..............................................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................5
3
Modification History ............................................................................6
4
Purpose of the Integrated Analysis Plan...............................................6
5
Objectives and Endpoints .....................................................................7
6
Overview of Planned Analyses.............................................................7
6.1
Main Analysis.......................................................................................7
7
Changes to the Planned Analyses in the Clinical Trial Protocol..........7
8
Protocol Deviations and Analysis Populations.....................................8
8.1
Definition of Protocol Deviations.........................................................8
8.2
Definition of Analysis Sets...................................................................8
9
General Specifications for Statistical Analyses....................................8
10
Trial Subjects......................................................................................10
10.1
Disposition of Subjects and Discontinuations....................................10
10.2
Protocol Deviations ............................................................................10
11
Demographics and Other Baseline Characteristics.............................10
11.1
Demographics.....................................................................................11
12
Previous or Concomitant Medications/Procedures.............................12
13
Treatment Compliance and Exposure.................................................12
14
Endpoint Evaluation ...........................................................................12
14.1
Primary Endpoint Analyses ................................................................12
14.2
Secondary Endpoint Analyses ............................................................12
14.2.1
Best Overall Response........................................................................12
14.2.2
Progression Free Survival...................................................................13
15
Safety Analyses ..................................................................................14
15.1
Adverse Events...................................................................................14
15.1.1
All Adverse Events.............................................................................15
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events...................................................................................16
15.2.1
Deaths .................................................................................................16
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15.2.2
Serious Adverse Events ......................................................................16
15.2.3
Adverse Events of Special Interest.....................................................16
16
Analyses of Other Endpoints..............................................................16
16.1
Pharmacokinetics................................................................................16
17
References...........................................................................................16
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2
List of Abbreviations and Definition of Terms
AE(s)
Adverse event(s)
AESI(s)
Adverse event(s) of special interest
BOR
Best overall response
CA-125
Cancer antigen 125
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose-limiting toxicities
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
GCIG
Gynecologic Cancer Intergroup
iAP
Integrated analysis plan
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse
Events
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetic(s)
PP
Patient profile
PR
Partial response
PT
Preferred Term
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SOC
System Organ Class
StDev
Standard deviation
TEAE
Treatment emergent adverse event
TFST
Time to first subsequent therapy
TTP
Time to progression 
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3
Modification History
Unique
Identifier for
iAP Version
Date of
iAP Version
Author
Changes from the Previous Version
1.0
27 November 2019
N/A – first version
4
Purpose of the Integrated Analysis Plan
The purpose of this integrated analysis plan (iAP) is to document technical and detailed
specifications for the main analysis of Protocol MS201943-0029. 
The Part A of the study was completed after enrollment of three patients and confirmation of the 
safety combination dose by the SMC. It was however decided not to continue with Part B. Details 
will provided in the study report. 
This core iAP is based upon Section 9 (Statistical Considerations) of the trial protocol and protocol
amendment and is prepared in compliance with ICH E9. 
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5
Objectives and Endpoints
Part A (Safety Run-in Period)
Objectives
Endpoints (Outcome Measures)
IAP 
section
Primary
To evaluate a safe, tolerable recommended 
Phase II dose (RP2D) of carboplatin + M6620 
in combination with avelumab in participants 
with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of dose-limiting toxicities (DLTs) during 
the DLT observation period
15
Secondary
To evaluate the safety and tolerability of 
carboplatin+ M6620 at the RP2D when used 
in combination with avelumab in participants 
with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer
Occurrence of Treatment Emergent Adverse Events 
(TEAEs) and treatment-related adverse events 
(AEs) according to National Cancer Institute 
Common Terminology Criteria for Adverse Events 
(NCI-CTCAE)
15
To evaluate the antitumor activity of 
carboplatin+ M6620 at the RP2D in 
combination with avelumab in participants 
with PARPi-resistant recurrent ovarian, 
primary peritoneal, or fallopian tube cancer

Confirmed best overall response (BOR) 

Progression-free survival (PFS) from date of
first dose of study intervention until progressive 
disease (PD) or death

Duration of response (DOR) as assessed from 
complete response (CR) or partial response 
(PR) until PD, death, or last tumor assessment

Time to progression (TTP) from first dose of 
study intervention until PD 
All the above by Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST v1.1), and/or 
cancer antigen 125 (CA-125) response 
(Gynecologic Cancer Intergroup [GCIG] criteria),as 
assessed by the Investigator.
Time to first subsequent therapy (TFST)
14
To characterize the pharmacokinetic (PK) 
profiles of avelumab and M6620 when given 
in combination with carboplatin
PK parameter estimates for M6620
PK summary statistics for avelumab
NA
6
Overview of Planned Analyses
6.1
Main Analysis
The reduced-scope main analysis is being completed following study cancellation and database 
lock.
7
Changes to the Planned Analyses in the Clinical Trial Protocol
The analyses stated in the protocol will not be completed in their entirety due to study cancellation.  
Time to first subsequent therapy (TFST) cannot be calculated since the date of first subsequent 
treatment was not recorded in the eCRF, and the decision was taken not to correct the error due to 
study stop.
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8
Protocol Deviations and Analysis Populations
8.1
Definition of Protocol Deviations
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 
Important protocol deviations include:
Participants that are dosed on the study despite not satisfying the inclusion criteria or meeting 
one or more exclusion criteria;
Participants that meet withdrawal criteria whilst on the study but are not withdrawn;
Participants that receive the wrong treatment or an incorrect dose;
Participants that receive an excluded concomitant medication;
Deviation from Good Clinical Practice.
Important protocol deviations will be based upon the study database and determined for all 
participants by either medical review processes, site monitoring or programming based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
All important protocol deviations are documented in SDTM datasets whether identified through 
site monitoring, medical review, or programming.
8.2
Definition of Analysis Sets
The analysis sets that are applicable to the analyses are defined in Table 1. 
Table 1
Analysis Sets
Population
Description
Enrolled
All participants who provided informed consent.
Safety (SAF)
All participants who receive at least 1 dose of any study intervention.
Analyses performed on the Safety Analysis Set will consider participants as treated.
There are no subgroup analyses planned.
9
General Specifications for Statistical Analyses
Tables will show data summarized overall; listings will be provided by participant; complete 
patient profiles will be generated based on collected data.
Definition of on-treatment period:
On-treatment period is defined as the time from the first dose of study intervention through 30 
days + last dose of study intervention, unless otherwise stated.
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Study intervention groups:
The study intervention group is defined and labelled as ‘Avelumab + M6620’.
Data handling after cut-off date:
Not applicable, as this will be the final analysis and no further data collection is planned.
Significance level:
There will be no statistical tests performed.
Presentation of continuous and qualitative variables:
Continuous variables will be summarized using descriptive statistics, i.e. 

number of participants, number of participants with non-missing values 

median

minimum, maximum
Qualitative variables will be summarized by counts and percentages.               
Unless otherwise stated the calculation of proportions will be based on the number of participants
in the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category.
Definition of baseline:
In general, the last non-missing measurement prior to the first dose of study intervention will serve
as the baseline measurement.
Definition of duration:
If not otherwise specified, duration will be calculated by the difference of start and stop date + 1 
(e.g. survival time (days) = date of death – date of first study intervention + 1).
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus 
date of event.  
Conversion factors:
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days.
Handling of missing data:
Missing data will not be replaced. 
In all listings, imputed values will be presented and flagged as such. 
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”.  
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Treatment day is defined relative to the date of first study intervention administration. Treatment 
Day 1 is the day of start of study intervention; the day before is defined as Treatment Day -1 (no 
Treatment Day 0 is defined).
All analyses will be performed using SAS® Software version 9.4 or higher. 
10
Trial Subjects
The subsections in this section include specifications for reporting participant disposition and
treatment/trial discontinuations.
10.1
Disposition of Subjects and Discontinuations
Analysis sets: SAF
Subject disposition and treatment discontinuations will be summarized in a table which will
include the following:

Total number of participants screened overall

Number of participants who discontinued from the trial prior to receiving any study 
intervention, overall and grouped by the main reason (i.e. screen failures)

Number of treated participants

Number and percentage of participants who discontinued treatment, and reasons for
treatment discontinuation

Number and percentage of treated participants who discontinued the trial, and reasons for 
trial discontinuation
A summary of participant enrollment by geographic region and country. Site codes will be used 
for the determination of the participant’s geographic region and country.
A by-participant listing will also be provided.
10.2
Protocol Deviations
Analysis sets: SAF
A listing of important protocol deviations will be provided.
11
Demographics and Other Baseline Characteristics
Analysis sets: SAF
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11.1
Demographics
Demographic characteristics will be summarized using the following information from the
‘Screening/Baseline Visit’ eCRF pages.

Demographic characteristics
-
Gender: Female
-
Race: White, Black or African American, Asian, American Indian or Alaska
Native, Native Hawaiian or Other Pacific Islander, Other, Unknown
-
Ethnic origin: Hispanic/Latino (Yes/No)
-
Age (years): summary statistics
-
Age categories: < 65 years, ≥65 years

65-< 75

75-< 85

≥85
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, ≥2
-
Height (cm)
-
Weight (kg)
-
Body Mass Index (BMI) (kg/m2)
-
Body Surface Area (BSA) (m²)
Specifications for computation:
Age (years)
(date of given informed consent - date of birth + 1) / 365.25 
In case of missing day for at least one date, but month and year available for both dates:
For the derivation of age, the day of informed consent and the day of birth will be set to 1 
and the formula above will be used
In case of missing month for at least one date, but year available for both dates:
For the derivation of age, the day and the month of informed consent and the day and month 
of birth will be set to 1 and the formula above will be used
BSA (m²) = ([height (cm) x weight (kg)] / 3600)1/2
BMI (kg/m²) = weight (kg) / [height (cm) x height (cm)] x 10000
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A listing of participant demographics will be provided.
12
Previous or Concomitant Medications/Procedures
Data presented in patient profiles.
13
Treatment Compliance and Exposure
Data presented in patient profiles.
14
Endpoint Evaluation
14.1
Primary Endpoint Analyses
Analysis sets: SAF
The primary objective is to assess the safety of the investigational treatment to safeguard the 
interests of trial participants and monitor the overall conduct of the clinical trial. The details 
regarding safety outputs are contained in Section 15.
14.2
Secondary Endpoint Analyses
Analysis sets: SAF
All efficacy endpoints described below will be listed by participant.
14.2.1
Best Overall Response
Analysis sets: SAF
Best overall response (BOR) will be assessed based on reported overall timepoint responses at 
different evaluation timepoints from the start date until documented disease progression in 
accordance to RECIST v1.1 according to the Investigator assessment, taking requirements for 
confirmation into account as detailed below. Dates of subsequent anti-cancer therapies were not 
collected, so that information will not be taken into account. Clinical deterioration will not be 
considered as documented disease progression.
1) BOR Based on Confirmed Responses:

CR = at least two determinations of CR at least 4 weeks apart (with no PD in-between)

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart (and not qualifying for a CR) (with no PD in-between)

SD (applicable only to participant with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after start date (and not qualifying for CR or PR).
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
Non-CR/non-PD (applicable only to participants with non-measurable disease at baseline) 
= at least one non-CR/non-PD assessment (or better) ≥6 weeks after start date (and not 
qualifying for CR or PR).

PD = progression ≤ 12 weeks after start date (and not qualifying for CR, PR or SD).

Not Evaluable (NE) = all other cases.
SD can follow PR only in the rare case that tumor increases by less than 20% from the nadir, 
but enough that a previously documented 30% decrease from baseline no longer holds. If this 
occurs the sequence PR-SD-PR is considered a confirmed PR. A sequence of PR – SD – SD –
PD would be a best response of SD if the window for SD definition has been met.
2) BOR Based on Unconfirmed Responses:

Unconfirmed CR = one objective status of CR documented before progression. 

Unconfirmed PR = one objective status of PR documented before progression (and not 
qualifying for CR).

SD (applicable only to participant with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after start date and before progression (and not qualifying 
for CR or PR).

Non-CR/non-PD (applicable only to participants with non-measurable disease at baseline) 
= at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after start date and before 
progression (and not qualifying for unconfirmed CR or unconfirmed PR).

PD = progression ≤ 12 weeks after start date (and not qualifying for unconfirmed CR, 
unconfirmed PR, SD or non-CR/non-PD).

NE = all other cases.  
Confirmed and Unconfirmed BOR will be presented in the efficacy listing.
14.2.2
Progression Free Survival
The progression free survival (PFS) time is defined as the time (in months) from the date of first 
dose of study intervention to the date of the first documentation of objective PD as per RECIST 
v1.1 as assessed by the Investigator, or death due to any cause, whichever occurs first.
The PFS data will be censored on the date of the last adequate tumor assessment in the following
cases:

For participants who do not have an event (PD or death)

For participants with an event after 2 or more missing tumor assessments.
Participants who do not have a baseline tumor assessment or who do not have any postbaseline
tumor assessments will be censored on the date of the first study intervention, unless death 
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occurred on or before the time of the second planned tumor assessment, in which case the death 
will be considered an event.
PFS time = (date of PD or death/censoring - date of first dose + 1)/30.4375 (months)
The PFS event or censoring, PFS time or censoring time, and the reasons for censoring will be 
presented in the efficacy listing.
15
Safety Analyses
Analysis sets: SAF
The reduced scope limits safety analyses to Adverse Events; all other data will be presented in the 
patient profiles.
15.1
Adverse Events
The severity of adverse events (AEs) will be graded using the latest NCI-CTCAE version, except 
where CTCAE grades are missing. No imputation of missing grades will be performed. Adverse 
events will be coded according to the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version at the time of database lock.

TEAEs: Any AEs that are reported (serious and non-serious) will be considered treatment 
emergent adverse events (TEAEs) with onset dates occurring on-treatment, or events which 
worsen on-treatment.

Related Adverse Events: AEs with relationship to study treatment of ‘Related’ reported 
by the Investigator, as well as those of unknown relationship (i.e., no answer to the 
question, ‘Relationship with study treatment’). Relationship is judged separately for each 
study treatment.

SAEs: Serious adverse events (as recorded on the Adverse Events Details eCRF page, 
Serious Adverse Event = ‘Yes’).

AEs Leading to Treatment Discontinuation: AEs leading to permanent discontinuation 
of study treatment (as recorded on the Adverse Events Details eCRF page, Action taken 
with study treatment = ‘Drug withdrawn’). Treatment discontinuation is recorded 
separately for each study treatment.

AEs Leading to Death: AEs leading to death (as recorded on the Adverse Events Details
eCRF page, Change in grade and outcome = ‘Fatal’ or Grade = ‘Grade 5 or death related 
to AE’).
AEs will be summarized by MedDRA preferred term (PT) as event category and MedDRA 
primary system organ class (SOC) as summary category. In general, each participant will be 
counted only once within each PT or SOC. 
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AEs with missing classifications regarding relationship to study treatment, and those with start 
date on or after the start of study treatment, will be considered as related to the study treatment.
Incomplete AE-related dates will be handled as follows:

If the onset date is missing completely or missing partially – but the onset month and year, 
or year, are equal to that of the study treatment start – then the onset date will be replaced 
by the minimum of the start of study treatment and the AE resolution date.

In all other cases, the missing onset day or month will be replaced by 1.

Incomplete stop dates will be replaced by the last day of the month (if only day is missing), 
if not resulting in a date later than the date of participant’s death or database lock. In the 
latter case, the date of death or database lock will be used to complete the stop date.

In all other cases the incomplete stop date will not be imputed. If the stop date of an AE is 
after the date of database lock, the outcome of the AE is ongoing at study close.
All AE tables will be restricted to TEAEs only. The AE tables will include the number and 
percentage of participants with at least one TEAE, by MedDRA SOC and PT (both sorted 
alphabetically), unless otherwise stated.
15.1.1
All Adverse Events
All AEs will be tabulated in an overall summary table to include:

Any TEAE

TEAEs leading to death

Serious TEAEs

TEAEs, grade ≥ 3

TEAEs leading to permanent treatment discontinuation

TEAEs leading to dose reduction

AESIs

DLTs

Related TEAEs

Related TEAEs, grade ≥ 3

Related serious TEAEs

Related TEAEs leading to death

Related TEAEs leading to permanent treatment discontinuation

Related TEAEs leading to dose reduction

Related AESIs
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A listing of all AEs with TEAEs flagged will be provided. This listing will be sorted by participant. 
This listing will additionally contain SOC, PT, grade, SAE (yes/no), DLT (yes/no), AESI (yes/no),
relatedness to study treatment (Avelumab [yes/no] / M6620 [yes/no] / Carboplatin [yes/no]), start 
date (+treatment day), stop date (+treatment day), grade, and outcome.
Additional TEAE summary tables include:

TEAEs by SOC, PT, and worst grade

Related TEAEs by SOC, PT, and worst grade

Non-serious TEAEs with frequency ≥ 5% by SOC and PT (as per CT.gov requirement)
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
Analysis sets: SAF
15.2.1
Deaths
A table for death events will be provided.
15.2.2
Serious Adverse Events
A table for SAEs will be provided.
15.2.3
Adverse Events of Special Interest
Adverse events of special interest (AESIs) will be determined using the following information
from the ‘Adverse Events Details’ eCRF page.
Categories that qualify the event:
Infusion-related reactions / hypersensitivity
irAEs / autoimmune disorders
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
A listing of the pharmacokinetic (PK) results will be provided.
17
References
There are no references.
16/17


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