A Phase II, Open-label, Single-arm Study of Berzosertib (M6620) in Combination With Topotecan in Participants With Relapsed Platinum-resistant Small-Cell Lung Cancer (DDRiver SCLC 250)
Phase: PHASE2
Conditions: Small-cell Lung Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

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Berzosertib + topotecan in relapsed platinum-resistant SCLC
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Phase II, open-label, single-arm study of 
berzosertib 
(M6620) 
in 
combination 
with 
topotecan 
in 
participants 
with 
relapsed 
platinum-resistant small-cell lung cancer
Study Number:
MS201923_0050
Protocol Version:
21 June 2021/Version 4.0
Merck Compound:
Berzosertib (M6620)
Merck Registered Compound Name in 
Japan:
Not applicable
Study Phase:
II
Short Title:
Berzosertib 
+ 
topotecan 
in 
relapsed 
platinum-resistant SCLC
Acronym or Abbreviation:
DDRiver SCLC 250
Coordinating Investigator:
, MD
Sponsor Name and Legal Registered 
Address:
Sponsor:
Affiliates of Merck KGaA, Darmstadt, Germany
For all countries, except the US and Canada:
Merck Healthcare KGaA, Darmstadt, Germany 
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250 Darmstadt, Germany
In the US and Canada:
EMD Serono Research & Development Institute, 
Inc. an affiliate of Merck KGaA, Darmstadt, 
Germany 
45A Middlesex Turnpike
Billerica, MA, 01821, USA
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Local Sponsor for Sites in Japan:
Merck Biopharma Co., Ltd. Japan
an affiliate of Merck KGaA, Darmstadt, Germany
Acro Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
Regulatory Agency Identifying 
Numbers:
IND:
EudraCT: 2020-004231-25
Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original protocol
07-Oct-2020
2.0
Global amendment 
20-Nov-2020
3.0
Global amendment
23-Dec-2020
3.1-JPN
Country-specific amendment
25-Mar-2021
3.2-USA
Country-specific amendment
27-Apr-2021
3.3-BEL
Country-specific amendment
27-Apr-2021
4.0
Global amendment
21-Jun-2021
Protocol Version 4.0 (21 June 2021)
Overall Rationale for the Amendment
The high-level rationale for the changes implemented in this amendment are to include:
!
All country-specific changes into a single global amendment (see Appendix 9 for descriptions 
and rationale of changes)
!
Clarification of weak
DDI potential
of berzosertib
via CYP3A4 inhibition and 
recommendations on precautions for coadministration of certain CYP3A4 substrates
!
Merck standards updates.
Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities
!
Clarify medical history assessment 
should include smoking history
!
Clarify cycle start may be delayed up 
to 7 days for scheduling conflicts
Text is amended to clarify study procedures.
2.3.1 Risk 
Assessment, 
Table 3
6.5.3 Prohibited 
Medicines and 
Precautions
Include text to describe DDI potential 
due to CYP3A4 inhibition and to 
recommend precautions when 
berzosertib is coadministered with 
sensitive CYP3A4 substrates with 
narrow therapeutic index
Berzosertib is a weak inhibitor of CYP3A4 at the 
dose of 210 mg/m2 and precautions are
recommended when berzosertib is 
co-administered with sensitive CYP3A4 substrates 
with a narrow therapeutic index.
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Section # and 
Name
Description of Change
Brief Rationale
5.2 Exclusion 
Criteria, item 2
Reduce the imaging time interval for 
assessment of stable disease from 
4 weeks to 2 weeks for patients with 
known, but stable, brain metastases
Time is reduced to eliminate delay to start study 
intervention in patients with actual stable brain 
metastases.
Section 5.3.1 
Meals and 
Dietary 
Restrictions
(pertains only 
to Japan)
Pertaining only to the country-specific 
V3.1-JPN amendment, restriction of 
Grapefruit Juice etc. are removed in this 
version.
Drug interactions by grapefruit and Seville 
oranges or other citrus fruits and their juices are 
predominantly by the inhibition of intestinal 
CYP3A4 activity without an apparent inhibition of 
hepatic CYP3A4. Since berzosertib is 
administered intravenously, its pharmacokinetics 
should not be affected by citrus fruits like 
grapefruit and Seville oranges. Hence, restriction 
of grapefruit juice, etc., are not included in this 
protocol.
Throughout
Minor editorial revisions for clarity,
consistency, and to address Merck 
standards updates.
Minor; therefore, have not been summarized.
- Confidential –
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 © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................4
Table of Tables
..............................................................................................................7
Table of Figures
..............................................................................................................8
1
Protocol Summary ................................................................................9
1.1
Synopsis................................................................................................9
1.2
Schema................................................................................................15
1.3
Schedule of Activities.........................................................................17
2
Introduction.........................................................................................25
2.1
Study Rationale...................................................................................25
2.2
Background.........................................................................................25
2.3
Benefit/Risk Assessment ....................................................................27
2.3.1
Risk Assessment.................................................................................27
2.3.2
Benefit Assessment.............................................................................30
2.3.3
Overall Benefit: Risk Conclusion.......................................................30
3
Objectives and Estimands...................................................................30
4
Study Design.......................................................................................42
4.1
Overall Design....................................................................................42
4.1.1
Safety Run-in Part (Japan-only) .........................................................42
4.2
Scientific Rationale for Study Design ................................................43
4.3
Justification for Dose..........................................................................44
4.3.1
Main Part of Global Phase II ..............................................................44
4.3.2
Safety Run-in Part (Japan-only) .........................................................44
4.4
End of Study Definition......................................................................44
5
Study Population.................................................................................45
5.1
Inclusion Criteria ................................................................................45
5.2
Exclusion Criteria...............................................................................47
5.3
Lifestyle Considerations .....................................................................49
5.3.1
Meals and Dietary Restrictions...........................................................49
5.3.2
Caffeine, Alcohol, and Tobacco .........................................................50
5.3.3
Activity ...............................................................................................50
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5.4
Screen Failures....................................................................................50
6
Study Interventions.............................................................................50
6.1
Study Interventions Administration....................................................50
6.2
Study Interventions Preparation, Handling, Storage, and 
Accountability.....................................................................................52
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................53
6.3.1
Study Intervention Assignment ..........................................................53
6.3.2
Blinding ..............................................................................................53
6.4
Study Intervention Compliance..........................................................53
6.5
Concomitant Therapy .........................................................................53
6.5.1
Rescue Medicine.................................................................................54
6.5.2
Permitted Medicines...........................................................................54
6.5.3
Prohibited Medicines and Precautions................................................54
6.5.4
Other Interventions.............................................................................55
6.6
Dose Selection and Modification........................................................56
6.6.1
Study Intervention Dose Modifications..............................................56
6.6.1.1
Berzosertib Dose Modifications .........................................................56
6.6.1.2
Topotecan Dose Modifications...........................................................57
6.7
Study Intervention After the End of the Study...................................59
6.8
Definition of Dose-limiting Toxicity (Safety Run-in Part Only) .......59
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................60
7.1
Discontinuation of Study Intervention................................................60
7.2
Participant Discontinuation/Withdrawal from the Study ...................61
7.3
Lost to Follow-Up...............................................................................61
8
Study Assessments and Procedures....................................................62
8.1
Efficacy Assessments and Procedures................................................62
8.1.1
Tumor Response.................................................................................62
8.1.2
Survival Follow-up .............................................................................63
8.1.3
Patient-Reported Outcomes................................................................63
8.2
Safety Assessments and Procedures ...................................................64
8.2.1
Physical Examinations........................................................................65
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8.2.2
Vital Signs ..........................................................................................65
8.2.3
Electrocardiograms.............................................................................65
8.2.4
Clinical Safety Laboratory Assessments ............................................66
8.3
Adverse Events and Serious Adverse Events.....................................66
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................67
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...67
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............67
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....68
8.3.5
Pregnancy ...........................................................................................68
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................69
8.3.7
Adverse Events of Special Interest.....................................................70
8.4
Treatment of Overdose .......................................................................70
8.5
Pharmacokinetics................................................................................70
8.6
Pharmacodynamics.............................................................................73
73
73
8.9
Immunogenicity Assessments ............................................................74
8.10
Medical Resource Utilization and Health Economics........................74
9
Statistical Considerations....................................................................74
74
74
9.3
Populations for Analyses ....................................................................76
9.4
Statistical Analyses.............................................................................77
9.4.1
Efficacy Analyses ...............................................................................77
9.4.2
Safety Analyses ..................................................................................80
9.4.2.1
Safety Run-in Part in Japan ................................................................82
9.4.3
Other Analyses....................................................................................83
9.4.4
Sequence of Analyses.........................................................................83
10
References...........................................................................................85
11
Appendices .........................................................................................86
Appendix 1
Abbreviations......................................................................................87
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Appendix 2
Study Governance...............................................................................90
Appendix 3
Contraception......................................................................................97
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................100
Appendix 5
Clinical Laboratory Tests .................................................................107
108
Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 .....................................................................................................109
Appendix 8
Performance Scales...........................................................................118
Appendix 9
Protocol Amendment History...........................................................119
Appendix 10
Sponsor Signature Page....................................................................125
Appendix 11
Coordinating Investigator Signature Page........................................126
Appendix 12
Principal Investigator Signature Page...............................................127
Table of Tables
Table 1
Schedule of Activities: Treatment, End of Treatment, and 
Follow-up Period ................................................................................18
Table 2
Triplicate Electrocardiogram Assessments and Pharmacokinetics 
Sampling Schedule .............................................................................23
Table 3
Berzosertib and Topotecan - Identified and Potential Risks with 
Mitigation Strategies...........................................................................27
Table 4
Objectives and Estimand Attributes (Main Part)................................31
Table 5
Objectives and Estimand Attributes (Safety Run-in Part in Japan)....36
Table 6
Study Interventions.............................................................................51
Table 7
Prohibited Concomitant Medications and Precautions During 
Berzosertib Treatment ........................................................................55
Table 8
Berzosertib Dose Modifications .........................................................57
Table 9
Topotecan Dose Modifications for Hematologic and 
Nonhematologic Toxicities.................................................................58
Table 10
Topotecan Dose Modifications for Renal Function (Regardless of 
Drug Relationship)..............................................................................58
76
Table 12
Populations for Analyses ....................................................................76
Table 13
Efficacy Analyses and Estimands (Main Part)...................................78
Table 14
Safety Endpoints (Main Part) .............................................................81
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Table 15
Safety Endpoints (Safety Run-in Part in Japan) .................................81
Table 16
Tolerability Judgment Boundaries for Target Toxicity Rate = 30%..82
Table 17
Protocol-Required Clinical Laboratory Assessments.......................107
Table of Figures
Figure 1
Main Part of Global Phase II Study Schema ......................................16
Figure 2
Schematic Structure Depicting the Safety Run-in Part in Japan ........16
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A Phase II, open-label, single-arm study of berzosertib (M6620) in combination 
with topotecan in participants with relapsed platinum-resistant small-cell lung cancer
Short Title: Berzosertib + topotecan in relapsed platinum-resistant small-cell lung cancer (SCLC)
Rationale: The purpose of this study is to assess efficacy, safety, tolerability, and 
pharmacokinetics (PK) of berzosertib in combination with topotecan in participants with relapsed, 
platinum-resistant SCLC. 
Objectives and Estimands (Main Part):
Objectives
Estimand Attributes
Primary
To assess efficacy of intervention in 
terms of objective response with 
berzosertib + topotecan
Endpoint: Objective response according to RECIST 1.1 as assessed by 
the IRC
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., regardless 
of the intercurrent event
!
Start of subsequent anticancer treatment: while not treated with 
subsequent anticancer therapy strategy; i.e., ignoring tumor 
assessments after the intercurrent event
!
Progression according to RECIST 1.1: while not progressed strategy, 
i.e., assessments up to the intercurrent event
Population Level Summary: Objective response rate
Secondary
To assess efficacy of intervention in 
terms of duration of response with 
berzosertib + topotecan
Endpoint: Duration of response according to RECIST 1.1 as assessed by 
the IRC. Measured by time from first documentation of objective response 
to progressive disease (PD) or death, occurring within 2 scheduled tumor 
assessments after last evaluable assessment or first study intervention
Population: Patients with relapsed, platinum-resistant SCLC with a 
confirmed objective response according to RECIST 1.1 as assessed by 
IRC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
! Death within 2 scheduled tumor assessments: composite strategy, i.e., 
will be considered as event of interest
! Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
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Objectives
Estimand Attributes
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
Population Level Summary:
!
Median duration of response
!
Kaplan-Meier estimates, including the Kaplan-Meier estimate at 
6 months
To assess efficacy of intervention in 
terms of progression-free survival 
(PFS) with berzosertib + topotecan
Endpoint: Progression-free survival according to RECIST 1.1 as assessed 
by the IRC. Measured by time from first study intervention to PD or death, 
occurring within 2 scheduled tumor assessments after last evaluable 
assessment or first study intervention
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e.,
will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
Population Level Summary:
!
Median PFS time
!
Kaplan-Meier estimates
To assess efficacy of intervention in 
terms of overall survival (OS) with 
berzosertib + topotecan followed by 
subsequent therapy
Endpoint: Overall survival. Measured by time from first study intervention 
to death
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan followed by subsequent anticancer 
treatment
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
Population Level Summary:
!
Median OS time
!
Kaplan-Meier estimates
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Objectives
Estimand Attributes
To assess the efficacy of intervention 
in terms of physical functioning, 
cough, dyspnea and chest pain, and 
overall health-related quality of life 
(HRQoL) based on PROs when 
treated with berzosertib + topotecan
Endpoint: Change from baseline in physical functioning measured by the 
European Organization for the Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ-C30); cough, dyspnea, and 
chest pain measured by EORTC QLQ-LC13 (lung cancer specific 
questionnaire); health state as measured by visual analogue scale (VAS) 
as a component of the EuroQol 5 Dimension 5 Level Scale (EQ-5D-5L)
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: while on treatment strategy, i.e., ignoring 
PRO assessments after the intercurrent event 
!
Start of subsequent anticancer treatment: while not treated with 
subsequent anticancer therapy strategy; i.e., ignoring PRO 
assessments after the intercurrent event
!
Death: while alive strategy, i.e., considering PRO assessments before 
the intercurrent event
Population Level Summary:
!
Mean changes from baseline analysis for multi-item scales in EORTC 
questionnaires (i.e., physical functioning and dyspnea) and VAS
!
Proportion of patients with ≥ 1 category improvement and proportion of 
patients with ≥ 1 category worsening in single-item symptoms (i.e., 
cough and chest pain)
To evaluate the safety and tolerability 
of berzosertib + topotecan
Endpoint: Occurrence of adverse events (AEs) and treatment-related AEs 
and occurrence of clinically significant changes in vital signs, laboratory 
parameters and 12-lead ECG findings 
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
In case DL2 is declared RP2D, data for participants receiving DL2 will in addition be analyzed as part of the main 
study.
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Objectives and Estimands (Safety Run-in Part in Japan): 
Objectives
Estimand Attributes
Primary
To confirm whether the regimen and 
recommended Phase II dose (RP2D) 
of berzosertib in combination with 
topotecan that were established in 
the Phase I study in non-Japanese 
can be safely applied to Japanese 
participants
Endpoint: 
Occurrence of dose-limiting toxicities (DLTs) until the end of Cycle 1 in 
Japanese participants, occurrence of AEs and treatment-related AEs and 
occurrence of clinically significant changes in vital signs, laboratory 
parameters and 12-lead ECG findings
Population:
!
Dose Level 1 (DL1): Japanese patients with advanced solid tumors, for 
which no effective standard therapy exists, or standard therapy has 
failed 
!
Dose Level 2 (DL2): Japanese patients with relapsed, 
platinum-resistant SCLC 
Treatment: Berzosertib + topotecan
Secondary
To assess efficacy of intervention in 
terms of objective response with 
berzosertib + topotecan
Endpoint: Objective response according to RECIST 1.1 as assessed by 
the Investigator
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., regardless 
of the intercurrent event
!
Start of subsequent anticancer treatment: while not treated with 
subsequent anticancer therapy strategy; i.e., ignoring tumor 
assessments after the intercurrent event
!
Progression according to RECIST 1.1: while not progressed strategy, 
i.e., assessments up to the intercurrent event
Population Level Summary: Objective response rate
To assess efficacy of intervention in 
terms of duration of response with 
berzosertib + topotecan
Endpoint: Duration of response according to RECIST 1.1 as assessed by 
the Investigator. Measured by time from first documentation of objective 
response to PD or death, occurring within 2 scheduled tumor assessments 
after last evaluable assessment or first study intervention
Population:
!
DL1: Japanese patients with advanced solid tumors with a confirmed 
objective response according to RECIST 1.1 as assessed by the 
Investigator
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC with a 
confirmed objective response according to RECIST 1.1 as assessed by 
the Investigator
Treatment: Berzosertib + topotecan
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Objectives
Estimand Attributes
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e., 
will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
Population Level Summary:
!
Median duration of response
!
Kaplan-Meier estimates, including the Kaplan-Meier estimate at 
6 months
To assess efficacy of intervention in 
terms of PFS with berzosertib + 
topotecan
Endpoint: Progression-free survival according to RECIST 1.1 as assessed 
by the Investigator. Measured by time from first study intervention to PD or 
death, occurring within 2 scheduled tumor assessments after last evaluable 
assessment or first study intervention
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e., 
will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
Population Level Summary:
!
Median PFS time
!
Kaplan-Meier estimates
To assess efficacy of intervention in 
terms of OS with 
berzosertib + topotecan followed by 
subsequent therapy
Endpoint: Overall survival. Measured by time from first study intervention 
to death
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan followed by subsequent anticancer 
treatment
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., 
ignoring the intercurrent event
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Objectives
Estimand Attributes
Population Level Summary:
!
Median OS time
!
Kaplan-Meier estimates
To assess the efficacy of intervention 
in terms of physical functioning, 
cough, dyspnea and chest pain, and 
overall HRQoL based on PROs when 
treated with berzosertib + topotecan
Endpoint: Change from baseline in physical functioning measured by the 
EORTC QLQ-C30; cough, dyspnea, and chest pain measured by EORTC 
QLQ-LC13 (lung cancer specific questionnaire); health state as measured 
by VAS as a component of the EQ-5D-5L
Population: 
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: while on treatment strategy, i.e., ignoring 
PRO assessments after the intercurrent event
!
Start of subsequent anticancer treatment: while not treated with 
subsequent anticancer therapy strategy; i.e., ignoring PRO 
assessments after the intercurrent event
!
Death: while alive strategy, i.e., considering PRO assessments before 
the intercurrent event
Population Level Summary:
!
Mean changes from baseline analysis for multi-item scales in EORTC 
questionnaires (i.e., physical functioning and dyspnea) and VAS
!
Proportion of patients with ≥ 1 category improvement and proportion of 
patients with ≥ 1 category worsening in single-item symptoms (i.e., 
cough and chest pain)
To characterize the pharmacokinetic 
(PK) profile of berzosertib 
Endpoint: PK parameters of berzosertib in plasma by non-compartmental 
analysis (NCA)
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Analyses for the Safety Run-in Part will include both DL1 and DL2 separately by dose level.
Overall Design: This is a multicenter, Phase II, open-label, single-arm study designed to assess 
the efficacy and safety of berzosertib in combination with topotecan in participants with relapsed, 
platinum-resistant SCLC (platinum-free interval [PFI] < 90 days) with only 1 prior line of systemic 
treatment. In Japan, a Safety Run-in Part will be conducted before enrollment into the Main Part 
of the Phase II study.
Number of Arms: 1
Blinding: No blinding
Number of Participants: Approximately 80 participants are planned to be assigned to study 
intervention. In the Safety Run-in Part in Japan, 3 to 9 participants at each dose level are planned.
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Study Intervention Groups and Duration: For this single-arm Phase II study, all participants 
will be assigned to receive berzosertib at a dose of 210 mg/m2 via intravenous (IV) administration 
on Day 2 and Day 5 of each 21-day cycle and topotecan at a dose of 1.25 mg/m2 via IV 
administration on Days 1 through 5 of each 21-day cycle.
For the Safety Run-in Part in Japan, the dose of berzosertib in Dose Level (DL) 1 will be 
105 mg/m2. Berzosertib and topotecan doses at DL2 will be the same as in the Main Part of the 
Phase II study. Details are shown in Section 1.2 and Section 4.1.
For each participant, the study will include a Screening Period lasting up to 28 days, a Study 
Intervention Period consisting of 21-day cycles of berzosertib + topotecan until disease 
progression or other criteria for study intervention discontinuation are met, an End-of-Treatment 
Visit, a Safety Follow-up Period of 30 days after last study intervention dose, and Efficacy and 
Survival Follow-up Visits every 12 weeks from last study intervention administration. During the 
Survival Follow-up, survival information and subsequent anticancer therapy given to the 
participant should be recorded. The Survival Follow-up Visits can occur as clinic visits or by 
telephone contact until death, lost to follow-up, study withdrawal of consent, or End of Study. 
Additionally, participants who discontinue study intervention for reasons other than disease 
progression or death will continue with regular imaging assessments until disease progression, 
addition of subsequent anticancer therapy, death, withdrawal of consent, lost to follow-up, or 
End of Study.
Involvement of Special Committees: Yes
An Independent Review Committee will perform blinded determinations as to whether the criteria 
for tumor response or progression are met according to Response Evaluation Criteria in Solid 
Tumors version 1.1. In addition, the study will be monitored regularly by an internal Safety 
Monitoring Committee. The Safety Run-in Part in Japan will additionally be regularly monitored 
by a Local Safety Monitoring Committee.
1.2
Schema
The Main Part of this study will enroll participants with relapsed SCLC who received 1 prior line 
of platinum-based treatment, and whose disease is considered to be resistant to platinum-based 
treatment, defined as platinum-free interval < 90 days. The schematic structure of the Main Part 
of this study is shown in Figure 1 below (see details in Section 5.1).
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Figure 1
Main Part of Global Phase II Study Schema
1L = 1 prior line; D = day; PFI = platinum-free interval; SCLC = small-cell lung cancer.
The schematic structure of the study and its Safety Run-in Part in Japan is shown in Figure 2 below. 
Section 4.1.1 presents more details of the Safety Run-in Part in Japan.
Figure 2
Schematic Structure Depicting the Safety Run-in Part in Japan
DL = dose level; DLT = dose-limiting toxicity; SCLC = small-cell lung cancer.
a
The participants may continue the study treatment after DLT evaluation period per Clinical Study Protocol.
b
If DL2 is considered safe by Safety Monitoring Committee, it can be the recommended Phase II dose. See 
Section 9.4.2.1 for details.
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1.3
Schedule of Activities
The Schedule of Activities (SoA) is presented in Table 1. The schedule for triplicate digital 
electrocardiograms (ECGs) and pharmacokinetic (PK) blood sample collection is provided in 
Table 2.
If a decision to permanently discontinue study intervention is made at a scheduled or unscheduled 
visit, that visit becomes the End-of-Treatment Visit with all relevant assessments conducted per 
Table 1. Otherwise, an End-of-Treatment Visit must occur within 7 days of last study intervention 
administration.
Survival follow-up may be conducted at the study site or via phone every 12 weeks until death, 
lost to follow-up, withdrawal of consent, or End of Study.
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Table 1
Schedule of Activities: Treatment, End of Treatment, and Follow-up Period
Assessments 
and 
Procedures
Screening
Cycle Duration = 21 Days
EOT
(within 
7 days 
after 
last 
dose)
Follow-up
Notes
(Cycle start may be delayed up to 7 days 
to accommodate scheduling conflicts, 
with approval from the Medical Monitor)
D -28 to -1
D1
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
Safety 
Follow-up 
30 Days 
after Last 
Dose 
(± 7D)
Efficacy 
and 
Survival 
every 
12 Weeks 
from Last 
Dose 
(± 2 weeks)
Informed 
Consent
X
Inclusion and 
Exclusion 
Criteria; 
Medical 
History
X
Confirm inclusion/exclusion before first study 
intervention dose based on Section 5.
Medical history to include verification of 
smoking status.
Hepatitis B 
(HBV)
X
Required at screening:
!
HBsAg
!
Total anti-HBc
!
Anti-HBsAg
!
HBV DNA: if HBsAg/anti-HBc or 
anti-HBc is positive
Required during Study Intervention Period, if 
past HBV or current HBV infection:
!
HBsAg and HBV-DNA every 12 weeks
Hepatitis C
(HCV)
X
Required at screening:
!
anti-HCV
!
HCV RNA: if anti-HCV is positive
Required during Study Intervention Period, if 
past or current HCV infection:
!
HCV RNA every 12 weeks
Physical 
Examination
X
X
X
X
Symptom-directed physical examinations 
performed as clinically indicated per 
Investigator’s judgment.
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Assessments 
and 
Procedures
Screening
Cycle Duration = 21 Days
EOT
(within 
7 days 
after 
last 
dose)
Follow-up
Notes
(Cycle start may be delayed up to 7 days 
to accommodate scheduling conflicts, 
with approval from the Medical Monitor)
D -28 to -1
D1
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
Safety 
Follow-up 
30 Days 
after Last 
Dose 
(± 7D)
Efficacy 
and 
Survival 
every 
12 Weeks 
from Last 
Dose 
(± 2 weeks)
Height
X
Weight
X
X
X
X
Vital Signs
X
X
X
X
Predose on all visits
Standard 
12-lead ECG
X
X
X
Standard 12-lead ECG – paper readout, see 
Section 8.2.3 for additional details
Hematology
X
X
X
X
X
X
X
Required at D3 at Cycle 1 in the Safety 
Run-in Part
Recommended at D8 and D15 at Cycle 1 
only; optional at subsequent cycles.
Baseline neutrophils should be ≥1,500/mm3
and platelets ≥100,000/mm3 prior to C1; for 
subsequent cycles, neutrophils should be 
> 1,000/mm3, platelets > 100,000/mm3, and 
hemoglobin ≥9 g/dL
See Table 17 for required Assessments
Serum 
Chemistry
X
X
X
X
X
Required at D3 at Cycle 1 in the Safety 
Run-in Part
See Table 17 for required Assessments
Coagulation
X
X
X
From Cycle 1 onwards, only if clinically 
indicated. See Table 17 for required 
Assessments
β-HCG, 
serum/urine 
(WOCBP only)
X
X
X
X
Serum test at Screening and EOT, urine test 
on D1 of each cycle and at Safety Follow-up
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Assessments 
and 
Procedures
Screening
Cycle Duration = 21 Days
EOT
(within 
7 days 
after 
last 
dose)
Follow-up
Notes
(Cycle start may be delayed up to 7 days 
to accommodate scheduling conflicts, 
with approval from the Medical Monitor)
D -28 to -1
D1
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
Safety 
Follow-up 
30 Days 
after Last 
Dose 
(± 7D)
Efficacy 
and 
Survival 
every 
12 Weeks 
from Last 
Dose 
(± 2 weeks)
Imaging 
Disease 
Assessment
X
At the end of every 6 weeks (± 1 week) after first dose (C1D1) until Week 36, then 
every 9 weeks (± 2 weeks) until PD as assessed by the IRC, death, withdrawal of 
consent, lost to follow-up, or End of Study, whichever comes first, regardless of 
study intervention modifications/discontinuation
Tumor assessment according to RECIST 
Version 1.1 (see Appendix 7)
Measurable disease at screening must be 
confirmed by the IRC prior to start of 
treatment. Not required for DL1 in Safety
Run-in Part.
Locally assessed PD must be verified by the 
IRC (see Section 8.1.1).
Brain scan
X
As clinically indicated until PD or new treatment starts
Baseline brain imaging by brain MRI 
(preferred) or CT, with contrast
ECOG PS
X
X
X
X
See Appendix 8
Karnofsky 
Scale
X
See Appendix 8
Concomitant 
Medications 
and 
Procedures
X
From time of signing ICF through Safety 
Follow-up Visit. 
See Table 2 for concomitant medication 
information collection on PK assessment 
days
AEs and SAEs
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Assessments 
and 
Procedures
Screening
Cycle Duration = 21 Days
EOT
(within 
7 days 
after 
last 
dose)
Follow-up
Notes
(Cycle start may be delayed up to 7 days 
to accommodate scheduling conflicts, 
with approval from the Medical Monitor)
D -28 to -1
D1
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
Safety 
Follow-up 
30 Days 
after Last 
Dose 
(± 7D)
Efficacy 
and 
Survival 
every 
12 Weeks 
from Last 
Dose 
(± 2 weeks)
Study Intervention Dispensation/Administration
Berzosertib 
Dosing
Global Phase II: 
210 mg/m2 IV on Day 2 
and Day 5 every 21 days
Safety Run-in Part in 
Japan: 
DL1 105 mg/m2 IV on 
Day 2 and Day 5 every 
21 days 
DL2: 210 mg/m2 IV on 
Day 2 and Day 5 every 
21 days
Participants from DL1 in Safety Run-in part 
may escalate to DL2 at the discretion of 
Investigator once the DL2 is confirmed to be 
tolerable in the Safety Run-in part.
Topotecan 
Dosing
1.25 mg/m2 IV on Days 1 
through 5 every 21 days
PRO 
questionnaires:
EORTC 
QLQ-C30,
EORTC 
QLQ-LC13, 
EQ-5D-5L
X
X
X
X
Details of PRO assessments are included in 
Section 8.1.3.
Not applicable in DL1 in the Safety Run-in 
Part.
Pharmacokinetic Assessments
Plasma PK 
Collection: 
berzosertib 
and topotecan 
See Table 2
Plasma PK samples for analysis of 
berzosertib (and 
) and/or 
topotecan collected as outlined in Table 2.
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Assessments 
and 
Procedures
Screening
Cycle Duration = 21 Days
EOT
(within 
7 days 
after 
last 
dose)
Follow-up
Notes
(Cycle start may be delayed up to 7 days 
to accommodate scheduling conflicts, 
with approval from the Medical Monitor)
D -28 to -1
D1
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
Safety 
Follow-up 
30 Days 
after Last 
Dose 
(± 7D)
Efficacy 
and 
Survival 
every 
12 Weeks 
from Last 
Dose 
(± 2 weeks)
AEs = adverse events; β-HCG = β-human chorionic gonadotropin; C = cycle; CT = computed tomography; D = Day(s); DL = dose level;
 
; ECG = electrocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; EORTC = European Organization for the Research and 
Treatment of Cancer; EOT = end-of-treatment; EQ-5D-5L = EuroQol 5 Dimension 5 Level Scale; HBc = hepatitis B core; HBsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; ICF = informed consent form; IRC = Independent Review Committee; IV = intravenous; MRI = magnetic resonance imaging; 
PD = progressive disease; PK = pharmacokinetic; PRO = patient-reported outcome; QLQ-C30 = Quality of Life Questionnaire; QLQ-LC13 = lung cancer specific 
questionnaire; RECIST = Response Evaluation Criteria in Solid Tumors; SAEs = serious adverse events; WOCBP = women of childbearing potential.
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Table 2
 Assessments and Pharmacokinetics Sampling Schedule
B = sample for berzosertib; C = Cycle; D = Day; DL = dose level; EOI = end of infusion; ECG = electrocardiogram; eCRF = electronic case report form; h = hour; 
PK = pharmacokinetic; T = sample for topotecan. 
a
That is: C8D2, C12D2, C16D2, etc.
b
PK Sampling times are relative to EOI of topotecan for T samples on C1D1, C1D3, C1D4 and C2D1, or relative to EOI for berzosertib for T + B samples on 
C1D2, C1D5, C4D2 and thereafter. ‡ For Safety Run-in Part in Japan, PK sampling for topotecan and berzosertib are to be scheduled for 23 h ± 2 hours (C1D3) 
and 47 h ± 2 hours (C1D4) after EOI for berzosertib. For main part, topotecan and berzosertib PK samples are to be taken at any time after EOI of topotecan. 
Exact time of sample collection should be recorded in the eCRF. See Section 6.1 for details of dose timing of topotecan and berzosertib.
c
Predose is up to 60 minutes before start of topotecan infusion. 
Visit
C1D1
C1D2
C1D3
C1D4
C1D5
C2D1
C2D2
C4D2 and 
every 4th
cycle 
thereaftera
/PK timing relative to EOI of study drugb
Timepoint
Predosec
PK
T
T+B
T+B
T
T+B
T+B
EOI 
(+ 15 minutes)
PK
T
T+B
T+B
T
T+B
T+B
1 h after EOIb
(± 15 minutes)
PK
T
T+B
T
2 h after EOIb, †
(± 15 minutes)
PK only
T+B
3 h after EOIb,
(± 30 minutes)
PK
T+B
7 h after EOIb, †
(± 30 minutes)
PK only
T+B
1 sample any
time after EOI
PK
T+B‡
T+B‡
≥ 30 minutes after 
last sample
PK only
T+B
T+B
T+B
Concomitant medicationse
X
X
X
X
X
X
X
X
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e
Record time and dose for each concomitant medication taken.
†
Only for the Safety Run-in Part in Japan.
‡
For Safety Run-in Part in Japan, PK sampling are to be scheduled for 23 h ± 2 hours (C1D3) and 47 h ± 2 hours (C1D4) after EOI for berzosertib. For main 
part, PK samples are to be taken at any time after EOI of topotecan.
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2
Introduction
Berzosertib (formerly known as M6620) is a free base drug substance that acts as a potent inhibitor 
of the ataxia telangiectasia mutated and Rad3-related (ATR) protein that is being developed for 
the treatment of malignancies as a single agent or in combination with chemotherapy and/or 
ionizing radiation or other anticancer agents.
Detailed information on the chemistry, pharmacology, efficacy, and safety of berzosertib is in the
Investigator’s Brochure (IB) and details regarding topotecan are in the topotecan product 
information.
2.1
Study Rationale
The purpose of this study is to assess efficacy, safety, tolerability, and PK of berzosertib in 
combination with topotecan in participants with relapsed, platinum-resistant SCLC. 
The results from a Phase I/II study of berzosertib + topotecan demonstrated clinical activity that 
suggested a potential benefit of the combination in participants with platinum-resistant SCLC in 
comparison with historical data of single agent topotecan (see Section 2.3.2) and a toxicity profile 
that largely mirrored that of topotecan as single agent (Thomas 2018; confidential data); thus, the 
berzosertib and topotecan combination has the potential of providing clinical benefit in this 
population with poor outcomes and high unmet medical need. This study may potentially support 
the indication of berzosertib in combination with topotecan as a standard of care treatment in 
patients with relapsed, platinum-resistant SCLC.
To date, there is no experience with berzosertib in Japanese patients. Therefore, a Japan-only 
Safety Run-in Part will take place to evaluate the safety, tolerability, and PK profile of berzosertib 
in combination with topotecan in Japanese participants. The rationale to have a safety run-in for 
the berzosertib and topotecan combination, instead of a classical Phase I dose escalation, is based 
on the assessment of expected low ethnic sensitivity in berzosertib PK and lack of plausible basis 
for PK interaction in Japanese patients. Accordingly, no added toxicity in Japanese participants is 
expected. The Safety Run-in Part consisting of 2 dose levels (DLs) will be conducted at Japanese
sites in parallel with the Main Part of the Global Phase II study. Japanese sites will continue the 
Main Part of Phase II after completion of the Safety Run-in Part, including the dose-limiting 
toxicity (DLT) evaluation and confirmation of tolerability at the recommended Phase II dose 
(RP2D). Participants enrolled into the Safety Run-in Part will follow the same eligibility criteria, 
study procedures and participants withdrawal criteria as outlined in the Phase II study, unless 
otherwise specified. The schematic structure of study and its Safety Run-in Part is shown in 
Figure 2 in Section 1.2. Section 4.1.1 presents more details of the Safety Run-in Part in Japan.
2.2
Background
Chemotherapeutic agents that induce DNA damage are an effective and common treatment option 
for patients with many types of solid tumors; however, many cancers, despite displaying initial 
sensitivity and clinical response to these agents, ultimately progress. One mechanism that has been 
proposed to protect tumor cells from DNA damage is the DNA damage response (DDR) pathway 
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regulated by the ataxia telangiectasia mutated (ATM) and ATR kinases. Theoretically, small 
molecule-mediated inhibition of ATR should enhance the effect of DNA damaging chemotherapy 
on cancer cells.
Berzosertib is a potent inhibitor of ATR that blocks ATR activity in cells, with a concentration 
resulting in 50% maximal inhibition of 20 nM. Based on nonclinical observations (refer to the 
latest IB), berzosertib has the potential to have a substantial therapeutic impact on a number of 
malignancies, including SCLC, in which defects in the DDR are known to be prevalent and in 
which cytotoxic chemotherapy is a standard of care.
An estimated 1.6 million new lung cancers are diagnosed worldwide each year, approximately 
15% of which are SCLC, the most aggressive form of lung cancer, characterized by a rapid 
doubling time and widespread metastases (Byers 2015). Small-cell lung cancer is a heterogeneous 
disease, including extremely chemosensitive and chemoresistant clones. While patients with 
extensive SCLC initially exhibit high response rates to first-line chemotherapy regimens and 
immunotherapy, typically consisting of a platinum, etoposide, and PD-L1 inhibitors (e.g.,
atezolizumab, durvalumab), most patients relapse with a median survival of 10 to 12 months 
(Horn 2018; Paz-Ares 2019). If the relapse is early, i.e., the chemotherapy-free interval is 
< 90 days (resistant disease), the prognosis is poorer, with response to most regimens ≤ 10% 
(NCCN 2020, von Pawel 2014). Worldwide, topotecan was the only approved agent in the 
second-line setting until recently. Based on a single-arm Phase II study with 105 participants, the 
US Food and Drug Administration granted lurbinectedin an accelerated approval (15 June 2020)
as second-line treatment in SCLC. Nonetheless, participants with early relapse (chemotherapy-
free interval < 90 days) had poorer outcomes, with a median overall survival (OS) time of 
5 months, a median progression-free survival (PFS) time of 2.6 months, and an objective response 
rate (ORR) of 22% (Trigo 2020).
The berzosertib + topotecan combination has shown promising clinical activity and a favorable 
safety profile in participants with solid tumors, including participants with platinum-resistant 
SCLC. A Phase I/II study with the berzosertib + topotecan combination established the 
recommended Phase II dose, with topotecan at 1.25 mg/m2 administered from Day 1 to Day 5, and 
berzosertib at 210 mg/m2 administered on Day 2 and Day 5, in cycles of 21 days. The toxicity 
profile of this regimen largely mirrored that of topotecan as single agent. The most common 
Grade 3 and 4 toxicities were hematological, such as anemia, leukopenia, and neutropenia (40% 
to 50% each) and thrombocytopenia (25%); however, with most participants having received 
granulocyte colony-stimulating-factor (G-CSF) prophylactically, complications such as febrile 
neutropenia were uncommon, and no treatment-related deaths occurred (Thomas 2018; 
confidential data). In terms of efficacy, there were 2 partial responses (PR) of ≥18 months, and 
≥7 months and 7 stable disease (SD) responses lasting ≥3 months (median: 9 months; range, 3 to 
12 months). Three of 5 participants with SCLC, all of whom had platinum-resistant disease, had a 
PR or prolonged SD of ≥6 months. In the subsequent Phase II portion of the study of berzosertib 
in combination with topotecan in participants with relapsed SCLC, there was an overall response 
rate of 36%: 30% in participants with platinum-resistant disease (n = 20) and 60% in participants 
with platinum-sensitive disease (n = 5). The median PFS time was 4.8 months (4.3 in platinum-
resistant and 7.4 in platinum-sensitive; confidential data). These results suggest a potential benefit 
of the combination in participants with platinum-resistant disease, defined by disease recurrence 
within 90 days from the last dose of platinum given in prior lines, in comparison with historical 
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data of single agent topotecan; thus, the berzosertib and topotecan combination has the potential 
of providing clinical benefit in this patient population with poor outcomes, few treatment options, 
and high unmet medical need.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of berzosertib are found in Section 4.2 and the IB.
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable.
2.3.1
Risk Assessment
In the Phase I (Thomas 2018) and Phase II (confidential data) berzosertib and topotecan 
combination studies, the toxicity profile of berzosertib + topotecan was similar to that of topotecan 
when given as a single agent. The combination of berzosertib with topotecan will be further 
assessed and evaluated for exacerbated toxicities or unforeseen AEs, as compared with historical 
data from berzosertib and topotecan as single agents, and from berzosertib in combination with 
topotecan.
Identified and potential risks of the study intervention and procedures are presented in Table 3.
Table 3
Berzosertib and Topotecan - Identified and Potential Risks with 
Mitigation Strategies
Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention: Berzosertib
Identified Risks for berzosertib in combination with chemotherapy
Gastrointestinal disorders such as 
nausea and vomiting 
Refer to the berzosertib IB.
Continuous safety monitoring is 
performed during the study per the 
SoA (Sections 1.3 and 8.1.3).
Hypersensitivity, including 
infusion-related reactionsa
Refer to the berzosertib IB
Exclusion criteria are in place to 
prohibit enrollment of participants 
with known hypersensitivity to the 
study interventions, a similar 
structural compound, or to one or 
more excipients used.
Continuous safety monitoring is 
performed during the study.
Premedication is permitted for 
participants who have experienced 
an infusion-related reaction 
(Section 6.5.2).
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Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Potential Risk for berzosertib in combination with chemotherapy
Risks associated with drug-drug 
interactions
No formal drug interaction studies 
have been conducted with berzosertib 
in humans; however, in a Phase I/II 
study of berzosertib in combination 
with topotecan, no drug interactions 
were reported with authorized 
concomitant medications and/or with 
topotecan. The toxicity profile of the 
study drugs combination largely 
mirrored that of topotecan as single 
agent.
Berzosertib is primarily metabolized 
by CYP3A4. Inhibitors of CYP3A4 
might be expected to decrease 
berzosertib’s clearance and inducers 
of CYP3A4 might be expected to 
increase its clearance. 
Berzosertib is a weak inhibitor of
CYP3A4. Concomitant administration 
of sensitive CYP3A4 substrates with 
a narrow therapeutic index should be 
considered with caution and careful 
monitoring for safety.
Based on in vitro data, berzosertib 
has the potential to be an inhibitor of 
BCRP and OATP1B3 at clinically 
relevant concentrations and may 
increase exposure of BCRP and 
OATP1B3 substrates.
For further information, refer to the 
berzosertib IB.
Concomitant administration with 
potent inhibitors or inducers of 
CYP3A4 is prohibited in this study. 
Concomitant administration with
sensitive CYP3A4 substrates with 
a narrow therapeutic index, BCRP 
and OATP1B3 substrates should 
be carefully considered.
Clinical protocol-specific 
instructions should be closely 
followed (see Sections 5.3 and 
6.5). 
Pregnancy, fertility, and lactation
There is a potential risk, based on its 
mechanism of action, that 
administration of berzosertib during 
pregnancy could cause fetal harm. 
For further information, refer to the 
berzosertib IB.
A negative serum pregnancy test is 
required for inclusion. Participants 
who get pregnant during the study 
must discontinue the study 
intervention (see Section 7.1).
Refer to the berzosertib IB for 
guidance regarding pregnancy, 
lactation, contraception and fertility 
and see protocol Section 5.1 and 
Appendix 3 for contraception 
requirements. 
Further, strict use of contraception 
is required; participants should be 
informed that fertility might be 
impaired long term and may opt to 
cryopreserve sperm or ova prior to 
treatment. Male participants must 
also use a condom with pregnant 
female partners during the study, 
since exposure to the study 
intervention through the ejaculate 
could harm an existing fetus.
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Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention: Topotecan (SmPC 2019)
Anemia
Moderate to severe (Hb ≤8.0 g/dL) in 
37% of patients (14% of courses). 
Adverse events are continually 
monitored during the study (see 
Section 8.1.3) and managed 
clinically, as indicated, including by 
study intervention interruption, 
dose modification or 
discontinuation.
Leukopenia (including neutropenia)
Abnormally low white blood cell count 
(leucopenia, neutropenia) that may be 
accompanied with fever and signs of 
infections (febrile neutropenia). 
Severe neutropenia (neutrophil count 
< 0.5 x 109/L) during Course 1 in 55% 
of patients, with duration ≥7 days in 
20% and overall in 77% of patients 
(39% of courses). In association with 
severe neutropenia, fever or infection 
occurred in 16% of patients during 
Course 1 and overall in 23% of 
patients (6% of courses). Median time 
to onset of severe neutropenia was 
9 days and the median duration was 
7 days.
Adverse events are continually 
monitored during the study (see 
Section 8.1.3) and managed 
clinically, as indicated, including by 
study intervention interruption, 
dose modification or 
discontinuation.
Thrombocytopenia
Severe (platelets < 25 x 109/L) in 25% 
of patients (8% of courses); moderate 
(platelets between 25.0 and 
50.0 x 109/L) in 25% of patients (15% 
of courses). Median time to onset of 
severe thrombocytopenia was Day 15 
and the median duration was 5 days.
Adverse events are continually 
monitored during the study (see 
Section 8.1.3) and managed 
clinically, as indicated, including by 
study intervention interruption, 
dose modification or 
discontinuation.
Study Procedures
Blood sampling
Blood sampling is required for 
participants as detailed in the SoA 
and are considered essential for the 
study’s scientific objectives. Blood 
sampling carries a risk of AEs 
including pain, bruising, bleeding, 
redness and swelling of the site/vein, 
and infection.
Minimization of blood sampling 
was thoughtfully considered during 
protocol development weighing risk 
to participants versus achievement 
of the study’s scientific objectives. 
Blood samples will be taken by 
qualified professional and every 
effort will be made to minimize any 
discomfort.
Tumor biopsies
Fresh tumor biopsies may be required 
for some participants as detailed in 
the SoA and inclusion criteria. 
Biopsies carry a risk of AEs including 
bleeding and infection.
Investigators are to use clinical 
judgment and not proceed with a 
biopsy if is clinically contra-
indicated or there is high risk of 
AEs. 
Imaging procedures
Imaging disease assessments are 
required for all participants as 
detailed in the SoA to monitor disease 
progression. These are associated 
with a risk of allergic reactions to 
contrast agents, exposure to ionizing 
radiation for some types of imaging 
(e.g., CT scans, bone scintigraphy), 
nephrogenic systemic fibrosis, and 
intracranial gadolinium deposition for 
Imaging procedures in this study will 
be conducted at a similar frequency 
to that in routine clinical practice.
Participants will be monitored for 
allergic reactions, as per routine 
clinical practice.
Selection of imaging modality will 
be guided by any identified risk 
factors, as described in the 
Imaging Manual.
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Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
gadolinium and contrast induced 
renal damage for iodinated contrast.
AEs = adverse events; CT = computed tomography; CYP3A4 = cytochrome P450 3A4; BCRP = breast cancer 
resistance protein; Hb = hemoglobin; IB = Investigator’s Brochure; OATP1B3 = organic anion transporting 
polypeptide 1B3; SoA = Schedule of Activities. 
a
Infusion-related reactions have been reported using a variety of terms to describe the same biologic event, including 
erythema, eyelid edema, face edema, flushing, hypersensitivity, infusion-related reaction, pruritus, pruritus allergic, 
rash, rash erythematous, rash macular, rash pruritic, and rhinitis allergic.
2.3.2
Benefit Assessment
!
Patients with relapsed, platinum-resistant SCLC have few treatment options. All participants 
in the current study will receive a current standard of care + berzosertib, which has the potential 
to improve their treatment outcome (see Section 2.2).
!
Participants in this study will be contributing to the process of developing new therapies in an 
area of unmet need, expanding the current standard of care by displacing the existing standard 
of care for recurrent platinum-resistant SCLC.
!
The medical evaluations and assessments in the current study protocol, with regular physical 
examinations, monitoring of AEs, and laboratory assessments, in many instances go beyond 
the local standard of care.
2.3.3
Overall Benefit: Risk Conclusion
Considering the measures taken to minimize the risk to participants in this study as outlined in
Table 3, the risks (potential and identified) associated with berzosertib in combination with 
topotecan are justified by the anticipated benefits that may be afforded to participants with 
relapsed, platinum-resistant SCLC, for which there are few treatment options.
3
Objectives and Estimands
Objectives and estimands are outlined in Table 4 and Table 5.
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Table 4
Objectives and Estimand Attributes (Main Part)
Objectives
Estimand Attributes
Primary
To assess efficacy of intervention in 
terms of objective response with 
berzosertib + topotecan
Endpoint: Objective response according to RECIST 1.1 as assessed by the IRC.
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., regardless of the intercurrent event
!
Start of subsequent anticancer treatment: while not treated with subsequent anticancer therapy strategy; i.e.,
ignoring tumor assessments after the intercurrent event
!
Progression according to RECIST 1.1: while not progressed strategy, i.e., assessments up to the intercurrent event
Population Level Summary: Objective response rate
Secondary
To assess efficacy of intervention in 
terms of duration of response with 
berzosertib + topotecan
Endpoint: Duration of response according to RECIST 1.1 as assessed by the IRC. Measured by time from first 
documentation of objective response to PD or death, occurring within 2 scheduled tumor assessments after last 
evaluable assessment or first study intervention.
Population: Patients with relapsed, platinum-resistant SCLC with a confirmed objective response according to RECIST 
1.1 as assessed by IRC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
! Death within 2 scheduled tumor assessments: composite strategy, i.e., will be considered as event of interest
! Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median duration of response
!
Kaplan-Meier estimates, including the Kaplan-Meier estimate at 6 months
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Objectives
Estimand Attributes
To assess efficacy of intervention in 
terms of PFS with berzosertib + 
topotecan
Endpoint: Progression-free survival according to RECIST 1.1 as assessed by the IRC. Measured by time from first 
study intervention to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment or 
first study intervention.
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e., will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median PFS time
!
Kaplan-Meier estimates
To assess efficacy of intervention in 
terms of OS with 
berzosertib + topotecan followed by 
subsequent therapy
Endpoint: Overall survival. Measured by time from first study intervention to death
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan followed by subsequent anticancer treatment
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median OS time
!
Kaplan-Meier estimates
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Objectives
Estimand Attributes
To assess the efficacy of intervention 
in terms of physical functioning, 
cough, dyspnea and chest pain, and 
overall HRQoL based on PROs when 
treated with berzosertib + topotecan
Endpoint: Change from baseline in physical functioning measured by the EORTC QLQ-C30; cough, dyspnea, and 
chest pain measured by EORTC QLQ-LC13; health state as measured by VAS as a component of the EQ-5D-5L
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: while on treatment strategy, i.e., ignoring PRO assessments after the intercurrent 
event 
!
Start of subsequent anticancer treatment: while not treated with subsequent anticancer therapy strategy; i.e., 
ignoring PRO assessments after the intercurrent event
!
Death: while alive strategy, i.e., considering PRO assessments before the intercurrent event
Population Level Summary:
!
Mean changes from baseline analysis for multi-item scales in EORTC questionnaires (i.e., physical functioning,
dyspnea) and VAS
!
Proportion of patients with ≥ 1 category improvement and proportion of patients with ≥ 1 category worsening in 
single-item symptoms (i.e., cough and chest pain)
To evaluate the safety and tolerability 
of berzosertib + topotecan
Endpoint: Occurrence of AEs and treatment-related AEs and occurrence of clinically significant changes in vital signs, 
laboratory parameters and 12-lead ECG findings 
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
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Objectives
Estimand Attributes
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Objectives
Estimand Attributes
AEs = adverse events; CYP = cytochrome P450; ECG = electrocardiogram; EORTC = European Organization for the Research and Treatment of Cancer; 
EQ-5D-5L = EuroQol 5 Dimension 5 Level Scale; HRQoL = health-related quality of life; IRC = Independent Review Committee; OS = overall survival; 
PD = progressive disease; PFS = progression-free survival; 
; 
; PRO = patient-reported outcome; 
QLQ-LC13 = lung cancer specific questionnaire; QLQ-C30 = Quality of Life Questionnaire; 
; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors version 1.1; SCLC = small-cell lung cancer; VAS = visual analogue scale.
In case DL2 is declared RP2D, data for participants receiving DL2 will in addition be analyzed as part of the main study.
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Table 5
Objectives and Estimand Attributes (Safety Run-in Part in Japan)
Objectives
Estimand Attributes
Primary
To confirm whether the regimen and 
RP2D of berzosertib in combination 
with topotecan that were established 
in the Phase I study in non-Japanese 
can be safely applied to Japanese 
participants
Endpoint: Occurrence of DLTs until the end of Cycle 1 in Japanese participants, occurrence of AEs and 
treatment-related AEs and occurrence of clinically significant changes in vital signs, laboratory parameters and 12-lead 
ECG findings
Population:
!
DL1: Japanese patients with advanced solid tumors for which no effective standard therapy exists, or standard 
therapy has failed
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC 
Treatment: Berzosertib + topotecan
Secondary
To assess efficacy of intervention in 
terms of objective response with 
berzosertib + topotecan
Endpoint: Objective response according to RECIST 1.1 as assessed by the Investigator.
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., regardless of the intercurrent event
!
Start of subsequent anticancer treatment: while not treated with subsequent anticancer therapy strategy; i.e., 
ignoring tumor assessments after the intercurrent event
!
Progression according to RECIST 1.1: while not progressed strategy, i.e., assessments up to the intercurrent event
Population Level Summary: Objective response rate
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Objectives
Estimand Attributes
To assess efficacy of intervention in 
terms of duration of response with 
berzosertib + topotecan
Endpoint: Duration of response according to RECIST 1.1 as assessed by the Investigator. Measured by time from first 
documentation of objective response to PD or death, occurring within 2 scheduled tumor assessments after last 
evaluable assessment or first study intervention.
Population: 
!
DL1: Japanese patients with advanced solid tumors with a confirmed objective response according to RECIST 1.1 
as assessed by Investigator
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC with a confirmed objective response according to 
RECIST 1.1 as assessed by Investigator
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e., will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median duration of response
!
Kaplan-Meier estimates, including the Kaplan-Meier estimate at 6 months
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Objectives
Estimand Attributes
To assess efficacy of intervention in 
terms of PFS with berzosertib + 
topotecan
Endpoint: Progression-free survival according to RECIST 1.1 as assessed by the Investigator. Measured by time from 
first study intervention to PD or death, occurring within 2 scheduled tumor assessments after last evaluable assessment 
or first study intervention.
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments: composite strategy, i.e., will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median PFS time
!
Kaplan-Meier estimates
To assess efficacy of intervention in 
terms of OS with 
berzosertib + topotecan followed by 
subsequent therapy
Endpoint: Overall survival. Measured by time from first study intervention to death
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan followed by subsequent anticancer treatment
Intercurrent Event Strategy:
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the intercurrent event
Population Level Summary:
!
Median OS time
!
Kaplan-Meier estimates
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Objectives
Estimand Attributes
To assess the efficacy of intervention 
in terms of physical functioning, 
cough, dyspnea and chest pain, and 
overall HRQoL based on PROs when 
treated with berzosertib + topotecan
Endpoint: Change from baseline in physical functioning measured by the EORTC QLQ-C30; cough, dyspnea, and 
chest pain measured by EORTC QLQ-LC13; health state as measured by VAS as a component of the EQ-5D-5L
Population: 
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: while on treatment strategy, i.e., ignoring PRO assessments after the intercurrent 
event
!
Start of subsequent anticancer treatment: while not treated with subsequent anticancer therapy strategy; i.e., 
ignoring PRO assessments after the intercurrent event
!
Death: while alive strategy, i.e., considering PRO assessments before the intercurrent event
Population Level Summary:
!
Mean changes from baseline analysis for multi-item scales in EORTC questionnaires (i.e., physical functioning and 
dyspnea) and VAS
!
Proportion of patients with ≥ 1 category improvement and proportion of patients with ≥ 1 category worsening in 
single-item symptoms (i.e., cough and chest pain)
To characterize the PK profile of 
berzosertib 
Endpoint: PK parameters of berzosertib in plasma by NCA
Population:
!
DL1: Japanese patients with advanced solid tumors
!
DL2: Japanese patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
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Objectives
Estimand Attributes
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Objectives
Estimand Attributes
AEs = adverse events; CYP = cytochrome P450; DL = dose level; DLT = dose-limiting toxicity; 
; EORTC = European Organization for the 
Research and Treatment of Cancer; HRQoL = health-related quality of life; NCA = non compartmental analysis; OS = overall survival; PD = progressive disease; 
PFS = progression-free survival;
; PK = pharmacokinetics; PRO = patient-reported outcome; QLQ-C30 = Quality of Life Questionnaire; 
QLQ-LC13 = lung cancer specific questionnaire;
; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; RP2D = 
recommended Phase II dose; SCLC = small-cell lung cancer; VAS = visual analogue scale.
Analyses for the Safety Run-in Part will include both DL1 and DL2 separately by dose level.
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4
Study Design
4.1
Overall Design
This is a multicenter, Phase II, open-label, single-arm study designed to assess the efficacy and 
safety of berzosertib in combination with topotecan in participants with relapsed, 
platinum-resistant SCLC (platinum-free interval [PFI] < 90 days) with only 1 prior line of 
systemic treatment. An Independent Review Committee (IRC) will perform blinded 
determinations as to whether the criteria for tumor response or progression are met according to 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1; see Appendix 2 for 
additional IRC details). 
For each participant, the study will include a Screening Period lasting up to 28 days, a Study 
Intervention Period consisting of 21-day cycles of berzosertib + topotecan until disease 
progression or other criteria for study intervention discontinuation are met (see Section 7), an 
End-of-Treatment Visit, a Safety Follow-up Period of 30 days after the last study intervention 
dose, and Efficacy and Survival Follow-up Visits every 12 weeks from the last study intervention 
administration. During the Survival Follow-up, survival information and subsequent anticancer 
therapy given to the participant should be recorded. The Survival Follow-up Visits can occur as 
clinic visits or by telephone contact until death, lost to follow-up, study withdrawal of consent, 
or End of Study. Additionally, participants who discontinue study intervention for reasons other 
than disease progression or death, will continue with regular imaging assessments (see Table 1
for details) until disease progression, start of subsequent anticancer therapy, death, withdrawal 
of consent, lost to follow-up, or End of Study.
An interim analysis with potential stop for futility will be conducted after the first 40 participants 
have completed their second on-treatment tumor assessment (or dropped-out/died prematurely).
Section 1.2 presents the Study Schema, Section 1.3, the Schedule of Activities, Section 4.4, the 
End of Study definition, and Section 6.7 study intervention after the end of study. 
4.1.1
Safety Run-in Part (Japan-only)
The Safety Run-in Part will be conducted at Japanese sites concurrently with the Main Part of 
the global Phase II study according to a Bayesian Optimal Interval Design (BOIN) (Yuan 2016). 
Japanese sites will continue the Main Part of Phase II after completion of Safety Run-in Part, 
including the DLT evaluation and confirmation of tolerability at the DL2. The starting dose of 
berzosertib and topotecan in the Safety Run-in Part is determined based on the safety data from 
the Phase I/II combination study of berzosertib and topotecan, Phase I study of single agent 
berzosertib as well as available safety data of single agent topotecan in Japanese and 
non-Japanese (PMDA 2011, Thomas 2018, confidential data). 
Participants enrolled into the Safety Run-in Part will follow the same eligibility criteria, study 
procedures (unless otherwise specified), and participants withdrawal criteria as outlined in the 
global Phase II study.
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The Safety Run-in Part will consist of the combination therapy of berzosertib with topotecan, up 
to 2 DLs, with a BOIN design, enrolling cohorts of 3 participants. Participants in DL1 will 
receive berzosertib at a dose of 105 mg/m2 intravenous (IV) every 21 days on Days 2 and 5, and 
topotecan at a dose of 1.25 mg/m2 IV every 21 days on Day 1 to 5. At DL2, participants will 
receive the same dose regimen as in the Main Part of the Phase II study (see Section 4.1). 
Participants enrolled on the DL1 may escalate to DL2 once the tolerability at DL2 is confirmed.
Of note, in the Safety Run-in Part, participants with advanced solid tumors will enroll in the DL1. 
Participants with relapsed platinum-resistant SCLC will enroll in the DL2. In case safety and 
tolerability of DL2 is confirmed, participants enrolled in the DL2 will be included in all study 
objectives, including efficacy evaluation, in the global Phase II Part of the study. The 
discontinued participants will remain in the overall safety and efficacy analyses as long as the 
Main Part of Phase II stipulates. 
Dose-limiting toxicities (DLTs) are defined in Section 6.8. 
Details on the BOIN design and escalation decisions are outlined in Section 9.4.2.
4.2
Scientific Rationale for Study Design
The selection of this study design (i.e., a single-arm, non-randomized, Phase II study) is based 
on the fact that topotecan in platinum-resistant SCLC yields a response rate of ≤10%, according 
to medical literature (NCCN 2020, von Pawel 2014); therefore, it is thought that a single-arm 
study in this specific patient population may serve as a confirmation of clinical proof-of-concept 
that the combination of berzosertib with topotecan adds clinical value to topotecan, as a single 
agent, according to historical controls. In addition, new drugs have been recently granted 
accelerated approval based on single-arm open-label Phase II studies, when able to demonstrate 
a positive benefit-risk ratio for diseases with high unmet medical need, such as relapsed SCLC. 
The primary endpoint of objective response is a clinically relevant measure of tumor control, 
particularly in SCLC, which is usually a malignancy with fast growth leading to dismal 
prognoses. In addition, other drugs in this setting obtained recent regulatory accelerated
approvals by means of studies where objective response was the primary endpoint (e.g., 
lurbinectedin). The secondary efficacy endpoints of duration of response, PFS, OS, and 
patient-reported outcomes (PROs) are standard measures of efficacy and will be supportive of 
the overall efficacy determination.
Berzosertib administration as single agent is well tolerated. Because there is no experience with 
berzosertib in Japanese patients, Japan-only Safety Run-in Part will be conducted to evaluate the 
safety, tolerability and PK of berzosertib in combination with topotecan in Japanese participants. 
The rationale to have a safety run-in for the berzosertib and topotecan combination, instead of a 
classic Phase I dose escalation, is based on the assessment of expected low ethnic sensitivity in 
berzosertib PK and lack of plausible basis for PK interaction in Japanese patients. Accordingly, 
no added toxicity in Japanese participants is expected (Paller 2014).
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4.3
Justification for Dose
4.3.1
Main Part of Global Phase II 
Based on the reported Phase Ib study (Thomas 2018), the starting study intervention doses for 
the combination in this study are as follows:
!
Berzosertib by IV administration at a dose of 210 mg/m2 on Day 2 and Day 5 of each 21-day 
cycle
!
Topotecan by IV administration at a dose of 1.25 mg/m2 on Days 1 through 5 of each 21-day 
cycle.
Section 6.6 provides the dose selection and modification information for this study.
4.3.2
Safety Run-in Part (Japan-only)
Two dose levels are planned in the Safety Run-in Part as shown below. The dose levels are 
designed based on the Phase I/II combination study of berzosertib and topotecan, Phase I studies
of single agent berzosertib as well as available safety data of single agent topotecan in Japanese 
and non-Japanese (PMDA 2011, Thomas 2018, confidential data).
DL1:
!
Berzosertib by IV administration at a dose of 105 mg/m2 on Day 2 and Day 5 of each 21-day 
cycle
!
Topotecan by IV administration at a dose of 1.25 mg/m2 on Days 1 through 5 of each 21-day 
cycle.
DL2 (same as the Main Part of global Phase II):
!
Berzosertib by IV administration at a dose of 210 mg/m2 on Day 2 and Day 5 of each 21-day 
cycle
!
Topotecan by IV administration at a dose of 1.25 mg/m2 on Days 1 through 5 of each 21-day 
cycle.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts as defined in 
Section 1.3 (Schedule of Activities) and fulfilled at least 1 of the following criteria: 
!
Minimum follow-up of 12 months after the last study intervention administration
!
Withdrawal of consent from the study
!
Lost to Follow-up
!
Died.
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The end of the study is defined as the date of completion for all participants (i.e., the last visit of 
the last participant).
The Sponsor may terminate the study at any time once access to berzosertib or topotecan for 
participants still benefiting is provisioned via a rollover study, expanded access, marketed 
product or another mechanism of access as appropriate.
5
Study Population
The criteria in Sections 5.1 and 5.2 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 are considered 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 
(where allowed by local laws and regulations) 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. In Japan, if a participant
is < 20 years, the written informed consent from his/her parent or guardian will be required 
in addition to the participant’s written consent. Once the participant reaches 20 years of age, 
participant’s written consent will be obtained.
Type of Participant and Disease Characteristics – Safety Run-in Part in Japan - DL1 Only
2.
Histologically proven advanced solid tumors, for which no effective standard therapy exists,
or standard therapy has failed or cannot be tolerated
3.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1 and Karnofsky 
Scale ≥ 70% (see Appendix 8)
Type of Participant and Disease Characteristics – Main Part of Global Phase II and DL2 
of Safety Run-in Part in Japan
4.
ECOG PS ≤ 2 and Karnofsky Scale ≥ 60% (see Appendix 8)
5.
Histologically confirmed SCLC
6.
Radiologically confirmed progression after first-line or chemoradiation platinum-based 
treatment (carboplatin or cisplatin), with or without immunotherapy, for treatment of limited 
or extensive stage SCLC, with a PFI < 90 days. The PFI is measured by the elapsed time 
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from the last day of the regimen of a platinum-based treatment until the first day of 
documented disease progression
7.
Measurable disease according to RECIST 1.1 at Screening. Evidence of measurable disease 
must be confirmed by the IRC prior to start of treatment
8.
Tumor tissue provision: archival (collected within 12 months before date of informed 
consent form [ICF]) signature for Screening) or fresh biopsy specimen, if medically feasible 
Type of Participant and Disease Characteristics – All Parts
9.
Have adequate hematologic function as indicated by:
! Platelet count ≥100,000/mm3
! Hemoglobin ≥9.0 g/L. Prior red blood transfusions are allowed
! Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within 14 days of 
obtaining the screening blood sample
! Total bilirubin level ≤1.5 × upper limit of normal (ULN), except in the case of known 
Gilbert syndrome, in which case total bilirubin must be ≤2 × ULN, an aspartate 
aminotransferase (AST) and an alanine aminotransferase (ALT) level ≤3.0 × ULN or 
≤5 × ULN in presence of liver metastases
! Adequate renal function defined as creatinine clearance ≥60 mL/min by calculation using 
the Cockcroft-Gault formula or measured by 24-hour urine collection. The Cockcroft-
Gault formula is (l40 - age) × weight [kg]) / (72 × serum creatinine [mg/dL]) × 0.85 (if 
female)
Sex
10. Are male or female
11. Contraceptive use by males or females will be consistent with local regulations on 
contraception methods for those participating in clinical studies
Male participants:
Agree to the following during the Study Intervention Period and for at least 6 months after the 
last study intervention dose:
!
Refrain from donating sperm
PLUS, either:
!
Abstain from any activity that allows for exposure to ejaculate
OR 
!
Use a male condom: When having sexual intercourse with a woman of childbearing 
potential (WOCBP), who is not currently pregnant, and advise her to use a highly 
effective contraceptive method with a failure rate of < 1% per year, as described in 
Appendix 3, since a condom may break or leak.
!
Male participants must use a condom with pregnant female partners
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Female participants:
Are not pregnant or breastfeeding (for sites in Japan, the participant is not eligible even if 
breastfeeding is suspended), and at least 1 of the following conditions applies:
!
Not a WOCBP 
OR
!
If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% 
per year), preferably with low user dependency, as described in Appendix 3 for the 
following time periods:
o
Before the first dose of the study intervention, if using hormonal contraception:

Has completed at least one 4-week cycle of an oral contraception pill and either 
had or has begun her menses
OR 

Has used a depot contraceptive or extended-cycle oral contraceptive for least 
28 days and has a documented negative pregnancy test using a highly sensitive 
assay
AND 
A barrier method, as described in Appendix 3.
o
During the Study Intervention Period
o
After the Study Intervention Period (i.e., after the last study intervention dose is 
administered) for at least 6 months after the last study intervention dose and agree 
not to donate eggs (ova, oocytes) for reproduction during this period
The Investigator evaluates the effectiveness of the contraceptive method in relationship 
to the first dose of study intervention.
o
Have a negative serum pregnancy test, as required by local regulations, within 
24 hours before the first study intervention dose.
Additional requirements for pregnancy testing during and after study intervention are in
Appendix 5.
Informed Consent
12. Capable of giving signed informed consent, as indicated in Appendix 2, which includes 
compliance with the requirements and restrictions listed in the ICF and this protocol. 
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Clinically relevant (i.e., active), uncontrolled intercurrent illness including, but not limited 
to, severe active infection including, severe acute respiratory syndrome coronavirus-2
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infection/coronavirus disease 2019, immune deficiencies,
uncontrolled diabetes, 
uncontrolled arterial hypertension, symptomatic congestive heart failure (New York Heart 
Association Classification ≥ Class III), unstable angina pectoris, myocardial infarction, 
uncontrolled cardiac arrhythmia, and cerebral vascular accident/stroke. Calculated QTc 
average (using the Fridericia correction calculation) of > 450 msec for males and 
> 470 msec for females. Any psychiatric illness/social situations that would limit 
compliance with study requirements. 
The following exceptions apply:
a.
Participants with human immunodeficiency virus infection are eligible if they are on 
effective antiretroviral therapy with undetectable viral load within 6 months, provided 
there is no expected drug-drug interaction. Human immunodeficiency virus testing is 
not mandated for study inclusion. If performed, the participant must be consented for 
testing as per local standard guidance.
b.
Participants with evidence of chronic hepatitis B virus (HBV) infection are eligible if 
the HBV viral load is undetectable on suppressive therapy (if indicated), and if they 
have ALT, AST, and total bilirubin levels < ULN, and provided there is no expected 
drug-drug interaction. See the Schedule of Assessments (SoA; Table 1) for tests 
required at screening and during Study Intervention Period.
c.
Participants with a history of hepatitis C virus (HCV) infection are eligible if they have 
been treated and cured. For participants with HCV infection who are currently on 
treatment, they are eligible if they have an undetectable HCV viral load, and if they 
have ALT, AST, and total bilirubin levels < ULN. See the SoA (Table 1) for tests 
required at screening and during Study Intervention Period.
2.
Unstable brain metastases; however, participants with known brain metastases may be 
enrolled in this clinical study if they are clinically stable (without evidence of progression 
by imaging for at least 2 weeks prior to the first study intervention dose and any neurologic 
symptoms have returned to baseline), have no evidence of new brain metastases, and are on 
a stable or decreasing dose of steroids for at least 14 days prior to study intervention. 
Participants with carcinomatous meningitis are excluded regardless of clinical stability. 
Screening central nervous system imaging is not mandatory.
3.
Prior malignant disease within the last 3 years. Exceptions include fully resected basal cell 
carcinoma of the skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully 
resected ductal carcinoma in situ of the breast, superficial or noninvasive bladder cancer, 
and Stage IA, Grade I endometrioid endometrial cancer with no myometrial invasion, that 
has undergone curative therapy. Participants with other localized malignancies treated with 
curative intent need to be discussed with the Medical Monitor.
4.
Participants with known history of Li-Fraumeni Syndrome and Ataxia Telangiectasia.
5.
Participants not recovered from AEs Grade > 1 from prior anticancer therapies, including 
surgeries. Exception: Grade 2 AEs not constituting a safety risk (e.g., alopecia), based on 
the Investigator’s judgment; must consult with the Medical Monitor prior to enrollment.
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Prior/Concomitant Therapy
6.
For participants in the Main Part of global Phase II and DL2 of Safety Run-in Part in Japan:
2 or more lines of prior systemic anticancer treatment, including retreatment with a 
platinum-based regimen
7.
Prior treatment with topoisomerase I inhibitor, including topotecan and irinotecan 
8.
Prior treatment with an ATR inhibitor
9.
Prior or concurrent treatment with a nonpermitted drug/intervention:
!
Participants who may have received any of the following anticancer therapy(ies) within 
the following time windows from the first day of study interventions administration:
o
Small molecule inhibitor therapy (including investigational) within 2 weeks or 
5 half-lives, whichever is longer
o
Any type of anticancer antibody or antibody drug conjugates within 3 weeks 
o
Systemic chemotherapy within 4 weeks (within 6 weeks for nitrosoureas/
mitomycin C)
o
Prior curative-intent high-dose radiotherapy within 4 weeks. Prior palliative 
radiotherapy to metastatic lesion(s) is permitted provided it was completed at least 
1 week prior to first day of study interventions administration and toxicities recovered 
to Grade ≤1. 
o
Any other type of anticancer therapy, not listed above, within 4 weeks.
!
Concomitant use of strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)
enzymes that cannot be discontinued for at least 1 week prior to administration of study 
intervention and for the duration of study intervention. 
!
Other prohibited concomitant medications as listed in Section 6.5.3.
Prior/Concurrent Clinical Study Experience
10. Concurrent participation in another interventional clinical study is not permitted. There are 
no restrictions on prior clinical study participation provided the above washout periods are 
followed.
Other Exclusions
11. Known hypersensitivity to the study interventions, a similar structural compound, or to one 
or more excipients used.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
There are no dietary restrictions.
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5.3.2
Caffeine, Alcohol, and Tobacco
No restrictions on caffeine, modest alcohol, or tobacco use apply during this study.
5.3.3
Activity
Electrocardiograms will be obtained after the participant has rested in a semi-supine position 
(Section 8.2.3).
Participants will abstain from strenuous exercise for 2 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities. 
Based on in vitro and in vivo assays, berzosertib has a phototoxic potential as it absorbs in the 
UV-visible radiation spectrum, and is widely distributed in tissues, including skin. Therefore, 
participants should be cautioned to minimize exposure to the sun and other sources of visible 
and UV radiation, and to take protective measures when necessary.
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once within 14 days, after the reason for the screening failure has been addressed. 
Rescreened participants will be assigned a new participant number and will undergo Screening 
procedures as planned in the protocol. Any previous screening tests can be used for rescreening, 
provided they are within the new screening window of -28 days.
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. Study 
intervention is used instead of “study drug, Investigational Medicinal Product, or study 
treatment”.
For this study, both berzosertib and topotecan are considered study interventions.
6.1
Study Interventions Administration
Berzosertib at a dose of 210 mg/m2 will be via IV administration over 60 minutes (± 10 minutes) 
and start approximately 15 minutes after completion of topotecan administration on Day 2 and 
Day 5, of each 21-day cycle. Topotecan at a dose of 1.25 mg/m2 will be via IV administration 
over 30 minutes on Days 1 through 5 of each 21-day cycle. Study intervention details are 
provided in Table 6.
Specific to DL1 in the Safety Run-in Part in Japan, the dose of berzosertib will be 105 mg/m2. 
Specific to the Safety Run-in Part in Japan, all participants, in principle, should undergo inpatient 
observation during Cycle 1 until at least Day 5 of study intervention. Inpatient observation could 
be extended on a case by case basis, as assessed by the Investigator.
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All other conditions will be the same as above. 
Prior to study intervention administration, baseline neutrophils should be ≥ 1,500/mm3 and 
platelets ≥ 100,000/mm3 prior to Cycle 1. For subsequent cycles, neutrophils should be 
> 1,000/mm3, platelets > 100,000/mm3, and hemoglobin ≥ 9 g/dL.
Investigators should prophylactically premedicate participants with corticosteroid and 
antihistamine before the first 2 berzosertib infusions. Premedication should be administered for 
subsequent berzosertib infusions based upon clinical judgment and presence/severity of prior
infusion -related reactions to berzosertib. See Table 6 for suggested premedication regimen with 
corticosteroids and antihistamine.
Prophylactic G-CSF will be administered according to local practice and topotecan label. Its 
administration as primary or secondary prophylaxis is highly recommended and can be adjusted 
according to institutional guidelines and clinical judgment. G-CSF may be used from Day 6, at 
least 24 hours after the last dose of topotecan.
Participants are planned to continue with study intervention until documented disease 
progression, discontinuation due to AEs, death, or withdrawal from the study, whichever occurs 
earlier.
Additional details of sourcing, packaging, including quantity per container, anticipated length of 
supply per container, and labeling of the study interventions will be defined in a separate 
Pharmacy Manual.
Table 6
Study Interventions
Intervention Name
Berzosertib 
Topotecan
Type 
Drug
Drug
Dose Formulation
Solution for infusion
Concentrate for solution for infusion
Unit Dose Strength
20 mg/mL
1 mg/mL topotecan free base
Dose Amount
Main Part: 210 mg/m2
Safety Run-in Part in Japan:
DL1: 105 mg/m2
DL2: 210 mg/m2
1.25 mg/m2
Premedication
Suggested premedication regimen: 
hydrocortisone (200 mg IV) and 
diphenhydramine (25 mg IV)
approximately 60 minutes before study 
intervention infusions. The regimen may 
be modified based on local treatment 
standards and guidelines, as appropriate, 
as long as not prohibited by the protocol 
(see Section 6.5.3)
Prophylactic or therapeutic use of 
antiemetic medication according to the 
topotecan product information is 
recommended, unless the specific 
medication is prohibited for other 
reasons, e.g., the antiemetic is also a 
strong CYP3A4 inhibitor (see Table 6)
Frequency
On Day 2 and Day 5 of each 21-day cycle
Days 1 through 5 of each 21-day cycle
Route of Administration
IV infusion
IV infusion
Use
Experimental
Experimental 
IMP and NIMP
IMP
SoC/IMP depending on local law
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Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor or 
locally by the study site, subsidiary, or 
designee
Packaging and Labeling
Study Intervention will be provided in 
 Each 
 will be labeled per country 
requirements.
Depending on the local regulations, 
topotecan may be either sourced from a 
local hospital pharmacy or supplied by 
the Sponsor (or designated service 
provider) and will be packaged/labeled 
according to local requirements.
Current/Former Name(s) 
or Alias(es)
Substance code MSC2527093A, M6620, 
VX-970
DL = dose level; IMP = Investigational Medicinal Product; IV = intravenous; NIMP = Non-Investigational Medicinal 
Product; SoC = standard of care.
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 will 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. Further guidance and information for study intervention accountability are provided 
in the Study Reference Manual.
!
Only participants enrolled in the study may receive study interventions and only authorized 
site staff may supply it. All study interventions will be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, per 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.
!
Study interventions accountability records at the study site will include the following:
! Confirmation of receipt, in good condition and in the defined temperature range.
! The inventory provided for the clinical study and prepared at the site.
! The dose each participant used during the study.
! The disposition (including return, if applicable) of any unused study interventions.
! Dates, quantities, batch numbers, container numbers, expiry dates, formulations, and the 
participant numbers.
!
The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study interventions provided were 
fully reconciled.
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!
Unused study interventions will not be discarded or used for any purpose other than the 
present 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 intervention(s) are 
provided in the Study Reference Manual.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
This is a single-arm study, all participants will receive the same study interventions. In the Safety 
Run-in Part in Japan, participants at DL1 will receive a lower berzosertib dose (105 mg/m2).
6.3.2
Blinding
Not applicable as this is a single-arm study. 
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the electronic case report 
form (eCRF). The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention.
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.
Additionally, on berzosertib PK and/or ECG assessment days and the day before (see Table 2), 
date, time, and dose amount of each concomitant therapy administration (e.g., each individual 
administration when a drug is taken twice daily) is to be recorded in addition to the regular 
collection of start and stop dates. Furthermore, the time for all meals taken up until the last 
triplicate digital ECG measurements on each ECG day are to be recorded. 
 
 
 
Contact the Medical Monitor for any questions on concomitant or prior therapy.
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6.5.1
Rescue Medicine
There is no specific treatment or medicine available to counteract the inhibition of ATR intended 
by berzosertib or topotecan. For any unwanted events during treatment with berzosertib and/or 
topotecan, the oncological standards in supportive care should be applied.
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.
Permitted premedications are described in Section 6.1.
6.5.3
Prohibited Medicines and Precautions
Any inadvertent use of prohibited medications during the Study Intervention Period will be 
reported as protocol deviations. These will be reviewed by the Sponsor and proportionate action 
taken. In cases where prohibited medication use is judged to significantly affect the participant’s 
safety or compromise the study’s scientific objectives, study participants will be permanently 
discontinued from the study.
Participants must not receive concurrent anticancer therapy (see Section 6.5.4 for details of 
concurrent palliative radiation therapy). 
Based on nonclinical findings, the concomitant administration of berzosertib with sensitive 
CYP3A4 substrates with a narrow therapeutic index, substrates of breast cancer resistance 
protein (BCRP), or organic anion transporting polypeptides (OATP) 1B3 should be considered
with caution and careful monitoring for safety. 
Because berzosertib is primarily metabolized by CYP3A4, inhibitors of CYP3A4 might be 
expected to decrease berzosertib’s clearance and inducers of CYP3A4 might be expected to 
increase its clearance.
The Investigator should refer to the topotecan summary of product characteristics (SmPC) or 
Package Insert for guidance on prohibited mediations during treatment. 
Prohibited concomitant medications and precautions during berzosertib treatment are listed in 
Table 7. 
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Table 7
Prohibited Concomitant Medications and Precautions During 
Berzosertib Treatment
Restricted Medication
Study Period
Screening Period
Treatment Period
Strong CYP3A4 inhibitors or inducers
!
Examples of strong CYP3A4 inhibitors include 
clarithromycin, diltiazem, idelalisib, cobicistat, 
HIV protease inhibitors, itraconazole, 
ketoconazole, posaconazole, voriconazole and 
nefazodone*.
!
Examples of strong CYP3A4 inducers include 
carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin and St. John's wort.
None allowed within 
7 days before the first 
dose of study intervention
None allowed until the 
permanent discontinuation 
of berzosertib
Precautions for Concomitant Medication
Sensitive CYP3A4 substrates with a narrow 
therapeutic index, substrates of BCRP, and 
OATP1B3
!
Examples of sensitive CYP3A4 substrates with a 
narrow therapeutic index include alfentanil, 
everolimus, sirolimus, and tacrolimus
!
Examples of substrates of BCRP include 
rosuvastatin and sulfasalazine
!
Examples of substrates of OATP1B3 include 
asunaprevir, atorvastatin, bosentan, danoprevir, 
docetaxel, fexofenadine, glyburide, imatinib, 
nateglinide, paclitaxel, pravastatin, repaglinide, 
simvastatin acid, and telmisartan
The use of sensitive CYP3A4 substrates with a narrow 
therapeutic index, substrates of BCRP and OATP1B3 
should be considered with caution and careful 
monitoring for safety
BCRP = breast cancer resistance protein; CYP3A4 = cytochrome P450 3A4; HIV = human immunodeficiency virus;
OATP1B3 = organic anion transporting polypeptide 1B3.
* Not approved in Japan.
6.5.4
Other Interventions
Radiation therapy is allowed on this study for palliative treatment e.g., for lesions that cause 
symptoms that cannot be adequately controlled by other means e.g., analgesics; however, the use 
of radiation therapy during the Study Intervention Period should be discussed with the Medical 
Monitor on a case by case basis considering the influence on imaging assessments of 
target/nontarget lesions. 
In addition, the Investigator should ensure that tumor assessments are recently obtained and 
reported as per RECIST 1.1, before initiation of radiation therapy. Berzosertib and topotecan 
should be withheld at least 1 day before the administration of radiation therapy; both drugs can 
be resumed after radiation therapy is completed, provided the participant has recovered from 
potential radiation therapy toxicities (Grade < 2 or back to baseline) and will derive benefit from 
resuming study treatment, as assessed by the Investigator. In case whole brain radiation therapy 
is administered, a wash-out period of ≥ 14 days is required before resuming study treatment.
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6.6
Dose Selection and Modification
Participants will receive berzosertib in combination with topotecan as per the initial treatment 
assignment (see Table 6) until the criteria are met as outlined in Section 4.4 (End of Study 
Definition) and/or Section 7.1 (Discontinuation of Study Intervention).
The justification for study intervention dose is presented in Section 4.3. Berzosertib and 
topotecan should be administered in combination, including during dose modifications and 
interruptions, unless one agent is permanently discontinued. 
In case a dose reduction is necessary, berzosertib and topotecan will be administered as outlined 
in Section 6.6.1. See Section 6.8 for specifics regarding dose modification during the Safety 
Run-in Part.
6.6.1
Study Intervention Dose Modifications
6.6.1.1
Berzosertib Dose Modifications
In the DL1 of the Safety Run-in Part in Japan, dose reduction from 105 mg/m2 is not allowed. 
Therefore, berzosertib should be discontinued if toxicity requiring dose modification is observed 
in DL1.
In the Main Part of the global Phase II and in the DL2 of the Safety Run-in Part, the dose of 
berzosertib may be reduced for the occurrence of drug-related toxicity using the following 
toxicity-dependent guidelines:
!
For Grade 4 hematologic toxicity: The dose of berzosertib will be reduced by 1 dose level 
(first dose reduction).
!
For Grade 3 nonhematologic toxicity: The dose of berzosertib will be reduced by 1 dose 
level (first dose reduction).
!
For Grade 4 nonhematologic toxicity: The dose of berzosertib will be reduced by 2 dose 
levels (equivalent to second dose reduction).
For liver function toxicity, please also see Section 7.1 as it may indicate potential severe liver 
injury (possible Hy’s Law) and study intervention discontinuation.
For pulmonary toxicity, study intervention should be interrupted in case of suspected interstitial 
lung disease (ILD), and permanently discontinued if ILD is confirmed.
Based on the criteria above, a maximum of 2 dose reductions will be permitted. Once the 
berzosertib dose has been reduced, it should not be re-escalated to the starting dose. If a second 
Grade 4 nonhematologic toxicity were to recur, treatment will be discontinued. Dose reduction 
levels are provided in Table 8.
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Table 8
Berzosertib Dose Modifications
Dose modifications for Grade 4 hematologic and Grade 3 nonhematologic drug-related adverse events
Starting dose
210 mg/m2
First dose reduction (1 dose level)
160 mg/m2
Second dose reduction (2 dose levels)
105 mg/m2
Dose modifications for Grade 4 nonhematologic drug-related adverse events
Starting dose
210 mg/m2
First dose reduction (2 dose levels)
105 mg/m2
In case of hematological toxicity during any cycle, treatment may be interrupted. Prior to 
initiation of the next cycle, neutrophils should be > 1,000/mm3, platelets > 100,000/mm3, and 
hemoglobin ≥ 9 g/dL.
In addition, in case of non-hematologic Grade 3 or higher toxicity during any cycle, treatment 
should be interrupted and may be resumed when all toxicities have returned to Grade ≤ 2; 
resumption may be at the discretion of the Investigator. 
Treatment interruptions due to a study intervention-related AE may occur for a maximum of 
21 days.
Participants who develop intolerance to berzosertib may continue on single agent topotecan at 
the discretion of the Investigator, administered every 3 weeks (on Days 1 to 5) at the same dose 
administered in combination therapy, until disease progression or other criteria for 
discontinuation are met (Section 7.1).
6.6.1.2
Topotecan Dose Modifications
The dose of topotecan may be reduced for drug-related toxicity using the toxicity-dependent 
guidelines in Table 9 and Table 10. Topotecan dose reductions will be accomplished by 
decreasing the dose of topotecan for each of the 5 days.
Based on the below criteria, a maximum of 2 dose reductions will be permitted. Once the 
topotecan dose has been reduced, it should not be re-escalated to the starting dose.
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Table 9
Topotecan Dose Modifications for Hematologic and Nonhematologic 
Toxicities
Topotecan 1st Dose 
Reduction (mg/m2)
Topotecan 2nd Dose 
Reduction (mg/m2)
Dose Modifications for Hematologic Toxicities
Toxicity
Grades 1 and 2
No adjustment
Not applicable
Grades 3 neutropenia persisting after Day 21 
1
0.75
Grade 4 thrombocytopenia or Grade 4 neutropenia 
with fever or infection or of duration ≥7 days
1
0.75
Dose Modifications for Nonhematologic Toxicities
Toxicity
Grades 1 and 2
No adjustment
Not applicable
Grades 3 and 4 (except Grade 3 nausea)
1
0.75
Table 10
Topotecan Dose Modifications for Renal Function (Regardless of Drug 
Relationship)
Creatinine Clearance (Cockcroft-Gault Formula)
Topotecan 1st Dose Reduction (mg/m2)
≥60 mL/min
No adjustment
40-59 mL/min
1
20-39 mL/min
0.75
< 20 mL/min
Discontinue
For liver function toxicity, please also see Section 7.1 as it may indicate potential severe liver 
injury (possible Hy’s Law) and study intervention discontinuation.
For pulmonary toxicity, study intervention should be interrupted in case of suspected ILD, and 
permanently discontinued if ILD is confirmed.
In case of hematological toxicity during any cycle, treatment may be interrupted. Prior to 
initiation of the next cycle, neutrophils should be > 1,000/mm3, platelets > 100,000/mm3, and 
hemoglobin ≥ 9 g/dL.
In addition, in case of non-hematologic Grade 3 or higher toxicity during any cycle, treatment 
should be interrupted and may be resumed when all toxicities have returned to Grade ≤ 2; 
resumption may be at the discretion of the Investigator. 
Treatment interruptions due to a drug-related AE may occur for a maximum of 21 days.
Participants who develop intolerance to topotecan may continue single agent berzosertib at the 
discretion of the Investigator, administered at the same schedule in combination therapy (on 
Days 2 and 5 of 21-day cycles), until disease progression or other criteria for discontinuation are 
met (Section 7.1).
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6.7
Study Intervention After the End of the Study
The Sponsor will not provide any additional care to participants after they leave the study 
(outside of potential continued treatment as described in Section 4.4) because such care would 
not differ from what is normally expected for patients with SCLC.
6.8
Definition of Dose-limiting Toxicity (Safety Run-in Part 
Only)
Participants enrolled in the Safety Run-in Part will be monitored for DLTs during the first cycle. 
DLT will be defined as any of the following AEs according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, assessed as 
drug-related by the Investigator and/or the Sponsor at any dose and judged not to be related to 
the underlying disease or any previous or concomitant medication or concurrent condition 
occurring during the DLT evaluation period (Cycle 1, 21 days).
Study accrual will be halted, pending discussions with the Safety Monitoring Committee (SMC)
or the study Sponsor, if there is an occurrence of a Grade 5 AE attributable to the study treatment. 
The SMC must confirm any DLT.
A DLT is defined as drug-related: 
!
Neutropenia Grade 4 for > 7 days’ duration* 
!
Febrile neutropenia (i.e., absolute neutrophil count < 1000/mm3 with single temperature of 
> 38.3 °C [101 °F] or a sustained temperature of ≥ 38 °C [100.4 °F] for more than one hour)
!
Infection (documented clinically or microbiologically) with Grades 3 or 4 neutropenia 
(absolute neutrophil count < 1.0 × 109/L) 
!
Thrombocytopenia ≥Grade 3;
! associated with clinically significant bleeding
! requiring platelet transfusion
!
Any Grade ≥ 3 non-hematological AEs, excluding the following:
! Single laboratory values out of normal range that have no clinical correlate and resolve to 
Grade ≤ 1 or to baseline within 7 days with adequate medical management or 
asymptomatic Grade 3 lipase or amylase elevation (> 5 × ULN) not associated with clinical 
manifestation of pancreatitis.
! Nausea or vomiting Grade 3 of ≤ 72 hours duration with adequate and optimal therapy.
! Diarrhea Grade 3 persisting ≤ 72 hours after initiation of medical management.
! Transient (≤ 72 hours) Grade 3 fatigue, local reactions, flu-like symptoms, fever, headache, 
hypertension that resolves to Grade ≤ 1 with adequate treatment.
! Nonrecurrent Grade 3 skin toxicity that resolves to Grade ≤ 1 in less than 7 days after 
initiation of medical management. 
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! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor that resolve to Grade ≤ 2 within 6 days.
! Infusion-related reaction resolving within 6 hours from the end of infusion and controlled 
with medical management.
! Any death clearly due to the underlying disease or extraneous causes.
!
Death due to drug-related AEs
!
Any drug-related toxicity including toxicities:
! that cause interruption of treatment for > 3 weeks (21 successive days). If a participant is 
deemed fit to restart treatment on Day 21 then this is not a DLT.
! that prevent the administration of ≥80% of the planned dose of berzosertib or topotecan.
! that in the opinion of the SMC is of potential clinical significance such that further dose 
escalation would expose participants to unacceptable risk.
* Note: In the event of a Grade 4 neutropenia, a full blood count must be performed no more 
than 7 days after the onset of the event to determine if a DLT has occurred. The participant will 
be closely monitored until resolution to Grade 3 or less.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for safety, efficacy, and survival follow-up. 
The SoA (Table 1) indicates data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed.
Participants will be withdrawn from study intervention for any of the following reasons:
!
A participant may withdraw from the study intervention at any time at his/her own request, 
and without giving a reason. The participant will continue follow-up, unless consent to study 
was withdrawn as well
!
Upon documentation of disease progression per RECIST 1.1 as determined by the 
Investigator and verified by the IRC, as outlined in Section 8.1.1.
!
General or specific changes in the participant’s condition that render the participant
unacceptable for further treatment in the judgment of the Investigator
!
Unequivocal clinical progression
!
A participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons
!
Pregnancy
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!
Confirmed ILD
!
Liver injury: 
The Investigator will consider discontinuation of study intervention for abnormal liver 
function when a participant meets 1 of the conditions outlined in the algorithm or if the 
Investigator believes that it is in best interest of the participant.
! All events of ALT or AST > 8 × ULN 
! All events of ALT or AST > 5 × ULN for more than 2 weeks
! All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (> 35% direct bilirubin) or 
ALT > 3 × ULN and international normalized ratio (INR) > 1.5, if INR measured 
! ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
These may indicate potential severe liver injury (possible Hy’s Law) and will be reported as 
a serious adverse event (SAE).
7.2
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. At the time of discontinuing from the study, if possible, a discontinuation 
visit will be conducted, as listed in the SoA (Table 1). The SoA specifies the data to collect at 
study discontinuation and follow-up, and any additional evaluations that need to be completed.
If the participant withdraws consent for future involvement in the study, any data collected up to 
that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed. A participant has the right at any time to request destruction of any 
biological samples taken. The Investigator will document this in the site study records.
Additional participants must be enrolled for each participant who withdraws from the study after 
signing consent and successfully meeting entry criteria but did not receive study intervention. 
The Investigator will secure the safety of the study participants and make every attempt to collect 
data.
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 will be taken if a participant fails to return to the clinic for a required study 
visit:
!
The site will 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.
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!
Before a participant is deemed “lost to follow-up”, the Investigator or designee will 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 will be documented 
in the participant’s medical record.
!
If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”.
8
Study Assessments and Procedures
!
Study assessments and procedures and their timing are summarized in the SoA (see 
Section 1.3).
!
No protocol waivers or exemptions are allowed.
!
Immediate safety concerns are 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, is essential 
and required for study conduct.
!
All screening evaluations will 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 (Table 1).
A maximum of 134 mL of blood will be collected in any 1-month period from each participant 
in the study, including any extra assessments that may be required.
8.1
Efficacy Assessments and Procedures
8.1.1
Tumor Response
A central imaging laboratory/IRC will be used to read and interpret all computed tomography 
(CT), magnetic resonance imaging (MRI) data, will confirm measurable disease at screening 
(see Section 5.1), and will independently verify progressive disease (PD). Radiographic images 
and clinical findings (such as physical assessments and biopsies) will be used by the Investigators 
for the local determination of disease progression and participant treatment decisions. See
Appendix 7 for additional information.
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Participants will have a chest/abdomen/pelvis imaging scan (e.g., CT, MRI) and, if clinically 
indicated, imaging scans of other body areas (e.g., neck) or other modalities (e.g., bone scan, 
positron emission tomography-CT [PET-CT]). A brain scan with contrast (MRI [preferred] or 
CT, with contrast) should be performed during screening and subsequently, as clinically 
indicated. Participants should have a repeat imaging scan as described in the SoA in Section 1.3. 
All imaging scans to assess disease progression should be performed using similar CT/MRI 
platforms and imaging techniques, including the use or absence of contrast, and should be of 
consistent anatomic locations with prior imaging scans, whenever possible. 
Imaging scans will be locally read. The applicable overall response category for each visit that 
includes disease assessment, based on evaluation of imaging scan, will be recorded in the eCRF. 
Imaging scans must also be uploaded or copied to the selected Imaging Research Organisation, 
as well as any relevant clinical information and study procedure (e.g., cytology and biopsy 
results). A central IRC, managed by an Imaging Research Organisation, will additionally read 
and interpret all radiographic scans for this study (see Appendix 2 for details of the IRC).
If PD has been determined locally at a time point, an expedited review by the IRC must be sought 
to verify the PD. Results of the IRC review will be communicated to the Investigator. While the 
Investigator is awaiting the results of the IRC review, the participant should not be discontinued 
from the study intervention, if judged feasible by the Investigator.
If the IRC review verifies PD, the participant should discontinue study intervention and 
subsequent tumor assessments are no longer required. If the IRC review does not verify PD, the 
participant should continue receiving the study intervention unless there is a medical reason for 
a change in therapy or discontinuation (e.g., clinical deterioration, or other criteria as specified 
in Section 7.1) as per Investigator’s clinical judgment. Participants will continue to have tumor 
assessments until the IRC determines PD.
Tumor assessments per protocol will be performed until PD is verified by the IRC, regardless of 
study intervention discontinuation or start of subsequent anticancer treatment. 
For assessment time points and procedures for primary, secondary, and 
 
efficacy endpoints, see Section 1.3 for the SoA. 
8.1.2
Survival Follow-up
Survival Follow-up Visits will be completed until End of Study (see Table 1 and Section 4.4). 
During Survival Follow-up, further anticancer treatment should be recorded.
8.1.3
Patient-Reported Outcomes
Patient-reported outcomes will be assessed by the EuroQol 5 Dimension 5 Level Scale 
(EQ-5D-5L), European Organization for the Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ-C30), and module QLQ-LC13 (lung cancer specific 
questionnaire), according to schedule specified in the SoA (see Table 1). The PROs 
questionnaires should be completed by the participant preferably prior to any of the other 
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trial-related assessments being performed, such as physical examinations, blood draws, and
study intervention administration. Participants will use a validated electronic tablet or validated 
site pad to record their responses to these questionnaires. In rare and extenuating circumstances 
when an electronic tablet or site pad is not available or not working properly, collection on 
validated paper questionnaires may be allowed to ensure data are collected and not lost.
The EQ-5D-5L comprises 5 questions and a visual analogue scale (VAS). The questionnaire is 
used to calculate the utility index, used in economic evaluations. The 5 items are mobility, 
self-care, usual activities of daily living, pain/discomfort, anxiety/depression with 5 descriptive 
levels ranging from “no problem to…” to “extreme…/unable to do….” The VAS ranges from 0
to 100 where 0 is “the worst health you can imagine” and 100 is “the best health you can 
imagine.” The recall period is defined as “today.”
The EORTC QLQ-C30 assesses the quality of life of cancer patients with 30 questions including 
the dimensions of activities of daily living, pain, fatigue, shortness of breath, appetite loss, 
nausea, vomiting, sleeping disturbances, diarrhea, difficulties to concentrate, anxiety and 
depression, memory loss, social activities, financial burden, impression of overall health and 
impression of overall quality of life. Questions 1-28 are measured in a range from 1 to 4 where 
1 represents “Not at All” and 4 represents “Very Much”, and questions 29 and 30 are measured 
in a range from 1 to 7 where 1 represents “Very poor” and 7 represents Excellent. The recall 
period is defined as “during the past week.”
The EORTC QLQ-LC13 comprises 13 questions incorporated into 1 multi-item scale designed 
to evaluate lung cancer symptoms such as dyspnea, different types of pain, cough, hemoptysis, 
dysphagia, sore mouth, alopecia, and peripheral neuropathy. For each domain and item, a linear 
transformation is applied to standardize the raw score to a range from 0 to 100, with 100 
representing the best possible function/quality of life, and highest burden of symptoms for 
symptom domains and single items. The recall period is defined as “during the past week.” Data 
will be collected by the clinical research organization and housed in a database.
For Safety Follow-up Visit that occurs within 7 days after End-of-Treatment Visit, PRO 
assessment can be skipped at the Safety Follow-up Visit. However, if the PRO assessment at 
End-of-Treatment Visit is missed, then PROs should be collected at the Safety Follow-up Visit.
Patient-reported outcome assessments at Efficacy and Survival Follow-up will be conducted at 
12 weeks and 24 weeks from last dose and can be conducted either at the study site or remotely, 
if permitted. As soon as a participant starts subsequent anticancer treatment, PRO will not be 
collected. 
The PRO assessments are not applicable to DL1 in the Safety Run-in Part in Japan.
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.
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Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. 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.
Participants should be observed for potential infusion-related reactions according to local 
practice.
8.2.1
Physical Examinations
Physical examinations will be performed and the ECOG PS and Karnofsky Scale should be 
recorded according to the SoA (Table 1). Symptom-directed physical examinations may be 
performed as clinically indicated per Investigator’s judgment.
!
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, neurological systems as well as head/neck, 
lymph nodes, and abdomen.
!
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular and respiratory systems, and abdomen (liver and spleen).
!
Investigators will pay special attention to clinical signs related to previous serious illnesses
and the study disease.
8.2.2
Vital Signs
!
Height (screening only) and weight at visits specified in the SoA (Table 1) will be measured 
and recorded.
!
Temperature (method of acquisition should be recorded), 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 will be preceded by at least 5 minutes of 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 if feasible) will be 
measured at the time points specified in the SoA (Table 1) with the participant in a 
semi-supine position after 5 minutes rest and will include temperature, systolic and diastolic 
blood pressure, and pulse.
8.2.3
Electrocardiograms
Safety ECGs
A standard single 12-lead ECG will be obtained as outlined in the SoA (Table 1) using an ECG 
machine with paper readouts that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals. 
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8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 5
at the time points listed in the SoA (Table 1). All samples will be clearly identified. 
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 local laboratories.
The Sponsor will receive a list of the local laboratory normal ranges before shipment of study 
intervention. Any changes to the ranges during the study will be forwarded to the Sponsor or 
designated organization.
The Investigator will review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports will be filed with the source documents.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are provided in Appendix 4.
The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. The 
Investigator remains responsible for following up AEs that are serious or that caused the 
participant to discontinue the study intervention or study, as specified in Section 8.3.3.
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Requests for follow-up will usually be made via the Study Monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
8.3.1
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information
All SAEs will be collected from the signing of the ICF until the 30-day follow-up visit as
specified in the SoA (Table 1). Beyond this reporting period, any new unsolicited SAEs that the 
Investigator spontaneously reports to the Sponsor will be collected and processed.
All AEs will be collected from the signing of the ICF until the 30-day follow-up visit as specified 
in the SoA (Table 1).
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance will this exceed 24 hours, as indicated in Appendix 4. The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available using the same 
procedure that was used for the initial report.
Investigators are not obligated to actively solicit AEs or SAEs after the end of study participation; 
however, if the Investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be reasonably related to 
the study intervention or study participation, the Investigator will promptly notify the Sponsor.
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. Care will 
be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrences.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Reasonable attempts to obtain this information will be made and documented. It is also the 
Investigator’s responsibility to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed. Further information on follow-up procedures is provided
in Appendix 4.
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8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators.
Individual Case Safety Reports will be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators, as necessary.
An Investigator who receives an Individual Case Safety Report describing a SUSAR or other 
specific safety information (e.g., Emerging Safety Issue Report, summary or listing of 
SAEs/SUSARs) from the Sponsor will review and then file it along with the IB in the 
Investigator’s Site File and will notify the IRB/IEC, if appropriate according to local 
requirements.
In this global clinical multicenter study, the Sponsor is in the best position to determine an 
unanticipated problem (as defined in US Regulations 21 CFR 312.66). The Sponsor will
immediately notify all Investigators of findings that could adversely affect the safety of 
participants, impact the conduct of the study, or alter the IRB’s approval/favorable opinion to 
continue the study. An unanticipated problem is a SAE that by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis report, specified in 
Section 2.3.
8.3.5
Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 6 months after the last 
study intervention administration.
If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of learning 
of the pregnancy and will follow the procedures specified below for collection of pregnancy 
information.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
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Collection of Pregnancy Information
Male participants with partners who become pregnant:
!
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner, who becomes pregnant while the participant is in this study. This applies only 
to participants who receive study intervention.
!
After obtaining signed consent from the pregnant female partner directly, the Investigator 
will record the pregnancy information on the appropriate form and submit it to the Sponsor 
within 24 hours of learning of the pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child 
will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.
Female Participants who become pregnant:
!
The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy. 
!
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information 
will be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.
!
A spontaneous abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such.
!
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as specified in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting.
!
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.
8.3.6
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs
The following disease-related events (DREs) are common in participants with SCLC and can be 
serious/life threatening:
!
Progressive disease
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Because PD is typically associated with the disease under study it will not be reported according 
to the standard process for expedited reporting of SAEs even though the event may meet the 
definition of a SAE. These events will be recorded on the applicable eCRF page. 
However, if either of the following conditions applies, then the event will be recorded and 
reported as an SAE:
!
The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant.
OR
!
The Investigator considers that there is a reasonable possibility that the event was related to 
study intervention.
8.3.7
Adverse Events of Special Interest
No AEs of special interest have been identified.
8.4
Treatment of Overdose
For this study, any dose of berzosertib or topotecan > 10% over the planned daily dose included 
in this study protocol or planned for an individual participant enrolled in the study will be 
considered an overdose.
The Sponsor does not recommend specific treatment for an overdose of either berzosertib or 
topotecan. If an overdose is suspected, monitor the participant for bone marrow suppression and 
institute supportive-care measures (such as prophylactic G-CSF and antibiotic therapy) as 
appropriate. Refer to the berzosertib IB and the topotecan product information for additional 
information.
Even if not associated with an AE or a SAE, any overdose is recorded in the eCRF and reported 
to global patient safety in an expedited manner. Overdoses are reported on a SAE and Overdose 
Report Form, following the procedure in Appendix 4, the section on Reporting SAEs.
8.5
Pharmacokinetics
Blood sampling for PK analysis will be collected according the Schedule in Table 2. PK results 
from NCA will be included in Safety-Run-in Part. Population PK and exposure-response results 
will be reported separately in a stand-alone report that may also include data from other studies.
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The following PK parameters will be calculated for berzosertib and 
, when 
appropriate:
Symbol
Definition
AUC0-tlast
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-tlast/Dose The Dose normalized AUC from time zero to the last sampling time (tlast) at 
which the concentration is at or above the lower limit of quantification. 
Normalized using the actual dose, using the formula AUC0-tlast /Dose.
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-tlast + Clast pred/ λz
AUC0-∞ /Dose
The dose normalized AUC from time zero extrapolated to infinity. 
Normalized using actual dose, using the formula AUC0-∞ /Dose.
AUC0-48h
The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to 48 hours. Calculated using the mixed log-linear trapezoidal rule 
(linear up, log down).
AUC0-48h/Dose The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to 48 hours. Calculated using the mixed log-linear trapezoidal rule 
(linear up, log down). Normalized using actual dose, using the formula 
AUC0-48h /Dose.
AUC0-72h
The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to 72 hours. Calculated using the mixed log-linear trapezoidal rule 
(linear up, log down).
AUC0-72h/Dose The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to 72 hours. Calculated using the mixed log-linear trapezoidal rule 
(linear up, log down). Normalized using actual dose, using the formula 
AUC0-72h /Dose.
Cmax
Maximum observed concentration 
Cmax
/Dose
The dose normalized maximum concentration. Normalized using the actual 
dose, and the formula Cmax /Dose.
Ceoi
The observed concentration at the end of the infusion period.
Ctrough
The concentration observed immediately before next dosing (corresponding 
to pre-dose or trough concentration for multiple dosing)
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Symbol
Definition
CL
The apparent total body clearance of study intervention following 
extravascular administration, CL = Dose/AUC0-∞.
 
 
 
 
Racc(Cmax)
The accumulation factor to assess the increase in maximum concentration 
until steady state is reached. Racc(Cmax) = (Cmax after multiple dose)/(Cmax after 
single dose)
tmax
The time to reach the maximum observed concentration collected during a 
dosing interval 
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification
VZ
The apparent volume of distribution during the terminal phase following 
intravenous administration. VZ = Dose/(AUC0-∞*λz) following single dose.
Whole blood samples of approximately 2 mL will be collected at each time point for 
measurement of plasma concentrations of berzosertib and its 
. For the determination 
of topotecan in plasma, whole blood samples of approximately 2 mL will be collected at each 
required time point. Collection times are specified in the SoA (Table 2). The actual date and time 
(24-hour clock time) of each sample will be recorded to calculate actual time elapsed since the 
prior dose administration. The sampling timing may be altered during the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.
The quantification of berzosertib in plasma and quantification of topotecan will be performed 
using validated assay methods.
 
Concentrations will be used to 
evaluate the PK of study intervention.
Remaining samples collected for analyses of study intervention concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the study.
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Details on processes for collection and handling of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF, according to local regulations.
8.6
Pharmacodynamics
Not applicable for this study.
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8.9
Immunogenicity Assessments
Not applicable for this study.
8.10
Medical Resource Utilization and Health Economics
Not applicable for this study.
9
Statistical Considerations
This section outlines the statistical analysis strategy and procedures for the study. Full details of 
all planned analyses will be described in the study Integrated Analysis Plan (IAP). 
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9.3
Populations for Analyses
The analysis populations are specified in Table 12. The final decision to exclude participants 
from any analysis population will be made during a data review meeting prior to database lock. 
Table 12
Populations for Analyses
Analysis Set
Description
Screening Analysis Set (SCR)
All participants who provided informed consent, regardless of the participant’s 
study intervention status in the study.
Full Analysis Set (FAS)/ 
Safety Analysis Set (SAF)
All participants who were administered any dose of any study intervention 
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Analysis Set
Description
DLT Analysis Set in Safety 
Run-in Part 
All participants who were administered any dose of any study intervention 
and were evaluable for DLT in the Safety Run-in Part in Japan.
For DLT analysis, participants are evaluable if at least one of the following 
criteria is fulfilled:
•
Received at least 80% of the planned cumulative dose of study 
interventions during the DLT period and completed the DLT period.
•
Experienced at least 1 DLT during the DLT period, regardless of the 
administered cumulative dose of study interventions and completion of 
the DLT period.
DLT = dose-limiting toxicity.
9.4
Statistical Analyses
In case DL2 is declared RP2D, i.e., Japanese participants to join in main part of study, data of 
DL2 will be analyzed together with the main study part. A subgroup analysis will be performed
to evaluate Japanese participants. Analyses for the Safety Run-in Part will include both DL1 and 
DL2 separately by dose level.
In order to provide overall estimates of treatment effects, data will be pooled across study sites. 
The factor “site” will not be considered in statistical models or for subgroup analyses due to the 
high number of participating study sites in contrast to the anticipated small number of 
participants enrolled at each site.
In general, continuous variables will be summarized using number (n), mean, median, standard 
deviation, minimum, maximum, 25% quartile and 75% quartile. Categorical variables will be 
summarized using frequency counts and percentages. Proportions are calculated based on the 
number of participants in the analysis set of interest, unless otherwise specified in the IAP. If not 
explicitly stated, no imputation will be used in the analyses.
9.4.1
Efficacy Analyses
All analyses on efficacy estimands will be conducted on the Full Analysis Set (FAS). The 
estimands framework is used in Table 13 to describe the analysis of primary and secondary 
efficacy estimands.
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Table 13
Efficacy Analyses and Estimands (Main Part)
Endpoint
Statistical Analysis Methods/Further Estimand Attributes
Primary
Objective Response 
Endpoint: Objective Response according to RECIST 1.1 as assessed by IRC
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: Treatment-policy strategy, i.e., regardless of the 
intercurrent event
!
Start of subsequent anticancer treatment: while not treated with subsequent 
anticancer therapy strategy; i.e., ignoring tumor assessments after the intercurrent 
event
!
Progression according to RECIST 1.1: While not progressed strategy, i.e.,
assessments up to the intercurrent event
Population Level Summary:
Objective response rate: The ORR will be determined as the proportion of patients with 
confirmed objective response of either PR or CR. Confirmation of the response according 
to RECIST 1.1 is required no sooner than 4 weeks after the initial documentation of CR or 
PR. The 95% CI for the ORR will be calculated using the Clopper-Pearson method.
Sensitivity Analysis:
As main estimator, but using Investigator assessment instead of IRC assessment
Supplementary Analysis:
As main estimator, but using unconfirmed objective response instead of confirmed 
objective response
Secondary
Duration of 
Response 
Endpoint: Duration of response according to RECIST 1.1 as assessed by IRC, measured 
by time from first documentation of objective response to PD or death, occurring within 2
scheduled tumor assessments after last evaluable assessment or first study intervention
Population: Patients with relapsed, platinum-resistant SCLC and confirmed objective 
response according to RECIST 1.1 as assessed by IRC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments after last evaluable assessment or first 
study intervention: Composite strategy, i.e., will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent 
event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
Population Level Summary:
!
Median duration of response
!
Kaplan-Meier estimates, including the Kaplan-Meier estimate at 6 months
Sensitivity Analysis:
As main estimator, but using Investigator assessment instead of IRC assessment
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Endpoint
Statistical Analysis Methods/Further Estimand Attributes
PFS 
Endpoint: Progression-free survival measured by time from first study intervention to PD 
according to RECIST 1.1 (by IRC) or death, occurring within 2 scheduled tumor 
assessments after last evaluable assessment or first study intervention
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Death within 2 scheduled tumor assessments after last evaluable assessment or first 
study intervention: composite strategy, i.e., will be considered as event of interest
!
Discontinuation of treatment: treatment-policy strategy, i.e., ignoring the intercurrent 
event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
Population Level Summary:
!
Median PFS time
!
Kaplan-Meier estimates
Sensitivity Analyses:
1. As main estimator, but considering all deaths as events, irrespective of time of last 
tumor assessment.
2. As main estimator, but using Investigator assessment instead of IRC assessment
3. As main estimator, but using while not on subsequent anticancer therapy strategy for 
IE start of subsequent anticancer treatment
OS
Endpoint: OS as measured by time from first study intervention to death
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan followed by subsequent therapy
Intercurrent Event Strategy: The endpoint will be analyzed regardless of whether the 
following intercurrent events had occurred (treatment-policy strategy):
!
Discontinuation of treatment: Treatment-policy strategy, i.e., ignoring the intercurrent 
event
!
Start of subsequent anticancer treatment: treatment-policy strategy, i.e., ignoring the 
intercurrent event
Population Level Summary:
!
Median OS time
!
Kaplan-Meier estimates
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Endpoint
Statistical Analysis Methods/Further Estimand Attributes
Physical functioning; 
cough, dyspnea, and 
chest pain; and 
overall health state
Endpoint: Change from baseline in physical functioning measured by the EORTC 
QLQ-C30; cough, dyspnea, and chest pain measured by EORTC QLQ-LC13; and health 
state as measured by VAS as a component of the EQ-5D-5L
Population: Patients with relapsed, platinum-resistant SCLC
Treatment: Berzosertib + topotecan
Intercurrent Event Strategy:
!
Discontinuation of treatment: while on treatment strategy, i.e., ignoring PRO 
assessments after the intercurrent event 
!
Start of subsequent anticancer treatment: while not treated with subsequent 
anticancer therapy strategy; i.e., ignoring PRO assessments after the intercurrent 
event
!
Death: while alive strategy, i.e., considering PRO assessments before the intercurrent 
event
Population Level Summary:
!
Mean changes from baseline analysis for multi-item scales in EORTC questionnaires 
(i.e., physical functioning, dyspnea) and VAS
!
Proportion of patients with ≥ 1 category improvement and proportion of patients with 
≥1 category worsening in single-item symptoms (i.e., cough and chest pain)
Sensitivity Analysis:
!
Discontinuation of treatment: treatment-policy strategy, i.e., regardless of the 
intercurrent event
CI = confidence interval; CR = complete response; DL = dose level; EORTC = European Organization for the 
Research and Treatment of Cancer; EQ-5D-5L = EuroQol 5 Dimension 5 Level Scale; IRC = Independent Review 
Committee; ORR = objective response rate; OS = overall survival; PD = progressive disease; 
PFS = progression-free survival; PR = partial response; PRO = patient-reported outcome; QLQ-C30 = Quality of 
Life Questionnaire; QLQ-LC13 = lung cancer specific questionnaire; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors version 1.1; RP2D = recommended Phase II dose; SCLC = small-cell lung cancer; VAS = visual 
analogue scale.
In case DL2 is declared RP2D, data for participants receiving DL2 will in addition be analyzed as part of the main 
study.
Efficacy of the Safety Run-in Part in Japan will be analyzed similarly to the main study part for 
the following populations:
!
DL1: Japanese participants with advanced solid tumors
!
DL2: Japanese participants with relapsed, platinum-resistant SCLC.
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set, except for evaluation of DLT
in the Safety Run-in Part in Japan.
The on-treatment period is defined as the time from first study intervention to the last study 
intervention date + 30 days.
Further details on safety analyses are summarized in Table 14 and Table 16.
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Table 14
Safety Endpoints (Main Part)
Endpoint
Statistical Analysis Methods
Primary
Not applicable
Secondary
AEs
The definitions, procedures for recording, evaluating, follow-up, and reporting of AEs are 
described in Appendix 4. AEs will be coded according to the latest available version of 
the MedDRA. Missing classifications concerning study intervention relationships will be 
considered related to the study interventions.
Analysis will be based on TEAEs, which are events with onset dates during the 
on-treatment period, or events with onset dates before the on-treatment period and 
worsening during the on-treatment period.
The following TEAEs will be presented in summaries by incidence and type according to 
MedDRA SOC and Preferred Term:
!
TEAEs
!
SAEs
!
TEAEs related to study interventions
!
NCI-CTCAE Grade ≥ 3 TEAEs
!
NCI-CTCAE Grade ≥ 3 study intervention-related TEAEs
!
TEAEs leading to temporary interruption of study interventions
!
TEAEs leading to permanent discontinuation of study interventions
!
TEAEs leading to dose modification
!
TEAEs leading to death.
Deaths
Death and primary reason for death, overall and during the treatment period, will be 
tabulated.
Laboratory Values
Baseline values are defined as the last value prior to first administration of study 
intervention. Only on-treatment values will be summarized. Laboratory values will be
graded using NCI-CTCAE (Version 5.0), if applicable. Non-gradable parameters will be 
classified as normal, high, or low.
Summary statistics for:
!
Absolute values
!
Change from baseline
!
Worst on-treatment grade
Shift tables (baseline versus worst on-treatment)
Vital Signs
!
Summary statistics for baseline and on-treatment values
!
Shift tables (baseline versus minimum/maximum on-treatment)
ECGs
!
Summary statistics for baseline and on-treatment values
!
Shift tables (baseline versus worst on-treatment)
AEs = adverse events; ECGs = electrocardiograms; MedDRA = Medical Dictionary for Regulatory Activities; 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; SAEs = serious 
adverse events; SOC = System Organ Class; TEAE = treatment-emergent adverse event.
Table 15
Safety Endpoints (Safety Run-in Part in Japan)
Endpoint
Statistical Analysis Methods
Primary
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Endpoint
Statistical Analysis Methods
Dose-limiting 
toxicity 
The number and proportion of participants experiencing a DLT (see Section 6.8) 
confirmed by the SMC during the DLT period will be reported by dose level. Analysis will 
be based on the DLT Analysis Set in the Safety Run-in Part.
AEs, Deaths, 
Laboratory 
Values, Vital 
Signs, ECGs
Endpoints will be analyzed as described in Table 14.
AEs = adverse events; DLT = dose-limiting toxicity; ECGs = electrocardiograms; SMC = Safety Monitoring 
Committee.
9.4.2.1
Safety Run-in Part in Japan
In the Safety Run-in Part in Japan, a BOIN design (Yuan 2016) will support DL decisions. Upon 
review of emerging data available, the Local SMC may recommend to the Sponsor approaches 
such as stop the Safety Run-in part or establish the RP2D in participants in Japan. The target 
DLT rate for the BOIN model will be 30%, leading to tolerability boundaries as shown in
Table 16.
Table 16
Tolerability Judgment Boundaries for Target Toxicity Rate = 30%
Judgment
Number of DLT evaluable participants treated 
at the current DL
3
4
5
6
7
8
9
Tolerability is confirmed in case the number of DLTs is ≤
0
0
1
1
1
1
2
Tolerability is not confirmed, in case the number of DLTs is ≥ 
2
2
2
3
3
3
4
DL = dose level; DLT = dose-limiting toxicity.
Cohorts of 3 participants will be enrolled. At least 3 DLT evaluable participants on a dose level 
are required to confirm the tolerability at DL1 or DL2. The maximum number of participants per 
dose level is 9. 
Example Readout (assuming all 3 participants in each cohort are DLT evaluable)
Decision Criteria on DL1:
!
If 0/3 participants with DLT: DL1 is considered safe. Escalate to DL2
!
If 1/3 participants with DLT: Enroll 3 additional participants on DL1
! If 1/6 participants with DLT: DL1 is considered safe. Escalate to DL2
! If 2/6 participants with DLT: Enroll 3 additional participants on DL1
!
If 2/9 participants with DLT: DL1 is considered safe. Escalate to DL2
!
If 3/9 participants with DLT: The Local SMC will provide recommendations based 
on emerging data available.
!
If ≥4/9 participants with DLT: Stop the Safety Run-in Part
! If ≥3/6 participants with DLT: Stop the Safety Run-in Part
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!
If ≥2/3 participants with DLT: Stop the Safety Run-in Part
Decision criteria on DL2:
!
If 0/3 participants with DLT: DL2 is considered safe
!
If 1/3 participants with DLT: Enroll 3 additional participants on DL2
! If 1/6 participants with DLT: DL2 is considered safe
! If 2/6 participants with DLT: Enroll 3 additional participants on DL2
!
If 2/9 participants with DLT: DL2 is considered safe
!
If 3/9 participants with DLT: The Local SMC will provide recommendations based on 
emerging data available.
!
If ≥4/9 participants with DLT: Stop the Safety Run-in Part
! If ≥3/6 participants with DLT: Stop the Safety Run-in Part
!
If ≥ 2/3 participants with DLT: Stop the Safety Run-in Part
If the Local SMC declares DL2 safe, it will be the RP2D in Japan, and Japanese sites may
continue the study in the Main Part of Phase II.
Participants are enrolled in cohorts of three and the decision whether a toxicity is indeed 
considered DLT is taken by the Local SMC. The SMC meetings are planned after each cohort, 
i.e., after the first three enrolled participants, after the first six enrolled participants, and so on. 
If, however, any concerns on safety/tolerability arise during the safety run-in, an ad hoc SMC 
meeting may be held at any time, and the local SMC may decide on holding or discontinuation 
of the Safety Run-in Part.
The final decision on evaluability will be made by the Local SMC (e.g., considering relevant 
deviations from dosing schedule).
9.4.3
Other Analyses
Baseline characteristics will be analyzed on the FAS. Summary statistics will be provided as 
described for continuous/categorical variables in Section 9.4.
Details on the PK analyses will be in the IAP that will be finalized before database lock. 
Integrated analyses across studies, such as the population PK analysis will be presented 
separately from the main clinical study report.
Noncompartmental PK analysis will be used to characterize the PK of berzosertib (and 
, if applicable) in participants from the Safety Run-in Part in Japan. Details will be 
described in the IAP.
9.4.4
Sequence of Analyses
Main Part of Global Phase II:
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The study will be monitored regularly by an internal SMC (see Appendix 2). The following 
analyses will be conducted:
!
An interim analysis for futility will be conducted after the first 40 participants have 
completed their second on-treatment tumor assessment (or dropped-out/died prematurely)
!
The primary analysis will be performed once all 80 participants have been followed for at 
least 3 months (or dropped-out/died prematurely)
!
A follow-up analysis will be performed once the end of study has been reached.
Safety Run-in Part in Japan:
The study will be monitored regularly by the Local SMC (see Appendix 2). Safety analysis will 
be performed after completion of the DLT evaluation period of each cohort in DL1 and DL2.
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10
References 
Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer.
2015;121(5):664-72.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.
Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in 
Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220-9.
NCCN Clinical Practice Guidelines in Oncology for Small Cell Lung Cancer. Version 1.2021. 
Available 
from: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
August 11, 2020.
O’Brien MER, Ciuleanu TE, Tsekov H, et al. Phase III Trial Comparing Supportive Care Alone 
with Supportive Care with Oral Topotecan in Patients with Relapsed Small-cell Lung Cancer. J 
Clin Oncol. 2006;24:5441-7. 
Paller CJ, Bradbury PA, S. Ivy SP, et al, Design of Phase I Combination Trials: 
Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug 
Steering Committee, Clin Cancer Res. 2014;20(16):4210-7.
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus 
platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): 
a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-39. 
PMDA Review Report of HYCAMTIN for Injection 1.1 mg. 2011 February 23.
Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1 Update and clarification. European Journal 
of Cancer 62 (2016) 132-7.
Thomas A, Redon CE, Sciuto L, et al. Phase I Study of ATR Inhibitor M6620 in Combination 
With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol. 2018;36(16):1594-
1602. 
Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-
cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-
54.
von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan 
as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 
2014;32(35):4012-19.
Yuan Y, Hess KR, Hilsenbeck SG, et al. Bayesian optimal interval design: a simple and well 
performing design for phase I oncology trials. Clin Cancer Res. 2016;22(17):4291-301.
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11
Appendices
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Appendix 1
Abbreviations 
AE(s)
Adverse event(s)
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATM
Ataxia telangiectasia mutated
ATR
Ataxia telangiectasia mutated and Rad3-related
BCRP
Breast cancer resistance protein
β-HCG
β-human chorionic gonadotropin
BOR
Best overall response
CI
Confidence interval(s)
CR
Complete response
CT 
Computed tomography 
CYP3A4
Cytochrome P450 3A4
DDR
DNA damage response
DL
Dose level
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
EORTC
European Organization for the Research and Treatment of Cancer 
EOT
End-of-Treatment
EQ-5D-5L
EuroQol 5 Dimension 5 Level Scale 
FAS
Full Analysis Set
FDG-PET
Fludeoxyglucose positron emission tomography
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
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G-CSF
Granulocyte colony-stimulating-factor
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HRT
Hormonal replacement therapy
HRQoL
Health-related quality of life 
IAP
Integrated Analysis Plan
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NIMP
Non-Investigational Medicinal Product
OATP
Organic anion transporting polypeptides
ORR
Objective response rate
OS
Overall survival 
PD
Progressive disease
PET-CT
Positron emission tomography- computed tomography
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PFI
Platinum-free interval
PFS
Progression-free survival
 
PK
Pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PR
Partial response
PRO
Patient-reported outcome
QLQ-C30
Quality of Life Questionnaire
QLQ-LC13
Lung cancer specific questionnaire
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RP2D
Recommended Phase II dose
SAE(s)
Serious adverse event(s)
SD
Stable disease
SCLC
Small-cell lung cancer
SMC
Safety Monitoring Committee
SmPC
Summary of product characteristics
SoC
Standard of care
SUSAR
Suspected unexpected serious adverse reaction
TEAE(s)
Treatment-emergent adverse event(s)
ULN
Upper limit of normal
VAS
Visual analogue scale
WOCBP
Woman of childbearing potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with enough, 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 (where allowed by local laws and regulations) and 
answer all questions on the study.
Participants will be informed that their participation is voluntary.
Participants or their legally authorized representative (where allowed by local laws and 
regulations) will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; the Japanese ministerial ordinance on GCP; local regulations; International 
Council for Harmonisation (ICH) guidelines; Health Insurance Portability and Accountability 
Act requirements, where applicable; and the IRB/IEC or study center.
The medical record will 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 will also sign the ICF.
If the ICF is updated during their participation in the study, participants will be re-consented to 
the most current, approved version.
A copy of the ICF(s) will be provided to the participant or the participant’s legally authorized 
representative (where allowed by local laws and regulations).
The original signed and dated consent will remain at the Investigator’s site and will be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes.
Participants who are rescreened are required to sign a new ICF.
There will be additional informed consent for optional pharmacogenetic sample collection and 
storage and for optional future research.
Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed consent. 
Any participant records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any identifiable information will not be transferred.
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The Sponsor will inform participants that their personal study-related data will be used per local 
data protection and privacy laws. The level of disclosure will also be explained to the participant
and pregnant partners (if applicable), who will be required to give consent for their data to be 
used, as specified in the informed consent.
The participant will 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.
Study Administrative
The Coordinating Investigator listed on the title page represents all Investigators for decisions 
and discussions on this study, per ICH Good Clinical Practice (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 clinical study report.
The 
study 
will 
appear 
in 
the 
following 
clinical 
studies 
registries: 
EudraCT 
number 2020-004231-25, www.ClinicalTrials.gov, and Japan Registry of Clinical Trials (jRCT).
The study will be conducted at approximately 41 study sites in Asia, Europe, and North America, 
including approximately 13 study sites in the US. 
The Sponsor will be responsible for supply and manufacture of berzosertib. Depending on the 
local regulations, topotecan may be either sourced from a local hospital pharmacy or supplied 
by the Sponsor (or designated service provider).
A SMC will review the emerging safety profile during review of the safety data and will monitor 
for any new safety signal observed during the conduct of the study. The composition and specific 
working procedures of the SMC will be described in a SMC Charter, which will be established 
prior to the start of recruitment.
Additional local SMC is organized for the Safety Run-in Part in Japan. The local SMC will 
periodically review all accumulating safety data and available pharmacokinetic (PK) data. The 
local SMC shall also confirm any DLT reported by Investigators and make recommendations to 
the Sponsor regarding possible changes to the conduct of the study such as
suspension/discontinuation of enrollment, and modifying the study including additional 
enrollment beyond the six participants. In addition to the regular SMC meetings, ad hoc meetings 
will be held as needed. 
An IRC will perform a blinded determination as to whether the criteria for tumor response or 
progression according to RECIST 1.1 are met. The role of the IRC will be to review radiographic 
image findings and relevant clinical information (e.g., cytology or biopsy results) for the 
determination of the time point overall response according to RECIST 1.1 for each participant. 
The IRC membership, assessment criteria details, mandate, and processes of the IRC will be 
defined in the IRC Charter.
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Details of structures and associated procedures will be defined in a separate Study Reference 
Manual, which will be prepared under the supervision of the Clinical Study Leader.
Refer to the Study Organization and the Study Sites in Japan in supporting document.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
!
Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
!
Applicable ICH GCP Guidelines
!
The Japanese ministerial ordinance on GCP 
!
Applicable laws and regulations
The Investigator will submit the protocol, protocol amendments (if applicable), ICF, Investigator 
Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and the IRB/IEC 
will review and approve them before the study is initiated.
The Sponsor initiates the study at a site after obtaining written approval from the Head of the 
study site, based on favorable opinion/approval from the concerned IRB.
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:
!
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.
!
Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures
!
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 
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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 participant. 
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 (or designee) 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 (or 
designee) physician to assist with the medical emergency.
Clinical Study Insurance and Compensation to Participants
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the participants, except for AEs caused by an intentional and/or significant 
deviation on the part of the Investigator, the study site, and/or the participant. The Sponsor takes 
out insurance to fulfill the responsibility.
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
Clinical Study Report
After study completion, the Sponsor will write a clinical study report in consultation with any 
Steering Committee or other relevant study-appointed committees or groups.
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 
The first publication will include the results of the analysis of at least the primary endpoints and 
will include data from the study site. The Investigator will inform the Sponsor in advance about 
any plans to publish or present data from the study. Any publications and presentations of the 
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results (abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, 
by Investigators or their representatives will require review by the Sponsor before submission. 
The Sponsor will not suppress publication but maintains the right to delay publication to protect 
intellectual property rights.
Posting of data on the European Clinical Trial Database (EudraCT), www.ClinicalTrials.gov and 
jRCT is planned and will occur 12 months after the last visit, or scheduled procedure, or another 
appropriate date to meet applicable requirements.
Data Quality Assurance
All participant study data will be recorded on printed or eCRFs or transmitted to the Sponsor or 
designee electronically (e.g., laboratory data). The Investigator is responsible for verifying that 
data entries are complete, accurate, legible, and timely by physically or electronically signing 
the eCRF. Details for managing eCRFs are in the Study Reference Manual.
The Investigator will maintain accurate documentation (source data) that supports the 
information in the eCRF.
The Investigator will 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.
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan (within 
the Clinical Operations Plan).
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. Details will be outlined in Data 
Management documents and procedures.
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, the Japanese ministerial ordinance on GCP, and all applicable 
regulatory requirements.
The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study 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.
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
The Investigator will keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file will identify each participant, contain the following 
demographic and medical information for the participant, and will be as complete as possible:
!
Participant’s full name, date of birth, sex, height, and weight
!
Medical history and concomitant diseases
!
Prior and concomitant therapies (including changes during the study)
!
Study identifier (i.e., the Sponsor’s study number) and participant’s study number.
!
Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site
!
Any medical examinations and clinical findings predefined in the protocol
!
All AEs
!
Date that the participant left the study, including any reason for early withdrawal from the 
study or study intervention, if applicable.
All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document will have the participant number and the procedure date; ideally, printed 
by the instrument used for the procedure. As necessary, medical evaluation of these records will
be performed, documented, signed and dated by the Investigator.
Data recorded on printed or eCRFs that are transcribed from source documents will be consistent 
with the source documents or the discrepancies will be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records will be available.
The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will be signed and dated by the Investigator 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 or a record 
retainer designated by the Head of the study site 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 CRF guidelines.
Study and Site Start and Closure
First Act of Recruitment
!
The study start date is the date when the clinical study will be open for recruitment.
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!
The first act of recruitment is the date the first participant signs an ICF and will be the study 
start date.
Study Closure and Site Termination
!
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 
enough 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:
! 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
! Inadequate recruitment of participants by the Investigator
! Discontinuation of further development of the Sponsor’s compound
!
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator will promptly inform the 
participants and assure appropriate participant therapy and/or follow-up.
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Appendix 3
Contraception
Woman of Childbearing Potential (WOCBP):
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry.
3. A postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range.
!
A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
!
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation*
!
Intrauterine device 
!
Intrauterine hormone-releasing system 
!
Bilateral tubal occlusion
!
Vasectomized partner: a highly effective contraceptive method provided that the partner is 
the sole sexual partner of a WOCBP and the absence of sperm has been confirmed. 
Otherwise, use an additional highly effective method of contraception. The spermatogenesis 
cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent - Combined (estrogen- and 
progestogen-containing) hormonal contraception associated with inhibition of ovulation
o
Oral
o
Intravaginal*
o
Transdermal*
o
Injectable*
!
Progestogen-only hormone contraception associated with inhibition of ovulation
o
Oral
o
Injectable*
!
Sexual abstinence: a highly effective method only if defined as refraining from 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.
* Not approved in Japan
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of 
contraceptive methods for clinical study participants.
Highly effective methods are those with a failure rate of < 1% per year when used 
consistently and correctly. Typical use failure rates differ from those when used consistently 
and correctly.
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary 
mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable 
methods of contraception for this study. Male condom and female condom cannot be used 
together (due to risk of failure with friction).
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
AE Definition
!
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to the 
study intervention or not.
!
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention. For surgical or diagnostic procedures, the condition/illness leading 
to such a procedure is considered as the AE rather than the procedure itself.
Events Meeting the AE Definition
!
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease).
!
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.
!
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
!
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
!
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication.
!
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or a SAE. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or a SAE if they fulfill the definition of an AE or 
SAE.
Events NOT Meeting the AE Definition
!
Unless judged by the Investigator to be more severe than expected for the participant’s 
condition, any clinically significant abnormal laboratory findings, other abnormal safety 
assessments that are associated with the underlying disease, the disease/disorder being studied, 
or expected progression, signs, or symptoms of the disease/disorder being studied.
!
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
!
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
!
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
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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) will not be reported as AEs/SAEs, unless the participant’s general 
condition is more severe than expected for the his/her condition and/or unless the outcome is 
fatal within the AE reporting period, as defined in Section 8.3.1.
Other Adverse Events to be Reported Using a Specialized Procedure or Form
!
All pregnancies occurring during the study and their outcome will be documented on the 
Pregnancy report form and Parent-Child/Fetus Adverse Event Report form as outlined in 
Section 8.3.5.
!
Overdoses associated with an AE or a SAE are recorded in the eCRF and reported to global 
patient safety in an expedited manner. Overdoses not related to an AE/SAE (without signs 
or symptoms) are recorded in eCRF on treatment forms and are reported to Drug Safety using 
SAE paper form.
SAE Definition
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
!
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE will be considered serious.
!
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
!
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.
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d. Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
!
Medical or scientific judgment will be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events are usually considered as serious.
!
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Any suspected transmission of an infectious agent via a study intervention is also considered an 
SAE for reporting purposes, as specified below for reporting SAEs.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
!
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
!
The Investigator will then record all relevant AE/SAE information in the eCRF.
!
As needed, Sponsor/designee may ask for copies of certain medical records (e.g., autopsy 
reports, supplemental lab reports, documents on medical history/concomitant medications, 
discharge letters), as supporting source documentation. All participant identifiers, except the 
participant number, will be redacted on these copies before submission to the 
Sponsor/designee.
!
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
!
Specific guidance is in the eCRF Completion and Monitoring Conventions.
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Assessment of Intensity
The Investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories:
!
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities.
!
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
!
Severe: An event that prevents normal everyday activities. Do not confuse an AE that is 
assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; 
both AEs and SAEs can be assessed as severe.
!
An event is defined as “serious” when it meets at least 1 of the predefined criteria specified 
in the definition of an SAE, NOT when it is rated as severe.
Investigators will reference the National Cancer Institute - Common Terminology Criteria for 
AEs (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 will 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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Assessment of Causality
!
The Investigator will assess the relationship between study intervention and each AE/SAE 
occurrence:
!
Unrelated: Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention. A reasonable 
alternative explanation will be available.
!
Related: Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention.
!
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
!
The Investigator will use clinical judgment to determine the relationship.
!
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated.
!
The Investigator will also consult the Investigator Brochure and/or Product Information, for 
marketed products, in his/her assessment.
!
For each AE/SAE, the Investigator will document in the medical notes that he/she has 
reviewed the AE/SAE and assessed causality.
!
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or its designee. To meet the reporting 
timeline, the causality assessment is not required for the initial report.
!
The Investigator may change his/her causality assessment after considering follow-up 
information and send a SAE follow-up report with the updated causality assessment.
!
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
!
The Investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations, as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the AE or SAE, as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals.
!
New or updated information will be recorded in the originally completed eCRF.
!
The Investigator will submit any updated SAE data to Sponsor/designee within 24 hours of 
receipt of the information.
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Reporting of SAEs
SAE Reporting by an Electronic Data Collection Tool
!
The primary mechanism for reporting an SAE to the Sponsor or its designee will be the 
electronic data collection tool.
!
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool, specified below, to report the event within 24 hours.
!
The site will enter the SAE data into the electronic system as soon as it becomes available.
!
After the study is completed at a site, the electronic data collection tool will be taken off-line 
to prevent the entry of new data or changes to existing data.
!
If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form or to the Sponsor’s safety 
department.
!
By exception, an SAE (or follow-up information) may be reported by telephone. The site will 
complete the electronic SAE data entry immediately thereafter.
SAE Reporting by a Paper Form
!
SAE reporting on a paper report form is used as a back-up method for an EDC system failure. 
The form includes completion instructions for the Investigator, names, addresses, and 
telephone and fax numbers. All information from the paper form will be transcribed into the 
electronic form as soon as the system becomes available.
!
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee.
!
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the form sent by overnight mail or courier service.
!
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the form within 24 hours after becoming aware of the event.
!
Additional documents (e.g., laboratory reports, autopsy report, hospital discharge letter) and 
relevant pages from the eCRF may be required in addition (e.g., medical history, concomitant 
medication). The data provided will be consistent with the information in the eCRF.
Reporting of Adverse Events of Special Interest
Not applicable; no adverse events of special interest have been identified.
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Reporting of Pregnancies
!
Pregnancy will be reported whether related to the study intervention using the applicable 
paper form.
!
The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event.
!
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee.
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Appendix 5
Clinical Laboratory Tests
Clinical Laboratory assessments are provided in Table 17.
Table 17
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Mean corpuscular volume 
White Blood Cell 
Count with Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Mean corpuscular hemoglobin
Hemoglobin
Hematocrit
Coagulation
Prothrombin time/INR
Activated partial thromboplastin time 
Biochemistry
Blood urea 
nitrogen or 
urea (if blood 
urea nitrogen 
cannot be 
performed)
Potassium
Aspartate aminotransferase
Bilirubin (total and 
direct)
Creatinine
Sodium
Alanine aminotransferase
Total protein
Glucose
Calcium
Alkaline phosphatase
Albumin
Lipase
Amylase
Magnesium
Phosphate
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.
Other Tests
!
Serum and urine human chorionic gonadotropin pregnancy test (as needed for women 
of childbearing potential).
!
Safety laboratory assessments, e.g., hematology, chemistry, will be performed locally. 
 will be tested in specialized laboratories/contract research organizations (to 
be determined).
Serology
Hepatitis B virus (HBV) 
Screening:
!
HBV surface antigen (HBsAg)
!
Total hepatitis B core antibody (anti-HBc)
!
Hepatitis B surface antigen antibody (anti-HBsAg) 
!
HBV DNA: if HBsAg/anti-HBc or anti-HBc is positive
Required during Study Intervention Period if past HBV or current HBV infection:
!
HBsAg and HBV-DNA every 12 weeks
Hepatitis C virus (HCV) 
Screening:
!
anti-HCV
!
HCV RNA: if anti-HCV is positive
Required during Study Intervention Period if past HBV or current HBV infection:
!
HCV RNA every 12 weeks
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Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1
The text below was obtained from Eisenhauer 2009 and Schwartz 2016.
Definitions
Response and progression will be evaluated in this study using the international criteria proposed 
by the RECIST Committee (Version 1.1). Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
! 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm)
! 10 mm caliper measurement by clinical exam (when superficial)
! 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques 
are all non-measurable.
Bone lesions:
! Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.
! Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
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! Blastic bone lesions are non-measurable.
Cystic lesions:
! Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
! Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same participant, these are preferred for selection as target lesions.
Lesions with prior local treatment:
! Tumor lesions situated in a previously irradiated area, or in an area subjected to other local 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition 
may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, 
an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. 
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Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination.
No photographs, no skin lesion measurement by calipers and no measurements on chest X-ray 
will be done in this study.
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the 
original source article cited above, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in studies where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit; however, they must normalize for a 
participant to be considered in complete response. Because tumor markers are disease specific, 
instructions for their measurement should be incorporated into protocols on a disease specific 
basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
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prostate-specific antigen response (in recurrent prostate cancer), have been published. In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in 1st-line studies in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between partial response 
(PR) and CR in rare cases if required by protocol (e.g., residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are known 
to be a potential adverse event (AE) of treatment (e.g., with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable tumor has met 
criteria for response or stable disease (SD) in order to differentiate between response (or SD) and 
progressive disease (PD).
RESPONSE CRITERIA
Evaluation of Target Lesions
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.
Partial response: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm. Electronic Case report forms 
(eCRFs) or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as
being ‘too small to measure’. When this occurs it is important that a value be recorded on the 
eCRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
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measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned. (Note: It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal 
and are frequently surrounded by fat, such as in the retroperitoneum; however, if a lymph node 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible; therefore, providing this default 
value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’.
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
When the participant also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the participant has only non-measurable disease. This circumstance arises in some 
Phase III studies when it is not a criterion of study entry to have measurable disease. The same 
general concept applies here as noted above; however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable), a useful test that can be applied when assessing participants 
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for unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the participant 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (e.g., some ‘new’ bone 
lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the participant’s baseline lesions show partial or complete response. For example, necrosis 
of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate PD. An example of this is the participant 
who has visceral disease at baseline and while on study has a brain CT or MRI ordered which 
reveals metastases. The participant’s brain metastases are considered to be evidence of PD even 
if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, e.g., because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan.
While fludeoxyglucose positron emission tomography (FDG-PET) response assessments need 
additional studies, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). 
New lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm:
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
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at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
Evaluation of Best Overall Response
The best overall response (BOR) is the best response recorded from the start of the study 
intervention until the end of treatment taking into account any requirement for confirmation. On 
occasion, a response may not be documented until after the end of therapy, so protocols should 
be clear if post treatment assessments are to be considered in determination of BOR. Protocols 
must specify how any new therapy introduced before progression will affect best response 
designation. The participant’s BOR assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 
Furthermore, depending on the nature of the study and the protocol requirements, it may also 
require confirmatory measurement. Specifically, in non-randomized studies where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either 1 the ‘BOR’. 
The BOR is determined once all the data for the participant is known. Best response 
determination in studies where confirmation of complete or PR IS NOT required: Best response 
in these studies is defined as the best response across all time points (for example, a participant 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a BOR 
of PR). When SD is believed to be best response, it must also meet the protocol-specified 
minimum time from baseline. If the minimum time is not met when SD is otherwise the best 
time point response, the participant’s best response depends on the subsequent assessments. For 
example, a participant who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD. The same participant lost to follow-up after the 
first SD assessment would be considered inevaluable.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
CR
Non-CR/non-PD
Not Evaluated
No
No
PR
PR
PR
Non-PD or not all evaluated
No
PR
SD
Not all evaluated
Non-PD or not all evaluated
Non-PD
No
No
SD
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.
See text for more details.
Note:
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
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based on increase in size of the nodes. As noted earlier, this means that participants with CR may 
not have a total sum of ‘zero’ on the eCRF. 
In studies where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the study must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most studies, it is reasonable to consider a participant with time point responses of 
partial response-NE-partial response as a confirmed response.
Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as ‘symptomatic deterioration’. 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response; it is a reason 
for stopping study therapy. 
Conditions that define ‘early progression, early death, and inevaluability’ are study-specific and 
should be clearly described in each protocol (depending on treatment duration, and treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. The use of 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In non-randomized studies where response is the primary endpoint, confirmation of PR and CR 
is required to ensure the responses identified are not the result of measurement error. This will 
also permit appropriate interpretation of results in the context of historical data where response 
has traditionally required confirmation in such studies. However, in all other circumstances, i.e., 
in randomized studies (Phase II or III) or studies where SD or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the interpretation 
of the study results. However, elimination of the requirement for response confirmation may 
increase the importance of central review to protect against bias, in particular in studies which 
are not blinded.
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In the case of SD, measurements must have met the SD criteria at least once after study entry at 
a minimum interval (in general not less than 6 to 8 weeks) that is defined in the study protocol.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of participants achieving SD for a minimum period of time is an endpoint of 
importance in a particular study, the protocol should specify the minimal time interval required 
between 2 measurements for determination of SD.
Note: The duration of response and SD as well as the progression-free survival are influenced 
by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to 
define a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between studies are to be made.
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Appendix 8
Performance Scales
Eastern Cooperative Oncology Group Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, for example, light housework, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities; up and 
about > 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair > 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
Karnofsky Scale
Percent
Description
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self, unable to carry on normal activity or to do active work
60
Requires occasional assistance, but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled, requires special care and assistance
30
Severely disabled, hospitalization indicated. Death not imminent
20
Very sick, hospitalization indicated. Death not imminent
10
Moribund, fatal processes progressing rapidly
0
Dead
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Appendix 9
Protocol Amendment History
The information for the current amendment is on the title page.
Protocol Version 3.3-BEL (27 April 2021)
Overall Rationale for the Amendment
The high-level rationale for the changes implemented in this country-specific amendment in 
Belgium are as follows:
!
Based on in vitro data and static modeling predictions, the drug-drug interaction (DDI)
potential of berzosertib was updated by removing “sensitive P-gp substrates” and adding 
“OATP1B3 substrates”. In addition, the instructions for concomitant use of breast cancer 
resistance protein (BCRP) and organic anion transporting polypeptides (OATP) 1B3 
substrates with berzosertib are provided.
!
The removal of sensitive P-gp substrates is also to align with the berzosertib Investigator’s 
Brochure Version 10.
Section # and 
Name
Description of Change
Brief Rationale
2.3.1 Risk 
Assessment; 
Table 3
The summary of data/rationale for risk 
and mitigation strategy for drug-drug 
interactions was updated to include 
additional information CYP3A4 inhibitors 
and BCRP and OATP1B3 substrates.
To clarify the potential risks associated with 
concomitant administration of berzosertib with 
BCRP and OATP1B3 substrates and 
recommended precautions.
6.5.3 Prohibited 
Medicines and 
Precautions, 
Table 7
Text and table were updated to include 
additional information for the 
administration of berzosertib with BCRP 
and OATP1B3 substrates. Sensitive 
P-gp substrates was removed.
To clarify the recommended precautions of
concomitant administration of berzosertib with 
BCRP and OATP1B3 substrates.
To align with berzosertib Investigator’s Brochure, 
Version 10.
Throughout
Minor clerical and document formatting 
revisions.
Minor; therefore, have not been summarized.
Protocol Version 3.2-USA (27 April 2021)
Overall Rationale for the Amendment
The high-level rationale for the changes implemented in this amendment are to include:
!
Implementation of verification of locally assessed disease progression by an Independent 
Review Committee (IRC) to secure an accurate progressive disease (PD) assessment.
Investigators will be requested to continue imaging until PD is verified by IRC in order to 
potentially reduce the number of censored observations for duration of response 
(DoR)/progression-free survival (PFS) according to IRC.
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Section # and 
Name
Description of Change
Brief Rationale
1.3 Schedule of 
Assessments, 
Revised Imaging Disease Assessment text 
to read: “…until disease progression as 
assessed by the IRC.”
Added the following note:
“Locally assessed PD must be verified by the 
IRC (see Section 8.1.1).”
To implement IRC verification of 
Investigator-assessed PD.
7.1
Discontinuation 
of Study 
Intervention
Second bullet is revised to read:
!
“Upon documentation of disease 
progression per RECIST 1.1 as 
determined by the Investigator and 
verified by the IRC, as outlined in 
Section 8.1.1.”
To implement IRC verification of 
Investigator-assessed PD.
8.1.1 Tumor 
Response
Text has been added to specify the tumor 
assessment requirements in the event of 
disease progression. 
To implement IRC verification of 
Investigator-assessed PD.
Throughout
Minor editorial and document formatting 
revisions.
Minor; therefore, have not been summarized
Protocol Version 3.1-JPN (25 March 2021) 
Overall Rationale for the Amendment 
The high-level rationale for the changes implemented in this amendment are to further ensure 
participant's safety.
Section # and Name
Description of Change
Brief Rationale
5.1 Inclusion Criteria Age
Added a description that participant's written consent 
will be obtained when participants reaches 20 years 
of age.
In Japan, ≥ 20 years of 
age is legally 
considered adult.
5.1 Inclusion Criteria
Female participants
Added a description that the participant is not eligible 
even if breastfeeding is suspended.
To clarify the eligibility 
for breastfeeding 
women.
6.1 Study Interventions 
Administration
Added a description that all participants, in principle, 
should undergo inpatient observation during Cycle 1 
until at least Day 5 of study intervention in the Safety 
Run-in Part in Japan.
In accordance with a 
Japanese local 
guideline, "Revision of 
'Guidelines for Clinical 
Evaluation of Anticancer 
Drugs' " (PFSB/ELD 
Notification No. 
1101001).
6.5.3 Prohibited Medicines
Table 7
5.3.1 Meals and Dietary 
Restrictions
Added a description that consumption of 
grapefruit/grapefruit juice, Seville or blood oranges is 
prohibited.
To show examples of 
prohibited food.
6.6.1 Study Intervention Dose 
Modifications
Added a description on dose interruption and 
discontinuation of berzosertib (Section 6.6.1.1) and 
topotecan (Section 6.6.1.2) when interstitial lung 
disease (ILD) is suspected and confirmed.
For participant's safety.
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7.1 Discontinuation of Study 
Intervention
Added confirmed ILD to the criteria for 
discontinuation of study intervention.
For participant's safety.
8.3.5 Pregnancy
The period of reporting pregnancy is set to 6 months 
after the last study intervention administration.
To align with the 
required period for 
contraception after the 
last study intervention 
administration.
PFSB = Pharmaceutical and Food Safety Bureau; ELD = Evaluation and Licensing Division.
Protocol Version 3.0 (23 December 2020)
Overall Rationale for the Amendment
The high-level rationale for the changes implemented in this amendment are to include:
!
The Safety Run-in Part in Japan
!
Assessments of patient-reported outcomes (PROs)
!
An additional exclusion criterion for QTc, modification on the exclusion criterion regarding 
New York Heart Association Classification and the wash-out period for previous anticancer 
antibody or antibody drug conjugates 
!
Additional minor Sponsor modifications. 
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Section # and Name
Description of Change
Brief Rationale
1.2 Schema
Table 1 Schedule of Activities
2.1 Study Rationale
3 Objectives and Estimands
4.1.1 Safety Run-in Part 
(Japan-only)
4.2 Scientific Rationale for 
Study Design
4.3.2 Safety Run-in Part 
(Japan-only)
5.1 Inclusion Criteria
6.1 Study Interventions 
Administration
6.3.1 Study Intervention 
Assignment
6.6.1.1 Berzosertib Dose 
Modifications
6.8 Definition of Dose-limiting 
Toxicity (Safety Run-in Part 
Only)
 
9.3 Populations for Analyses
9.4.2 Safety Analyses
9.4.3 Other Analyses
9.4.4 Sequence of Analyses
The following were added regarding the Safety Run-in 
Part in Japan:
Figure 2 to show the schematic structure.
In Table 1, berzosertib dosing for Dose Level (DL) 1 
and DL2 and description that external confirmation of 
measurable disease and PROs are not applicable for 
DL1. 
In Section 2.1, rationale.
In Section 3, objectives and estimands.
In Sections 4.1.1, 4.2 and 4.3.2, study design, 
rationale and dose justification.
In Section 5.1, an inclusion criterion.
In Sections 6.1, 6.3.1 and 6.6.1.1, specified the dose 
and dose modification of berzosertib.
Section 6.8, definition of dose limiting toxicity (DLT).
In Section 8.8, tumor biopsy is optional for 
participants in DL1.
In Section 9.3, definitions of analysis sets.
In Section 9.4.2, an endpoint for DLT in Table 15.
In Section 9.4.3, other analyses.
In Section 9.4.4, sequence of analyses.
To implement Safety 
Run-in Part in Japan to 
join the Main Part of 
global Phase II study.
1.1 Synopsis
Added “To assess health-related quality of life 
(HRQoL) based on patient-reported outcomes (PROs) 
when treated with berzosertib + topotecan” as a 
secondary objective with its estimand attributes.
To collect information 
regarding participants’ 
perspective of their 
functioning and 
symptoms.
1.3 Schedule of Activities
Added the PRO assessments with necessary notes to 
the schedule of activities.
To specify the PRO 
assessment schedule. 
3 Objectives and Estimands
Added “To assess health-related quality of life 
(HRQoL) based on PROs when treated with 
berzosertib + topotecan” as a secondary objective as 
well as an 
 objective with its 
estimand attributes.
Additionally, the underlined phrase was added to the 
following sentence: “
 
 
f CYPs/transporters, in plasma, may be 
conducted”.
To add PRO 
assessment objectives.
 
 
 
 
 
4.2 Scientific Rationale for 
Study Design
Specific rationale for PRO assessments is provided.
For clarification of 
rationale.
5.2 Exclusion Criteria
Added exclusion criterion for the upper limit of QTc 
interval, modified the exclusion criterion regarding 
New York Heart Association Classification
To ensure participant 
safety and clarify.
8.1.1 Tumor Response
Inserted a new subheading ‘Tumor Response’.
To assist with the 
structure of the 
document. 
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Section # and Name
Description of Change
Brief Rationale
8.1.2 Patient-Reported 
Outcomes
Inserted a new subheading ‘Patient-Reported 
Outcomes’ with the required information regarding the 
assessment.
PROs complement 
objective clinical 
endpoints such as tumor 
response, duration of 
response and 
progression-free 
survival.
9.4.1 Efficacy Analyses
Added the PROs endpoint in Table 13 with its 
statistical analysis methods/further estimand 
attributes.
To add statistical 
considerations for PRO 
endpoint analysis.
Throughout
Applied country-specific adaptation to comply with 
regulatory requirements in Japan.
To conduct the study in 
Japan.
Throughout
Minor editorial and document formatting revisions
Minor; therefore, have 
not been summarized.
Protocol Version 2.0 (20 November 2020)
Overall Rationale for the Amendment
The high-level rationale for the changes implemented in this amendment are to update the 
eligibility criteria and to provide clarification on study intervention aspects (premedication, 
G-CSF use, and treatment interruption/resumption).
Section # and 
Name
Description of Change
Brief Rationale
5.2 Exclusion 
Criteria
Added exclusion for participants with known 
history of Li-Fraumeni Syndrome and Ataxia 
Telangiectasia.
To eliminate the potential risk for 
increased toxicity in participants with 
such history.
Table 1 Schedule of 
Activities
6.1 Study 
Interventions 
Administration
6.6.1.1 Berzosertib 
Dose Modifications
6.6.1.2 Topotecan 
Dose Modifications
Hematologic criteria for neutrophils, platelets, and 
hemoglobin for subsequent dosing of berzosertib 
and topotecan were added.
In Sections 6.6.1.1 and 6.6.1.2 only, revised 
sentence from:
“In addition, in case of Grade 3 or higher toxicity 
during any cycle, treatment may be interrupted 
and may be resumed when all toxicities have 
returned to Grade ≤ 2, at the discretion of the 
Investigator” 
To:
“In addition, in case of non-hematologic Grade 3 
or higher toxicity during any cycle, treatment 
should be interrupted and may be resumed when 
all toxicities have returned to Grade ≤ 2; 
resumption may be at the discretion of the 
Investigator”.
To provide additional instructions for 
guidance prior to dosing, treatment 
interruption and resumption.
5.3.3 Activity
Added statement regarding berzosertib phototoxic 
potential with cautionary instructions of protective 
measures.
For clarification.
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Section # and 
Name
Description of Change
Brief Rationale
6.1 Study 
Interventions 
Administration
Added the following:
-
A specific statement regarding 
prophylactic premedication of 
corticosteroids and antihistamines 
-
Specific recommendations regarding the 
use of G-CSF as primary prophylaxis
To provide more specific guidance 
about premedication and G-CSF 
administration
6.5.4 Other 
Interventions
Added a requirement of a ≥14-day wash-out 
period in case whole brain radiation therapy was 
administered.
For clarification, given the potential for 
increased neurotoxicity.
Throughout
Minor document formatting revisions
Minor; therefore, have not been 
summarized
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Appendix 10
Sponsor Signature Page
Study Title:
A Phase II, open-label, single-arm study of berzosertib 
(M6620) in combination with topotecan in participants 
with relapsed platinum-resistant small-cell lung cancer
Regulatory Agency Identifying 
Numbers:
IND: 
EudraCT: 2020-004231-25
Clinical Study Protocol Version:
21 June 2021/Version 4.0
I approve the design of the clinical study:
____________
_____________
____________________________
Signature
Date of Signature
Name, academic degree:
, MD
Function/Title:
Institution:
Address:
Telephone number:
E-mail address:
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Appendix 12
Principal Investigator Signature Page
Study Title:
A Phase II, open-label, single-arm study of berzosertib 
(M6620) in combination with topotecan in participants 
with relapsed platinum-resistant small-cell lung cancer
Regulatory Agency Identifying 
Numbers:
IND: 
EudraCT: 2020-004231-25
Clinical Study Protocol Version:
21 June 2021/Version 4.0
Site Number:
I, the undersigned approve the design of the clinical study, 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 on 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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