Phase I Study to Evaluate the Mass Balance, PK, Metabolism and Excretion of Berzosertib (Intravenous) Containing Microtracer [14C]Berzosertib in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 208)
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
Phase I study to evaluate the mass balance, 
pharmacokinetics (PK), metabolism and excretion 
of berzosertib (intravenous) containing microtracer 
[14C]berzosertib in participants with advanced solid 
tumors
Study Number:
MS201923_0008
Protocol Version:
15 June 2021/Version 1.0
Merck Compound:
Berzosertib
Merck Registered Compound Name in 
Japan:
Not Applicable
Study Phase:
Phase I
Short Title:
Berzosertib Human Mass Balance Study
Acronym:
DDRiver Solid Tumors 208
Principal Investigator:
, MD, PhD
 
 
 
 
 
 
 
 
 
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
64293, Darmstadt, Germany
Regulatory Agency Identifying 
Number:
EudraCT: 2021-002226-24
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Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
I N F O R M A T I O N
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Keywords
Unique terms not already on the Title Page:
!
Topotecan
!
Ataxia telangiectasia mutated and Rad3-related 
(ATR) protein
!
ATR inhibitor 
!
M6620
- 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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Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................3
1
Protocol Summary ................................................................................7
1.1
Synopsis................................................................................................7
1.2
Schema..................................................................................................9
1.3
Schedule of Activities...........................................................................9
2
Introduction.........................................................................................18
2.1
Study Rationale...................................................................................18
2.2
Background.........................................................................................19
2.3
Benefit/Risk Assessment ....................................................................20
2.3.1
Risk Assessment.................................................................................21
2.3.2
Benefit Assessment.............................................................................24
2.3.3
Overall Benefit: Risk Conclusion.......................................................24
3
Objectives and Estimands...................................................................24
4
Study Design.......................................................................................26
4.1
Overall Design....................................................................................26
4.1.1
Period 1: Berzosertib Mass Balance Study.........................................27
4.1.1.1
Period 1: Clinical Research Unit Discharge Criteria..........................27
4.1.2
Period 2: Extension with Berzosertib in Combination with 
Topotecan ...........................................................................................28
4.2
Scientific Rationale for Study Design ................................................28
4.3
Justification for Dose..........................................................................28
4.4
End of Study Definition......................................................................29
5
Study Population.................................................................................29
5.1
Inclusion Criteria ................................................................................30
5.2
Exclusion Criteria...............................................................................32
5.3
Lifestyle Considerations .....................................................................36
5.3.1
Meals and Dietary Restrictions...........................................................36
5.3.2
Caffeine, Alcohol, Tobacco, and Cannabinoid...................................36
5.3.3
Activity ...............................................................................................36
5.4
Screen Failures....................................................................................37
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5.5
Criteria for Temporarily Delaying the Administration of Study 
Intervention.........................................................................................37
6
Study Intervention(s) and Concomitant Therapies.............................37
6.1
Study Intervention(s) Administration.................................................37
6.1.1
Period 1: Study Intervention Administration......................................38
6.1.2
Period 2: Study Intervention Administration......................................38
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................39
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................40
6.3.1
Study Intervention Assignment ..........................................................40
6.3.2
Blinding ..............................................................................................41
6.4
Study Intervention Compliance..........................................................41
6.5
Dose Modification ..............................................................................41
6.5.1
Berzosertib Dose Modifications (Period 2 Only) ...............................41
6.5.2
Topotecan Dose Modifications...........................................................42
6.6
Continued Access to Study Intervention after the End of the Study..44
6.7
Treatment of Overdose .......................................................................44
6.8
Concomitant Therapy .........................................................................44
6.8.1
Rescue Medicine.................................................................................44
6.8.2
Permitted Medicines...........................................................................44
6.8.3
Prohibited Medicines..........................................................................44
6.8.4
Other Interventions.............................................................................46
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................46
7.1
Discontinuation of Study Intervention................................................46
7.2
Participant Discontinuation/Withdrawal from the Study ...................47
7.3
Lost to Follow-Up...............................................................................47
8
Study Assessments and Procedures....................................................48
8.1
Efficacy Assessments and Procedures................................................48
8.2
Safety Assessments and Procedures ...................................................49
8.2.1
Physical Examinations........................................................................49
8.2.2
Vital Signs ..........................................................................................49
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8.2.3
Electrocardiograms.............................................................................49
8.2.4
Clinical Safety Laboratory Assessments ............................................50
8.3
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ............................................................................................50
8.3.1
Method of Detecting Adverse Events and Serious Adverse Events...51
8.3.2
Follow-up of Adverse Events and Serious Adverse Events ...............51
8.3.3
Regulatory Reporting Requirements for Serious Adverse Events .....51
8.3.4
Pregnancy ...........................................................................................52
8.3.5
Cardiovascular and Death Events.......................................................52
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................53
8.3.7
Adverse Events of Special Interest.....................................................53
8.4
Pharmacokinetics................................................................................53
..55
56
8.7
Immunogenicity Assessments ............................................................56
8.8
Medical Resource Utilization and Health Economics........................56
9
Statistical Considerations....................................................................56
9.1
Statistical Hypotheses.........................................................................56
9.2
Sample Size Determination ................................................................56
9.3
Analyses Sets......................................................................................57
9.4
Statistical Analyses.............................................................................57
9.4.1
Efficacy Analyses ...............................................................................57
9.4.2
Safety Analyses ..................................................................................58
9.4.3
Other Analyses....................................................................................59
9.4.4
Sequence of Analyses.........................................................................60
10
References...........................................................................................61
11
Appendices .........................................................................................62
Appendix 1
Abbreviations......................................................................................63
Appendix 2
Study Governance...............................................................................66
Appendix 3
Contraception and Barrier Requirements ...........................................71
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................73
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Human Mass Balance Study
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Appendix 5
Eastern Cooperative Oncology Group Performance Status................80
Appendix 6
Clinical Laboratory Tests ...................................................................81
82
Appendix 8
Protocol Amendment History.............................................................83
Appendix 9
Sponsor Signature Page......................................................................84
Appendix 10
Principal Investigator Signature Page.................................................85
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Human Mass Balance Study
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1
Protocol Summary
1.1
Synopsis
Protocol Title: Phase I study to evaluate the mass balance, pharmacokinetics (PK), metabolism 
and excretion of berzosertib (intravenous) containing microtracer [14C]berzosertib in participants 
with advanced solid tumors
Short Title: Berzosertib Human Mass Balance Study
Rationale: The mass balance study will determine drug-related entities present in circulation and 
provide a comprehensive understanding of biotransformation pathways and clearance mechanisms 
in humans. The mass balance study may identify potential contributors to interparticipant 
variability. In this respect, the performance of a mass balance study is recommended by guidance 
documents such as the European Medicines Agency (EMA) drug interaction guideline on the 
investigation of drug interactions, the International Council for Harmonisation (ICH) M3 and the 
Food and Drug Administration (FDA) Metabolites in Safety Testing (MIST) guidance.
Objectives and Estimands:
Objectives
Estimand Attributes
Primary
To determine the rates and routes of 
excretion and mass balance of 
berzosertib following single 
intravenous administration of 
210 mg/m2 of [14C]berzosertib to 
participants with advanced solid 
tumors (Period 1).
Endpoint: Percent urinary recovery (feurine), percent fecal recovery 
(fefeces), percent total recovery in urine and feces (fetotal) of total 
radioactivity over the entire period of collection.
Population: Participants with advanced solid tumors.
Treatment: Single dose berzosertib.
To characterize the PK of berzosertib 
in plasma and urine; and of 
drug-related material (total 
radioactivity) in plasma and whole 
blood (Period 1).
Endpoint: PK parameters: Cmax, AUC0-tlast, AUC0-∀#t1/2, CL, Vz, and Vss
of berzosertib and Cmax, AUC0-tlast, AUC0-∀# t1/2 of total radioactivity in 
plasma; PK parameters (Cmax, AUC0-tlast, AUC0-∀# t1/2) of total 
radioactivity in blood.
PK parameters of berzosertib in urine: cumulative amount excreted in 
urine (Ae and feurine (%)), renal clearance (CLR).
Population: Participants with advanced solid tumors.
Treatment: Single dose berzosertib.
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Human Mass Balance Study
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Objectives
Estimand Attributes
Secondary
To evaluate the safety and tolerability 
of berzosertib (Period 1) and 
berzosertib + topotecan (Period 2).
Endpoint: Occurrence of treatment-emergent adverse events (TEAEs)
and treatment-related adverse events (AEs) and occurrence of clinically 
significant changes in vital signs, laboratory parameters and 12-lead
electrocardiogram (ECG) findings.
Population: Participants with advanced solid tumors.
Treatment: Single dose berzosertib and berzosertib in combination with 
topotecan.
Overall Design: This is a single group, sequential period, unblinded study with treatment of 
berzosertib single dose (Period 1 Mass Balance), followed by berzosertib in combination with 
topotecan (Period 2 Extension) in participants with advanced solid tumors.
Brief Summary:
The purpose of Period 1 of this study is to provide a definitive quantitative characterization of 
the mass balance, rates and routes of elimination, and metabolic pathways after a single 
intravenous administration of [14C]berzosertib. The purpose of Period 2 is to assess safety and 
efficacy of berzosertib in combination with topotecan.
Number of Participants: A total of approximately 6 participants (or more) will be treated with 
study intervention such that approximately 4 to 6 PK evaluable participants are anticipated to be 
obtained. If the initial group of 6 leads to fewer than 4 evaluable participants, the cohort will be 
increased up to a maximum of 12 participants, until 4 participants have completed all study 
procedures for Period 1 and are evaluable.
Study Intervention Groups and Duration: Period 1 represents the period for assessment of the 
mass balance, PK, metabolism, and elimination of berzosertib. During Period 1, admission to the 
CRU is required until the discharge criteria are met, with a maximum confinement period of 
15 days (Day -1 plus 14 days).
After completing Period 1, within 7 days of discharge from the clinical research unit (CRU), if no 
study withdrawal criteria are met, participants may enter Period 2 Extension of the study and will 
continue with 21-day cycles of berzosertib in combination with topotecan until disease progression 
or other criteria for study intervention discontinuation are met, an End-of-Treatment Visit, and a 
Safety Follow-up Period of 30 days (± 7 days) after last study intervention dose. Berzosertib will 
be administered at a dose of 210 mg/m2 intravenous (IV) on Day 2 and Day 5 and topotecan by IV 
administration at a dose of 1.25 mg/m2 on Days 1 through 5 of each 21-day cycle.
Involvement of Special Committee(s): No
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Human Mass Balance Study
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1.2
Schema
The study will consist of 2 periods (1 and 2; see Figure 1):
!
Period 1: Mass balance inpatient period, with single dose [14C]berzosertib in 4 to 6 PK 
evaluable participants with advanced solid tumors
!
Period 2: Extension period. After completion of Period 1, participants from Period 1 will 
continue with berzosertib in combination with topotecan.
Figure 1
Schema
Note: for details, see the Section 1.3, Section 4.1, Section 4.1.1.1, and Sections 6.1.1 and 6.1.2.
1.3
Schedule of Activities
The schedule of activities (SoA) for Period 1 for the mass balance study is presented in Table 1. 
The Period 1 schedule of blood and plasma samples is provided in Table 2. The Period 1 schedule 
of urine and fecal samples is provided in Table 3. 
The SoA for Period 2 for the berzosertib and topotecan combination is presented in Table 4. 
8  to 14
Confinement
1
2
4
5
6
7
-28 to -2
-1
Check-in
Screening
[14C]Berzosertib
PERIOD 1
Mass Balance/Pharmacokinetics
PERIOD 2
3
Discharge
Berzosertib (210 mg/m2, D2, D5)
+ Topotecan (1.25 mg/m2, D1-D5) every 21 days 
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Human Mass Balance Study
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Table 1
Period 1 Schedule of Activities: Mass Balance Study
Activity
Screening
Period 1
Notes
D-28 to -2
D-1 
D1 
Predose
D1 D2 D3 D4 D5
D6
D7
Discharge 
D8 to D14
Safety Follow-up 
(only if not 
continuing to 
Period 2; 30 days 
after single dose)
Informed 
Consent
X
Confinement 
to CRU
X
X
X
X
X
X
X
X
X
X
Note: D8 to D14 assessments are 
obtained once, prior to discharge from 
the CRU
-Discharge occurs once criteria are met 
(see details in Section 4.1.1.1)
-Maximum stay up to 15 days (D-1 plus 
14 days)
Inclusion and 
Exclusion 
Criteria; 
Medical 
History
X
X
-Should be checked during Screening 
and either at D-1 or D1 Predose
-Medical history includes collection of 
prior therapy
Demographics
X
Physical 
Examination
X
X
X
X
Symptom-directed physical 
examinations performed as clinically 
indicated per Investigator’s judgment.
Height
X
Weight
X
X
X
X
X
Obtain weight either at D-1 or D1 
Predose.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Obtain vital signs either at D-1 or D1 
Predose.
Standard 
12-lead ECG
X
X
X
X
X
Obtain ECG either at D-1 or D1 
Predose
Urine Cotinine
X
X
At Screening and D-1
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Activity
Screening
Period 1
Notes
D-28 to -2
D-1 
D1 
Predose
D1 D2 D3 D4 D5
D6
D7
Discharge 
D8 to D14
Safety Follow-up 
(only if not 
continuing to 
Period 2; 30 days 
after single dose)
Covid 19 PCR 
Testing
X
If test is positive, discussion with 
Medical Monitor is required.
Hematology
X
X
X
X
Serum 
Chemistry
X
X
X
X
Coagulation
X
X
X
Plasma for 
Radioactivity
X
Screening for 14C levels by AMS
FSH and 
Estradiol
X
Serum test at Screening, as needed if 
not a WOCBP only
β-HCG, 
Serum/Urine 
(WOCBP only)
X
X
X
Serum test at Screening and D8 to 
D14, urine test on D-1
Imaging 
Disease 
Assessment
X
ECOG PS
X
X
X
X
Single Dose 
14C-
berzosertib IV 
X
Dose: berzosertib 210 mg/m2 IV 
solution containing ~3 μCi of 
[14C]berzosertib over 60 minutes
Oral Laxative 
Administration
X
If not medically contra-indicated, oral 
laxative(s) of osmotic properties with 
short onset of action, such as 
magnesium hydroxide and lactulose 
may be administered to ensure fecal 
output is complete for mass balance 
assessment
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Human Mass Balance Study
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Activity
Screening
Period 1
Notes
D-28 to -2
D-1 
D1 
Predose
D1 D2 D3 D4 D5
D6
D7
Discharge 
D8 to D14
Safety Follow-up 
(only if not 
continuing to 
Period 2; 30 days 
after single dose)
Concomitant 
Medications, 
Therapies and 
Procedures
X
X
AEs and SAEs
Blood Sample 
Collection 
See Table 2, Period 1 for Blood Sampling Collection 
Schedule
 
Urine Sample 
Collection 
See Table 3, Period 1 for Urine Collection Sample Schedule
For TR, berzosertib PK and metabolite 
profiling
Fecal Sample 
Collection 
See Table 3 Period 1 for Fecal Collection Sample Schedule
For TR and metabolite profiling
Vomitus
X
Collect vomitus if event occurs any 
time after dosing on Day 1 and/or 
Day 2
AE = adverse event; AMS = accelerator mass spectrometry; β-HCG = β-human chorionic gonadotropin; CRU = Clinical Research Unit; D = Day(s); 
ECG = electrocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; FSH = follicle-stimulating hormone; IV = intravenous; PCR = 
polymerase chain reaction; PK = pharmacokinetic; SAEs = serious adverse events; TR = total radioactivity; WOCBP = woman of childbearing potential.
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Table 2
Period 1 Blood and Plasma Samples
Timepoint (min / hour)
Blood 
Samplesa
Plasma 
Samplesb
Plasma 
Samples for 
Metabolite 
Profiling
Plasma 
Samples for 
ex vivo 
Plasma 
Protein 
Binding
D1 Predose (60 min before BOI) 
X
X
X
0.5 hours post BOI (∃5 min)
X
X
EOIc (% 5 min before EOI to & 1 min after EOI) 
X
X
X
X
0.5 hours post EOId (∃5 min)
X
X
1 hours post EOId (∃15 min)d
X
X
X
2 hours post EOId(∃15 min)d
X
X
3 hours post EOId (∃30 min)d
X
X
4 hours post EOId (∃45 min)d
X
X
X
8 hours post EOId (∃1 hour)d
X
X
X
12 hours post EOId (∃1 hour)d
X
X
X
X
24 hours after BOI (∃1 hour)e
X
X
X
X
48 hours after BOI (∃2 hours)e
X
X
X
72 hours after BOI (∃3 hours)e
X
X
X
X
96 hours after BOI (∃4 hours)e
X
X
X
120 hours after BOI (∃4 hours)e
X
X
X
144 hours after BOI  (∃4 hours)e
X
X
168 hours after BOI  (∃4 hours)e,f
X
X
X
BOI = beginning of infusion; EOI = end of infusion; IV = intravenous; PK = pharmacokinetics; TR = total radioactivity.
a
For determination of TR.
b
For determination of TR and berzosertib PK.
c
The window for collection of the EOI time point is between 5 minutes before completion of infusion to 1 minute 
after completion of infusion. In the event that the IV infusion is interrupted, 2 additional PK samples (1 sample 
drawn when the infusion is stopped, and 1 sample drawn when the infusion is restarted) should be collected so 
that the participant may be considered evaluable.
d
      Samples are to be collected after completion of berzosertib IV infusion on Day 1.
e
      Samples are to be collected after beginning of berzosertib IV infusion on Day 1.
f
Samples will continue to be collected in 24-hour intervals until discharge criteria are met, for metabolite profiling 
samples in 48-hour intervals.
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Human Mass Balance Study
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Table 3
Period 1 Urine and Fecal Samples
Time Interval (hour)
Urine Collectiona
Feces Collectionb
Predose (-24 to 0 hours) (before BOI)
X
X
0 (BOI)-4 hours post EOIc
X
X (0-24 hours after BOI)
4-12 hours post EOI 
X
12 post EOI-24 hours after BOI
X
24-48 hours after BOI
X
X
48-72 hours after BOI
X
X
72-96 hours after BOI
X
X
96-120 hours after BOI
X
X
120-144 hours after BOI
X
X
144-168 hoursd after BOI
X
X
BOI = beginning of infusion; EOI = end of infusion; PK = pharmacokinetics; TR = total radioactivity
a
For determination of TR, berzosertib PK, and metabolite profiling
b
For determination of TR and metabolite profiling.
c
Collection of urine should start from BOI and until 4 hours post EOI for this collection interval. 
d
Samples will continue to be collected in 24-hour intervals until discharge criteria are met.
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Human Mass Balance Study
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Table 4
Period 2 Schedule of Activities: Treatment, End of Treatment, and Follow-up Period
Assessments and 
Procedures
Cycle Duration = 21 Days
EOT
(within 7 days
after last 
dose)
Follow-up
30 days after 
last dose 
(± 7 days)
Notes
D1 
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
C1D1 up to 7 days after 
discharge in Period 1
Cycle start may be 
delayed up to 7 days to 
accommodate scheduling 
conflicts
Review Inclusion 
and Exclusion 
Criteria; Medical 
History
X
Physical 
Examination
X
X
X
Weight
X
X
X
Vital Signs
X
X
X
X
X
X
X
Predose on all visits
Standard 12-lead 
ECG
X
X
Hematology
X
X
X
X
X
Recommended at D8 and 
D15 at Cycle 1 only, 
optional at subsequent 
cycles.
Baseline neutrophils 
should be ≥ 1,500/μL and 
platelets ≥100,000/μL
prior to C1; for 
subsequent cycles, 
neutrophils should be 
> 1,000/μL, 
platelets > 100,000/μL, 
and hemoglobin ≥ 9 g/dL
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Human Mass Balance Study
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Assessments and 
Procedures
Cycle Duration = 21 Days
EOT
(within 7 days
after last 
dose)
Follow-up
30 days after 
last dose 
(± 7 days)
Notes
D1 
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
C1D1 up to 7 days after 
discharge in Period 1
Cycle start may be 
delayed up to 7 days to 
accommodate scheduling 
conflicts
Serum Chemistry
X
X
X
Coagulation
X
X
β-HCG, Urine 
(WOCBP only)
X
X
X
Imaging Disease 
Assessment
At the end of every 6 weeks (± 1 week) after first dose (C1D1) until Week 24, then every 9 weeks 
(± 2 weeks) until disease progression, start of new anticancer therapy, death, withdrawal of consent, lost to 
follow-up, or End-of-Study, whichever comes first, regardless of study intervention 
modifications/discontinuation
ECOG PS
X
X
X
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Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
I N F O R M A T I O N
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Assessments and 
Procedures
Cycle Duration = 21 Days
EOT
(within 7 days
after last 
dose)
Follow-up
30 days after 
last dose 
(± 7 days)
Notes
D1 
(± 3)
D2
D3
D4
D5
D8
(± 3)
D15
(± 3)
C1D1 up to 7 days after 
discharge in Period 1
Cycle start may be 
delayed up to 7 days to 
accommodate scheduling 
conflicts
Concomitant 
Medications and 
Procedures
X
AEs and SAEs
Berzosertib
X
X
Dosing: 210 mg/m2 IV on 
D2 and D5 every 21 days
Topotecan
X
X
X
X
X
Dosing: 1.25 mg/m2 IV on 
Days 1 through 5 every 
21 days
AEs = adverse events; β-HCG = β-human chorionic gonadotropin; C = Cycle; D = Day(s); ECG = electrocardiogram; ECOG PS= Eastern Cooperative Oncology 
Group Performance Status; EOT = end of treatment; IV = intravenous; SAEs = serious adverse events; WOCBP = woman of childbearing potential.
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Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
I N F O R M A T I O N
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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
Mass balance study in humans is part of a standard clinical development program and its results 
will be included in the submission package for the marketing authorization applications. The 
mass balance study will determine drug-related entities present in circulation and provide a 
comprehensive understanding of biotransformation pathways and clearance mechanisms in 
humans. The mass balance study may identify potential contributors to inter-participant 
variability. In this respect, the performance of a mass balance study is recommended by guidance 
documents such as the European Medicines Agency (EMA) drug interaction guideline on the 
investigation of drug interactions, the International Council for Harmonization (ICH) M3 and 
the Food and Drug Administration (FDA) Metabolites in Safety Testing (MIST) guidance.
The berzosertib human mass balance study will consist of 2 periods (Periods 1 and 2). Period 1 
will evaluate mass balance and metabolism after a single intravenous administration of 
[14C]berzosertib. Period 2 consists of an extension of the study where participants will receive 
berzosertib in combination with topotecan until disease progression or other criteria for study 
intervention discontinuation are met.  
The purpose of Period 1 of this study is to provide a definitive quantitative characterization of 
the mass balance, rates and routes of elimination, and metabolic pathways after a single 
intravenous administration of [14C]berzosertib. Such definitive characterization will help guide 
understanding of the potential for patient-specific (e.g., renal function, hepatic function) or 
extrinsic (e.g., concomitant medications with potential to affect drug metabolism) factors to 
affect berzosertib pharmacokinetics (PK) and thereby, is important to inform the need for future 
clinical pharmacology studies (e.g., special population studies in patients with organ impairment, 
drug-drug interaction [DDI] as a victim, etc.).
The purpose of Period 2 is to assess safety and efficacy of berzosertib in combination with 
topotecan. The results from a Phase I/II study of berzosertib + topotecan demonstrated clinical 
activity across different tumor types, particularly in participants with platinum-resistant small 
cell lung cancer (SCLC), high grade neuroendocrine tumors, or tumor with DNA damage 
response (DDR) deficiencies. In addition, topotecan has clinical activity in several other 
malignancies such as gynecological, soft tissue, and brain tumors (topotecan product 
information), which can be potentialized with the combination with berzosertib. In terms of 
safety, comparison with historical data of single agent topotecan, the berzosertib and topotecan 
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Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
I N F O R M A T I O N
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combination has a toxicity profile that largely mirrored that of topotecan as single agent (Thomas 
2018; Thomas 2021). Thus, the berzosertib and topotecan combination has the potential of 
providing clinical benefit in advanced solid tumor patients with poor outcomes and high unmet 
medical need.
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 DDR pathway regulated by 
the 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 and clinical data (refer to 
the latest IB), berzosertib has the potential to have a substantial therapeutic impact on a number 
of malignancies, particularly in combination with chemotherapeutic agents such as gemcitabine, 
platinum agents, and topotecan (Konstantinopoulos 2020; Thomas 2018, Thomas 2021). 
Following intravenous (IV) dosing of 14C-labeled berzosertib to rats, means of 10.4% and 81.1% 
of the administered radioactivity were excreted in urine and feces, respectively, by 96 hours 
postdose. The high percentage of radioactivity eliminated in feces after IV dosing indicates 
biliary excretion was the major route of elimination of 14C-berzosertib-derived radioactivity. The 
overall mean recovery of radioactivity after IV dosing to rats was 94.3% (Study 8302826 Final 
Report 2015). After IV administration to bile duct-cannulated dogs (Vertex Study I135 
Nonclinical Study Report 2012), little unchanged berzosertib was detected in dog urine and bile 
(3.59% and 6.46%, respectively). These data indicated that berzosertib was eliminated primarily 
through metabolism in nonclinical species.
In a subsequent study in human hepatocytes and liver microsomes, biotransformation of 
14C-berzosertib revealed multiple metabolites. Exploratory metabolite profiling performed on 
pooled plasma samples from 6 participants revealed 3 circulating metabolites i.e. a carboxylic 
acid metabolite (M11) and 2 glucuronides, the likely acyl glucuronide of M11 (M17) and the 
direct glucuronide of parent (M14). In humans, the mean percentage of berzosertib excreted 
unchanged in the urine was approximately 5% to 6%, indicating minimal renal clearance of the 
unchanged drug. Overall, human in vitro and in vivo data indicated metabolism is the primary 
clearance mechanism of berzosertib. 
The plasma PK of berzosertib are characterized by a moderate to high clearance (approximately 
60 L/h), high distribution volume (approximately 1250 L) and a mean terminal elimination 
half-life of approximately 17 hours across all dose groups (18 to 480 mg/m2). Systemic 
exposures of berzosertib (Cmax and AUC0-∞) tended to increase proportionally with increasing 
dose after IV administration of the drug as monotherapy. Mean berzosertib plasma exposures, 
when berzosertib was given 1 day after administration of gemcitabine, cisplatin, carboplatin, 
carboplatin plus avelumab, or in combination with irinotecan were largely comparable to the 
corresponding values of berzosertib when administered alone at equivalent doses. In Parts A and 
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Berzosertib
Human Mass Balance Study
MS201923_0008
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B of Study MS201923-0001, the mean percentage of berzosertib excreted unchanged in the urine 
was approximately 5% to 6%, indicating minimal renal clearance of the unchanged drug. 
Exploratory metabolite profiling was performed on pooled plasma samples from 6 participants 
administered berzosertib at a dose of 72 mg/m2 (Study MS201923-0001). Three circulating 
metabolites were detected: M11 (MSC2699092A), a de-alkylation product (major), M14, a direct 
glucuronide (minor), and M17, a glucuronide of M11 (minor). No clinical DDI studies to assess 
the victim or perpetrator potential of berzosertib have been conducted.
Berzosertib was extensively metabolized via oxidative metabolism pathways, cytochrome P450 
(CYP)3A4 as the principal isozyme based on preliminary in vitro assessment. Berzosertib is a 
P-glycoprotein (P-gp) substrate but not a Breast Cancer Resistance Protein (BCRP) substrate. 
Using both basic and static mechanistic modeling prediction, berzosertib is in general not 
expected to elicit clinically meaningful DDI as a perpetrator based on in vitro assessment 
(potential for CYP induction, inhibition of CYPs, uridine diphosphate glucuronosyltransferases 
(UGTs), P-gp, organic anion transporting polypeptide (OATP)1B1, and OCT1 inhibition) at 
maximum unbound berzosertib concentrations observed in humans. A weak DDI risk is 
predicted for inhibition of CYP3A4 and according to EMA criteria, a possible DDI risk is 
predicted for BCRP and OATP1B3. As berzosertib is primarily metabolized by CYP3A4, strong 
inhibitors and inducers of CYP3A4 are expected to impact berzosertib exposure.
The berzosertib + topotecan combination has shown promising clinical activity and a favorable 
safety profile in participants with solid tumors. 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; Thomas 2021). In the Phase I portion, in terms 
of efficacy, there were 2 partial responses (PRs) 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 (Thomas 2018). 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) (Thomas 2021). These results suggest a potential benefit 
of the combination in patients with platinum-resistant SCLC, defined by disease recurrence 
within 90 days from the last dose of platinum given in prior lines; thus, the berzosertib and 
topotecan combination is being further investigated in this patient population with poor outcomes 
(NCT04768296).
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of berzosertib (and topotecan) may be found in the respective IBs.
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Human Mass Balance Study
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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
The planned intravenous infusion of 210 mg/m2 of berzosertib will contain approximately 
∋0.111 MBq (∋3 μCi) of radioactivity (14C) per participant. The radioactive burden due to low 
amounts of radioactivity (approximately ∋( μCi) planned to be administered per participant is 
considered to pose negligible risk above the background cosmic radiation. The estimated 
radiation burden is far below the recommended dose limit for public of 1 mSv per year (Study 
No. MSI2047A-2047AX, M6620 – Radiation Burden Calculation Report 2020). The safety 
profile of berzosertib from clinical studies performed to date suggests that berzosertib is well 
tolerated when administered as single agent.
In the Phase I (Thomas 2018) and Phase II (Thomas 2021) 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 adverse events (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 5.
Table 5
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 8.3).
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 1 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 6.1).
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Human Mass Balance Study
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Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Potential risks for berzosertib in combination with chemotherapy
Risks associated with DDIs
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.
Refer to the berzosertib IB.
Concomitant administration with 
potent inhibitors or inducers of 
CYP3A4 is prohibited in this study.
In Period 1, moderate inhibitors 
and inducers of CYP3A4 and 
inhibitors of P-gp are also 
prohibited. 
Clinical protocol-specific 
instructions should be closely 
followed (see Section 6.8.3). 
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.
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 and 
barrier 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.
Increased toxicity in patients with 
Li Fraumeni Syndrome or ataxia 
telangiectasia
Based on non-clinical findings, 
increased toxicity in patients with 
Li-Fraumeni Syndrome or ataxia 
telangiectasia was classified as an 
important potential risk.
Exclusion of patients with 
Li_Fraumeni Syndrome or ataxia 
telangiectasia
Study Intervention: Topotecan (SmPC 2019)
Anemia
Moderate to severe (Hb ≤8.0 g/dL) 
in 37% of patients (14% of courses). 
AEs are continually monitored 
during the study (see Section 8.3) 
and managed clinically, as 
indicated, including by study 
intervention interruption, dose 
modification or discontinuation.
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Berzosertib
Human Mass Balance Study
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Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Leukopenia (including 
neutropenia)
Abnormally low white blood cell 
count (leukopenia, neutropenia) that 
may be accompanied with fever and 
signs of infections (febrile 
neutropenia). Severe neutropenia 
(neutrophil count < 0.5 × 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.
AEs are continually monitored 
during the study (see Section 8.3) 
and managed clinically, as 
indicated, including by study 
intervention interruption, dose 
modification or discontinuation.
Thrombocytopenia
Severe (platelets < 25 × 109/L) in 
25% of patients (8% of courses); 
moderate (platelets between 25.0 
and 50.0 × 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.
AEs are continually monitored 
during the study (see Section 8.3) 
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 is 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.
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 
gadolinium and contrast-induced 
renal damage for iodinated contrast.
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.
AEs = adverse events; CT = computed tomography; CYP3A4 = cytochrome P450 3A4; DDI = drug-drug interaction; 
Hb = hemoglobin; IB = Investigator’s Brochure; 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.
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Human Mass Balance Study
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2.3.2
Benefit Assessment
!
All participants in the current study will receive [14C]berzosertib in Period 1 and berzosertib 
in combination with topotecan in Period 2, 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 
areas of unmet needs.
!
The medical evaluations and assessments in the current study protocol, with regular physical 
examinations, monitoring of AEs, imaging disease assessments, 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 risk to participants in this study, as outlined in 
Table 5, the risks (potential and identified) associated with berzosertib (and in combination with 
topotecan) are justified by the anticipated benefits that may be afforded to participants with 
advanced solid tumors.
3
Objectives and Estimands
Table 6
Periods 1 and 2: Objectives and Estimand Attributes
Objectives
Estimand Attributes
Primary
To determine the rates and routes of 
excretion and mass balance of 
berzosertib following single 
intravenous administration of 
210 mg/m2 of [14C]berzosertib to 
participants with advanced solid 
tumors (Period 1).
Endpoint: Percent urinary recovery (feurine), percent fecal recovery 
(fefeces), percent total recovery in urine and feces (fetotal) of total 
radioactivity over the entire period of collection.
Population: Patients with advanced solid tumors.
Treatment: Single dose berzosertib.
To characterize the PK of berzosertib 
in plasma and urine; and of 
drug-related material (total 
radioactivity) in plasma and whole 
blood (Period 1).
Endpoint: PK parameters: Cmax, AUC0-tlast, AUC0-∀#t1/2, CL, Vz, and Vss
of berzosertib and Cmax, AUC0-tlast, AUC0-∀# t1/2 of total radioactivity in 
plasma; PK parameters (Cmax, AUC0-tlast, AUC0-∀# t1/2) of total 
radioactivity in blood.
PK parameters of berzosertib in urine: cumulative amount excreted in 
urine (Ae and feurine (%)), renal clearance (CLR).
Population: Patients with advanced solid tumors.
Treatment: Single dose berzosertib.
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Berzosertib
Human Mass Balance Study
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Objectives
Estimand Attributes
Secondary
To evaluate the safety and tolerability 
of berzosertib (Period 1) and
berzosertib + topotecan (Period 2.)
Endpoint: Occurrence of TEAEs and treatment-related AEs and 
occurrence of clinically significant changes in vital signs, laboratory 
parameters and 12-lead ECG findings.
Population: Patients with advanced solid tumors.
Treatment: Single dose berzosertib and berzosertib in combination with 
topotecan.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
To assess efficacy of intervention in 
terms of objective response of 
berzosertib + topotecan therapy 
(Period 2).
Endpoint: Objective response according to RECIST 1.1 as assessed 
by the Investigator.
Population: Patients with advanced solid tumors.
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.
AE = adverse event; DME = drug-metabolizing enzyme; ECG = electrocardiogram; PK = pharmacokinetic(s); 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; TEAE = treatment-emergent adverse 
event
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Berzosertib
Human Mass Balance Study
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4
Study Design
4.1
Overall Design
Study Design
Single group; see Section 1.2 for Study Schema
Control Method
None (i.e., uncontrolled)
Single or Multicenter
Multicenter
Control Group
Not applicable
Study Population Type
Patients with advanced solid tumors
Level and Method of 
Blinding
Open-label study
Bias Minimalization 
Method(s)
See Section 6.3
Study Intervention 
Assignment Method
Not applicable, open-label study
Involvement of Special 
Committee(s):
No
Total Duration of Study 
Participation per 
Participant
Screening: 27 days (from D-28 to D-2)
Period 1 ([14C]berzosertib single dose): confinement maximum 
up to 15 days (D-1 plus 14 days)
Safety Follow-up (if not entering Period 2): 30 days after single 
dose administered
Period 2 (berzosertib in combination with topotecan):
Study Intervention consisting of 21-day cycles until disease 
progression or other criteria for study intervention 
discontinuation are met.
Safety Follow-up (at the end of Period 2): 30 days (± 7 days) 
after last dose of study intervention
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 Endof-Study.
Provisions for Study 
Extension or Entry into 
Roll-Over Studies
See Section 6.6
Adaptive Aspects of 
Study Design
Not applicable
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This is a single group, sequential period, unblinded study with treatment of berzosertib single 
dose (Period 1 Mass Balance), followed by berzosertib in combination with topotecan (Period 2 
Extension) in participants with advanced solid tumors.
4.1.1
Period 1: Berzosertib Mass Balance Study
Period 1 represents the period for assessment of the mass balance, PK, metabolism, and 
elimination of berzosertib. 
During Period 1, admission to the clinical research unit (CRU) is required until the discharge 
criteria are met (see Section 4.1.1.1), with a maximum confinement period of 15 days (Day -1 
plus 14 days). Patients who meet all inclusion criteria and none of the exclusion criteria will be 
admitted to the clinical facility on the morning of Day -1 for predose samples collection. 
Following the collection of Day 1 predose assessments and samples (if any), participants will 
receive a single dose of 210 mg/m2 of [14C]berzosertib IV solution (containing approximately 
∋3 μCi of [14C]berzosertib) via an intravenous infusion for 1 hour. The actual amount of 
administered radioactivity will be documented for each participant. 
Participants will be closely monitored for AEs throughout the period. Safety will be assessed by 
monitoring vital signs, physical examinations, electrocardiogram (ECGs), and clinical laboratory 
tests.
Blood will be collected at prespecified time points for analyses of berzosertib and drug-related 
material, and metabolite profiling over the confinement period. The mean terminal elimination 
half-life (t1/2) of berzosertib as parent drug is approximately 17 hours (range 14.2 to 17.6 h) in 
adults with advanced solid tumors. The human t1/2 of metabolites of berzosertib is not known; 
therefore, the t1/2 of total drug-related material (parent drug + metabolites) cannot be accurately 
estimated. The estimated confinement period of 7 days (approximately 5 t1/2) takes into account 
potential metabolites that may have t1/2 that are up to 2 times that of parent drug for characterizing 
the PK of total radioactivity (TR) and excretion of drug-related material in urine and feces. 
Complete urinary and fecal output will be collected until discharge from the clinical unit and 
analyzed for total drug-related material and products of berzosertib biotransformation. To ensure 
defecation prior to release from the clinical facility, oral laxatives of osmotic properties 
(e.g., magnesium hydroxide, lactulose) may be administered as needed. 
For those not participating in Period 2, a Safety Follow-up Visit should be performed 30 days 
after the single dose of berzosertib in Period 1.
4.1.1.1
Period 1: Clinical Research Unit Discharge Criteria
Admission to the CRU is required, with a maximum confinement period of 15 days (Day -1 plus 
14 days), until the following discharge criteria are met: 
!
At least 85% of the total dose of radioactivity has been collected 
OR
!
The excretion of radioactivity in the urine and feces combined has declined to ≤ 1% of the 
total administered radioactivity for at least 2 consecutive days
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4.1.2
Period 2: Extension with Berzosertib in Combination with 
Topotecan
After completing Period 1, within 7 days of discharge from the CRU, if no study withdrawal 
criteria are met, participants may enter Period 2 Extension of the study and will continue with 
21-day cycles of berzosertib in combination with topotecan until disease progression or other 
criteria for study intervention discontinuation are met, an End-of-Treatment Visit, and a Safety 
Follow-up Period of 30 days (± 7 days) after last study intervention dose. Berzosertib will be 
administered at a dose of 210 mg/m2 IV on Day 2 and Day 5 and topotecan by IV administration 
at a dose of 1.25 mg/m2 on Days 1 through 5 of each 21-day cycle.
4.2
Scientific Rationale for Study Design
The study design is based on the regulatory guidance (FDA and EMA) to characterize rates and 
routes of elimination, mass balance and clearance pathways. The PK and disposition of any drug 
is governed by several processes, including organ distribution, and elimination by metabolism 
and/or transport processes, and ultimately excretion. Period 1 of this study is designed to 
elucidate these processes, a [14C]-radiotracer of berzosertib will be used, which allows the 
detection, tracking, and quantification of parent drug and metabolites in biological samples.  
Since a berzosertib mass balance study can only be performed in patients with cancer, and only 
a single-dose administration of berzosertib is required, the Period 2 Extension will consist of a 
combination of berzosertib with topotecan, which is a regimen potentially active in several solid 
tumors, particularly SCLC, high grade neuroendocrine tumors, or tumor with DDR deficiencies.
4.3
Justification for Dose
Berzosertib will be administered in Period 1, the mass balance portion of this study, as a single 
1-hour IV infusion of 210 mg/m2 containing approximately ∋3 μCi of [14C]berzosertib as the 
radioactive tracer to allow mass balance evaluation and quantitative metabolite profiling in 
plasma, urine, and feces. Since radioactivity used in this study is approximately ∋3 μCi, 
accelerator mass spectrometry (AMS) analysis, a highly sensitive method for the detection of 
radioactive 14C, will be used to assess the recovery and PK of TR, and perform metabolite 
profiling. Depending on the excretion profile of [14C]berzosertib, traditional radioactivity 
detection methods such as liquid scintillation counting will also be explored for recovery of TR 
and mass balance determination.
The radioactive burden due to low amounts of radioactivity (approximately ∋3 μCi) planned to 
be administered per participant is considered to pose negligible risk above the background 
cosmic radiation. The estimated radiation burden is far below the recommended dose limit for 
public of 1 mSv per year (Study No. MSI2047A-2047AX, M6620 – Radiation Burden 
Calculation Report 2020). 
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The selected 210 mg/m2 of berzosertib is based on the reported Phase I study, which determined 
the combination of berzosertib and topotecan to be safe and tolerable (Thomas 2018). The 
starting study intervention doses for the combination in the Period 2 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 6.5 provides the dose selection and modification information for this study.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study periods, including the 
Safety Follow-up Visit, as shown in Section 1.3 (SoAs for Periods 1 and 2) and fulfilled at least 
1 of the following criteria: 
!
Withdrawal of consent from the study
!
Lost to Follow-up
!
Died.
The end of the study is defined as the date of last contact (related to this study) with the last 
participant who participates in this study (Safety Follow-up Visit).
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.
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Category
Criterion
Age
1.
Are ≥ 18 years of age at the time of signing the informed 
consent.
Type of Participant 
and Disease 
Characteristics
2.
Histologically proven advanced
solid tumors that are 
considered appropriate for treatment in Period 2 of this study, 
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 (see Appendix 5)
4.
Evaluable disease according to Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) at Screening. 
5.
Have adequate hematologic function as indicated by:
!
Platelet count ≥100,000/mm3
!
Hemoglobin ≥9.0 g/dL. Prior red blood cell 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), 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)
!
Suitable venous access for the study-required blood 
sampling (including PK sampling)
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Sex and 
Contraception/Barrier 
Requirements
6.
All sexes allowed
The Investigator confirms that each participant agrees to use 
appropriate contraception and barriers, if applicable. The 
contraception, barrier, and pregnancy testing requirements are 
below. 
7.
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: 
o
Abstain from any activity that allows for exposure to 
ejaculate
OR 
o
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
Female participants:
Are not pregnant or breastfeeding, 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:
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Category
Criterion

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 3.
Informed Consent
8.
Capable of giving signed informed consent, as indicated in
Appendix 2, which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and 
this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Category
Criterion
Medical Conditions
1.
Clinically relevant (i.e., active), uncontrolled intercurrent illness 
including, but not limited to, severe active infection including, 
acute respiratory syndrome coronavirus-2 infection/coronavirus 
disease 2019 (Covid 19), immune deficiencies, uncontrolled 
diabetes, uncontrolled arterial hypertension, symptomatic 
congestive heart failure (New York Heart Association 
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Category
Criterion
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, including 
required inpatient confinement. Known hepatic cirrhosis or 
severe pre-existing hepatic impairment.
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 DDI. 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
DDI with berzosertib due to treatment 
medication (see Table 11). 
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, and provided there is no expected DDI with 
berzosertib due to treatment medication (see Table 11).
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 
administration 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.
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Category
Criterion
3.
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.
4.
Participants with known history of Li-Fraumeni Syndrome and 
ataxia telangiectasia.
5.
Irregular defecation patterns (< 1 defecation/2 days or excessive 
diarrhea).
6.
Persistent diarrhea (≥ Grade 2) lasting > 3 days within 2 weeks 
before the first dose of study intervention.
7.
History of urinary and/or fecal incontinence.
8.
Major surgery within 14 days before the first dose of study 
intervention or scheduled surgery during Period 1 of the study.
9.
Participation in a trial involving administration of 14C labeled 
compound(s) within last 6 months prior to start of study 
intervention.
10. Total 14C radioactivity measured by AMS in plasma (during 
screening) exceeding 14C/12C ratio 1.1E-12
11. Radiotherapy within 14 days before the first dose of study 
intervention
12. Prior treatment with an ATR inhibitor
13. Prior 
or 
concurrent 
treatment 
with 
a 
nonpermitted 
drug/intervention from the first dose of study intervention 
administration:
!
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:
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Category
Criterion
a. Small 
molecule 
inhibitor 
therapy 
(including 
investigational) within 2 weeks or 5 half-lives, whichever 
is longer
b. Any type of anticancer antibody or antibody drug 
conjugates within 3 weeks 
c. Systemic chemotherapy within 4 weeks (within 6 weeks 
for nitrosoureas/ mitomycin C)
d. 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. 
e. Any other type of anticancer therapy, not listed above, 
within 4 weeks.
!
Concomitant use of medication or supplements that are 
known strong and moderate inhibitors (Period 1 only) of 
CYP3A4 enzymes that cannot be discontinued within 
5 times the inhibitor half-life (if a reasonable half-life 
estimate is known) or 7 days prior to administration of study 
intervention and for the duration of study intervention.
!
Concomitant use of medication or supplements that are 
known strong and moderate CYP3A4 inducers that cannot 
be discontinued 4 weeks prior to administration of study 
intervention and for the duration of study intervention.
!
Concomitant use of medication or supplements that are 
known inhibitor of P-gp that cannot be discontinued within 
5 times the inhibitor half-life (if a reasonable half-life 
estimate is known) or for 7 days prior to administration of 
study intervention and for the duration of study intervention 
(Period 1 only).
!
Food and beverage containing grapefruit within 7 days 
before the first dose of study interventions. Note that food 
and beverages containing grapefruit, Seville orange, and 
star fruit are not permitted during the study (Period 1 only).
!
No history of amiodarone use in the 6 months before the 
first dose of berzosertib.
!
Admission or evidence of illicit drug use, drug abuse, or 
alcohol abuse.
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Category
Criterion
!
Other prohibited concomitant medications as listed in 
Section 6.8.3
Prior/Concurrent 
Clinical Study 
Experience
14. 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
15. Known hypersensitivity to the study interventions, a similar 
structural compound, or to one or more excipients used.
16. Smokers (use of tobacco products or nicotine-containing 
smoking cessation agents in the previous 1 month). Urine 
cotinine levels will be measured during screening and admission 
on Day -1 for all participants (Period 1 only). Smokers will be 
defined as any participant who reports tobacco use and/or who 
has a urine cotinine ≥ 500 ng/mL.
17. Donation or loss of more than 450 mL of blood in the 60 days 
prior to screening. 
18. Is not willing to comply with dietary and fluid restrictions.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
During Period 1 only, abstain from consumption of the following from 7 days before the start of 
study intervention: Seville oranges, grapefruit or grapefruit juice, and star fruit.
There are no dietary restrictions for Period 2.
5.3.2
Caffeine, Alcohol, Tobacco, and Cannabinoid
! No restrictions on caffeine or modest alcohol use apply during this study.
! Use of tobacco products will not be allowed from 1 month prior to screening until after the 
final follow-up visit.
5.3.3
Activity
Participants will abstain from strenuous exercise for 2 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities (e.g., 
watching television or reading). 
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.
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5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once within 7 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.
5.5
Criteria for Temporarily Delaying the Administration of 
Study Intervention 
See Section 6.5 in this protocol.
6
Study Intervention(s) and Concomitant Therapies
Study intervention is any investigational interventions, 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”.
6.1
Study Intervention(s) Administration
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.
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Table 7
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
Periods 1 and 2: 210 mg/m2
Containing ~3 μCi of [14C]berzosertib in 
Period 1
Period 2 only: 1.25 mg/m2
Premedication
Suggested premedication regimen: 
hydrocortisone (200 mg IV) and a locally 
available antihistamine 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 6.8.3)
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 11)
Frequency
Period 1: Single dose on Day 1
Period 2: On Day 2 and Day 5 of each 
21-day cycle
Period 2: 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 (in 
Hungary)
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 
vials. Each vial will be labeled per country 
requirements.
Depending on the local regulations (in 
Hungary), 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
CYP = Cytochrome P450; IMP = Investigational Medicinal Product; IV = intravenous; NIMP = non-investigational 
medicinal product; SoC = standard of care.
6.1.1
Period 1: Study Intervention Administration
Berzosertib will be administered after predose samples and assessments are performed in 
Period 1, the mass balance portion of this study, as a single 1-hour IV infusion of 210 mg/m2
containing ∋3 μCi of [14C]berzosertib as the radioactive tracer to allow mass balance evaluation 
and quantitative metabolite profiling in plasma, urine, and feces.
6.1.2
Period 2: Study Intervention Administration
In Period 2, berzosertib at a dose of 210 mg/m2 will be administered via IV over 60 minutes 
(± 10 minutes) and start approximately 15 minutes after completion of topotecan administration 
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on Day 2 and Day 5, of each 21-day cycle. Topotecan at a dose of 1.25 mg/m2 will be 
administered via IV over 30 minutes on Days 1 through 5 of each 21-day cycle. Study 
intervention details are provided in Table 7.
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 7 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.
6.2
Study Intervention(s) 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 intervention(s), 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 Pharmacy Manual.
! Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) 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 intervention(s) 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(s) each participant used during the study.
! The disposition (including return, if applicable) of any unused study intervention(s).
! Dates, quantities, batch numbers, container numbers, expiry dates, formulations, and the 
participant numbers.
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! The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study intervention(s) provided were 
fully reconciled.
! Unused study intervention(s) 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 intervention(s) accountability forms.
! Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Pharmacy Manual.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
After obtaining informed consent, participants will receive a subject number. This number will 
ensure identification throughout the study. Only subjects that pass screening according inclusion 
and exclusion criteria will be enrolled in the treatment part of the study.
This is a single-arm study, all participants will receive the same study interventions. 
Administration will be supervised by the Principal Investigator and clinical site staff. The date 
and time of administration, the volume of the IMP will be documented in the electronic Case 
Report Form (eCRF).
Trial medication will be prepared and distributed by Good Manufacturing Practice (GMP) 
pharmacies specialized for that service in compliance with ICH Good Clinical Practice (GCP)
and GMP guidance.
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6.3.2
Blinding
Not applicable as this is an open-label 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 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
Dose Modification
There will be no dose modification for the single dose of [14C]berzosertib in Period 1 of this 
study. If during Period 1 there is a need to interrupt or slow the IV infusion, contact the project 
clinician or designee as soon as possible for consideration of participant replacement as 
appropriate.
In Period 2, participants will receive berzosertib in combination with topotecan as per Table 7
until the criteria are met as outlined in Section 4.4 (End of Study Definition) and/or Section 7.1
(Discontinuation of Study Intervention). 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 Sections 6.5.1 and 6.5.2, respectively. See Section 7 for information regarding discontinuation 
of study intervention and participant discontinuation/withdrawal.
The justification for study intervention dose is presented in Section 4.3.
6.5.1
Berzosertib Dose Modifications (Period 2 Only)
In Period 2, 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.
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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.
Table 8
Berzosertib Dose Modifications
Dose modifications for Grade 4 hematologic and Grade 3 nonhematologic drug-related AEs
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 AEs
Starting dose
210 mg/m2
First dose reduction (2 dose levels)
105 mg/m2
AE = adverse event.
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).
6.5.2
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.
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 weekly (on Days 2 and 5 of 21-day cycles) at the 
same dose administered in combination therapy, until disease progression or other criteria for 
discontinuation are met (Section 7.1).
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6.6
Continued Access to 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 advanced solid tumors.
6.7
Treatment of Overdose
For this study, any dose of berzosertib or topotecan greater than 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 has no specific recommendation for treating an overdose. The Investigator will use 
his/her clinical judgment to manage any overdose, considering the symptoms and any site 
procedures or standards.
Even if not associated with an AE or a serious adverse events (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.
6.8
Concomitant Therapy
Record in the eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study, including 
any changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.8.1
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.
6.8.2
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. 
6.8.3
Prohibited Medicines
Prohibited concomitant medications during berzosertib treatment are listed in Table 11. 
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 
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safety or compromise the study’s scientific objectives, study participants will be permanently 
discontinued from the study. 
Participants must not receive concurrent anticancer therapy. 
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.
Berzosertib is a substrate of P-gp. 
The Investigator should refer to the topotecan summary of product characteristics (SmPC) or 
Package Insert for guidance on prohibited mediations during treatment. 
Table 11
Prohibited Concomitant Medications During Berzosertib Treatment
Restricted Medication/Food
Screening and Treatment Period
Medication:
Strong CYP3A4 inhibitors (Periods 1 & 2)
!
Examples of strong CYP3A4 inhibitors include 
clarithromycin, diltiazem, idelalisib, cobicistat, 
HIV/HBV/HCV protease inhibitors, itraconazole, 
ketoconazole, posaconazole, voriconazole and 
nefazodone.
Moderate CYP3A4 inhibitors (Period 1 only)
!
Examples of moderate CYP3A4 inhibitors 
include Aprepitant, cimetidine, ciprofloxacin, 
clotrimazole, crizotinib, cyclosporine, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, imatinib, isavuconazole (or 
isavuconazonium), tofisopam, verapamil
P-gp inhibitors (Period 1 only)
!
Examples of P-gp inhibitors azithromycin 
(Zithromax), captopril, carvedilol, felodipine, 
quercetin, quinidine, ranolazine, ticagrelor
Food (Period 1 only)
!
Grapefruit, Seville orange, exotic citrus fruits 
and star fruit or beverages containing these 
fruits
None allowed within 7 days before the first dose of study 
intervention and until the permanent discontinuation of 
berzosertib
Strong CYP3A4 inducers (Periods 1 & 2)
!
Examples of strong CYP3A4 inducers include 
apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin and St. John's 
wort.
Moderate CYP3A4 inducer (Period 1 only)
•
Examples 
of 
moderate 
CYP3A4 
inducers 
Bosentan, 
Efavirenz, 
Modafinil, 
Nafcillin, 
Rifabutin
None allowed within 4 weeks prior to the first dose of 
study intervention and until the permanent 
discontinuation of berzosertib
CYP3A4 = cytochrome P450 3A4; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency 
virus; P-gp = P-glycoprotein.
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6.8.4
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 
interventions 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.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for safety, 30 days after the last dose of study intervention. The SoA 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
!
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
!
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.
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!
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 
SAE.
7.2
Participant Discontinuation/Withdrawal from the Study
! A participant may discontinue from the study at any time, at his/her own request or at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.
! At the time of study discontinuation, if possible, a discontinuation visit will be conducted, as 
listed in the SoA. 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 revokes consent for 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 and the eCRF and inform the 
Sponsor. The samples will be destroyed.
! 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. 
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.
! 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 or caretaker (where allowed by local regulations) for 
information. These contact attempts will be documented in the participant’s medical record.
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! 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.
! 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.
! No more than 400 mL of blood may be drawn in a 2-week period.
Where allowed by local law/regulations, samples collected during this clinical study may be 
transferred to a biobank and used for future research outside the clinical protocol when 
additional consent for this purpose is given. Transfer to the biobank will be documented and 
any testing of coded biobank samples will not be reported in the Clinical Study Report (CSR).
The long-term storage of samples after study completion for future research may be 
performed with all sample types collected in the study (e.g., PK or pharmacogenomics) if the 
participant consents to optional future medical research.
8.1
Efficacy Assessments and Procedures
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.
Participants will have a chest/abdomen/pelvis imaging scan (e.g., computed tomography [CT], 
magnetic resonance imaging [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 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 
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contrast, and should be of consistent anatomic locations with prior imaging scans, whenever 
possible. 
Imaging scans will be locally read, and the Investigator should continue treatment administration 
until progressive disease (PD). The applicable overall response category for each visit that 
includes disease assessment, based on evaluation of imaging scan, will be recorded in the eCRF. 
Determination of participant study disposition (i.e., discontinuation or extension of therapy) will 
be based on disease progression as interpreted from the local evaluation of the imaging scan. 
Tumor assessments per protocol will be performed until PD or start of subsequent anticancer 
treatment, whichever comes first, regardless of study intervention discontinuation. 
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, 
electrocardiograms, and laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. 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.
8.2.1
Physical Examinations
Physical examinations will be performed and the ECOG PS should be recorded according to the 
SoA (Table 1 and Table 4). 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 and neurological systems.
! A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
! Investigators will pay special attention to clinical signs related to previous serious illnesses.
8.2.2
Vital Signs
! Blood pressure and participant’s position; pulse; respiratory rate; temperature and location of 
measurement, weight, and height (at Screening only) will be measured and recorded.
! 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) and measured 
with an automated device. Manual techniques will be used only if an automated device is not 
available.
8.2.3
Electrocardiograms
! Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically measures heart rate, PR, RR, QRS, QT, and QTcB or QTcF. 
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! ECGs will be recorded after 5 minutes of rest.
8.2.4
Clinical Safety Laboratory Assessments
! Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 6
at the time points listed in the SoA. 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 the local laboratory.
! The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study must be forwarded to the Sponsor.
! The Investigator will review each laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE, unless it does not meet the 
AE definition, as specified in Appendix 4. The laboratory reports will be filed with the source 
documents.
! Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at monthly intervals during study intervention administration.
! Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at the end of the relevant systemic exposure of the study intervention plus an 
additional 30 days and correspond with the time frame for female participant contraception 
in Section 5.1 (Inclusion Criteria).
! Additional serum or highly sensitive urine pregnancy tests may be conducted, as determined 
necessary by the Investigator or required by local regulation, to establish the absence of 
pregnancy at any time during the study.
8.3
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting
! The definitions of an AE and a SAE are 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 8.3.2.
! Requests for follow-up will usually be made via the Sponsor or Clinical Research 
Organization (CRO)-designated study team member, although in exceptional circumstances 
the global patient safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
! 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.
! All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at 
the time points specified in the SoA (Section 1.3). Beyond this reporting period, any new 
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unsolicited SAEs that the Investigator spontaneously reports to the Sponsor will be collected 
and processed.
! 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 information on 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.
8.3.1
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.
8.3.2
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 in 
Appendix 4.
8.3.3
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 Board (IRB)/ Independent Ethics Committee 
(IEC), and Investigators.
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Individual Case Safety Reports will be prepared for suspected unexpected serious adverse 
reactions (SUSARs) 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 file it in the Investigator’s Site File and will 
notify the IRB/IEC, if appropriate according to local requirements.
8.3.4
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 dose.
! If a pregnancy is reported, the Investigator will record the pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of female participant or female 
partner of male participant (after obtaining the necessary signed informed consent from the 
female partner) pregnancy.
! While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. Adverse pregnancy 
outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered and reported as SAEs. 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.
! The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner 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 for a healthy newborn. In case of a congenital anomaly or other illness of the 
newborn, follow-up will continue until the illness has resolved or there is a definite outcome 
of the event.
! 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 8.3.3. 
While the Investigator is not obligated to actively seek this information in former study 
participants/pregnant female partner, 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 or be withdrawn from the study.
8.3.5
Cardiovascular and Death Events
Not applicable for cardiovascular events.
For death events refer to Appendix 4 for more information.
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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 advanced solid 
tumors and can be serious/life threatening:
!
Progressive disease
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 AE/SAE (instead of a DRE):
!
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
Pharmacokinetics
Whole blood samples of approximately 12 to 24 mL will be collected at each time point for 
measurement of whole blood (total radioactivity) and plasma concentrations of total 
radioactivity, and berzosertib and metabolite profiling and identification (MetID). Collection 
times are specified in the SoA and Table 2. Details of timepoints and required blood volumes 
will be captured in the laboratory manual. 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.
Urine and feces samples for measurements of concentrations of total radioactivity, berzosertib 
(urine only) and for metabolic profiling will be collected as specified in the SoA (Table 3). The 
actual start and end date and time (24-hour clock time) of each urine and feces fraction as well 
as the volume (urine) and the weight (feces) of each collection fraction will be recorded. The 
accepted time deviations from planned whole blood and plasma sampling times that will not be 
considered a protocol deviation are listed in Table 2.
The quantification of berzosertib in plasma and urine, will be performed using validated assay 
methods. In addition, known berzosertib metabolites may be measured and samples will be used 
for metabolic profiling. Concentrations will be used to evaluate the PK of study intervention and 
TR (and metabolites, if applicable).
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Remaining samples collected for analyses of berzosertib, metabolite profiling and TR 
concentration may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.
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.
The following PK parameters will be calculated for berzosertib and total radioactivity in plasma 
and whole blood 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-∀
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-t
The partial area under the concentration-time curve (AUC) from time 
zero (= dosing time) to a defined time ‘t’. Calculated using the mixed 
log-linear trapezoidal rule (linear up, log down). Timepoint ‘t’ will be 
defined upon receipt of the metabolite profiling data.
Cmax
Maximum observed concentration.
Ceoi
The observed concentration at the end of the infusion period.
CL 
(berzosertib 
only)
The total body clearance of study intervention following intravenous
administration, CL = Dose /AUC0-∞.
tmax
The time to reach the maximum observed concentration collected during 
a dosing interval.
t1/2
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 
(berzosertib 
only)
The volume of distribution during the terminal phase following 
intravenous administration. VZ = Dose/(AUC0-∞*λz).
Vss 
(berzosertib 
only)
An estimate of the volume of distribution at steady-state based on the last 
predicted concentration, calculated as CL * MRTiv.
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Symbol
Definition
MRTiv (berzosertib 
only)
The mean residence time extrapolated to infinity, calculated as 
(AUMC0-∞/AUC0-∞ )-T/2, where T is the infusion duration.
The following PK parameters will be calculated for berzosertib (urine only) and total 
radioactivity in urine and feces, when appropriate:
Symbol
Definition
Aet1-t2, urine
Amount excreted in urine between times t1 (= start) and t2 (= end), 
calculated per collection interval and cumulative.
Aet1-t2, feces
Amount excreted in feces between times t1 (= start) and t2 (= end), 
calculated per collection interval and cumulative.
Aetotal
Total (cumulative) amount radioactivity recovered in urine and feces over 
the entire collection period.
CLR 
(berzosertib 
only)
The renal clearance of study intervention. CLR= Ae0-t_urine/AUC0-t
fe (%)
(berzosertib 
only)
Percent of dose excreted as an unchanged berzosertib in urine.
fet1-t2, urine %
Fraction of administered drug that is excreted in urine between times t1 
(= start) and t2 (= end), calculated per collection interval and cumulative.
fet1-t2, feces %
Fraction of administered radioactivity that is excreted in feces between times 
t1 (= start) and t2 (= end), calculated per collection interval and cumulative.
fetotal %
Total (cumulative) fraction of administered radioactivity recovered in 
urine and feces over the entire collection period.
Free fraction (%unbound) of berzosertib in plasma may be summarized by time points and pool 
of time points as permitted by the data. In case vomitus is collected, total radioactivity will be 
assayed and results listed. Details will be provided in the Integrated Analysis Plan (IAP).
Additional PK parameters may be calculated, if appropriate. Methodology for the calculation of 
PK parameters will be detailed in the IAP.
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8.6
Biomarkers
Not applicable.
8.7
Immunogenicity Assessments
Not applicable.
8.8
Medical Resource Utilization and Health Economics
Not applicable.
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 IAP. 
9.1
Statistical Hypotheses
The statistical analysis of study data will be purely descriptive; no hypothesis tests will be 
performed.
9.2
Sample Size Determination
A total of approximately 6 participants (or more) will be treated with study intervention such 
that approximately 4 to 6 PK evaluable participants are anticipated to be obtained. If the initial 
group of 6 leads to fewer than 4 evaluable participants, the cohort will be increased up to a 
maximum of 12 participants, until 4 participants have completed all study procedures for 
Period 1 and are evaluable.
The decision to enroll additional participants will be taken on a case-by-case basis, in agreement 
between the Sponsor and the Investigator. 
For participants who experience emesis during the first 48 hours after the end of [14C]berzosertib 
administration, the vomitus should be collected as much as possible and assayed for total 
radioactivity. 
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A participant who has any missing urine or feces samples that impact assessment of mass balance 
or does not have sufficient PK sampling to derive the primary PK parameters, is not considered 
evaluable.
9.3
Analyses Sets
The analysis sets are specified below.
Analysis Set
Description
SCR 
All participants, who provided informed consent, regardless of the participant’s study 
intervention status in the study.
FAS / SAF
All participants, who were administered any dose of any study intervention. 
PKAS
The PKAS is a subset of the SAF and will consist of all participants, who receive the 
single dose of study intervention in Period 1 and provide at least one measurable 
post-dose concentration. A measurement BLQ is considered a valid measurement. 
All PK analyses will be based on this analysis set.
BLQ = below lower limit of quantification; FAS = Full Analysis Set; PK = pharmacokinetic; PKAS = Pharmacokinetics 
Analysis Set; SAF = Safety (Analysis Set); SCR = Screening (Analysis Set) 
9.4
Statistical Analyses
Statistical analysis will be performed using the computer program package SAS® System 
(release 9.2 or later version; SAS Institute, Cary NC, US), or R (R Core Team, 2020. R: A 
Language 
and 
Environment 
for 
Statistical 
Computing, 
Vienna, 
Austria. 
https://www.R-project.org/). More details on the statistical analyses will be presented in the IAP 
prior to database lock. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
The statistical analysis will not be started until all data have been cleaned and checked for 
plausibility, and until all necessary coding and assessments have been completed. 
All data recorded during the study will be presented in individual data listings. 
All data will be evaluated as observed, no imputation method for missing values. The handling 
of concentration values below the limit of quantification will be described in the IAP.
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 12.
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Table 12
Efficacy Analyses and Estimands (Period 2)
Endpoint
Statistical Analysis Methods/Further Estimand Attributes
Objective Response 
Endpoint: Objective Response according to RECIST 1.1 as assessed by the Investigator
Population: Patients with advanced solid tumors
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
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set (SAF).
Medical history and AE terms will be coded with the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA) (Version 23.0 or later); concomitant medication will be 
coded with World Health Organization (WHO) Drug Dictionary, WHO Drug Reference List and 
Anatomical Therapeutic Chemical Classification System, latest versions. Versions of 
dictionaries used for coding will be defined in the Data Management Plan. 
The on-treatment period is defined as the time from first study intervention to the last study 
intervention date + 30 days.
Table 13
Safety Endpoints
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
!
TEAEs related to study interventions.
The following AEs will be listed:
!
SAEs
!
NCI-CTCAE Grade ≥ 3 TEAEs 
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Endpoint
Statistical Analysis Methods
!
TEAEs leading to dose modification or temporary/permanent interruption of study 
interventions
!
TEAEs leading to death.
Deaths
Death and primary reason for death will be listed.
Laboratory Values
Baseline values are defined as the last value prior to first administration of study 
intervention in the respective period. 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 (Period 2 only; baseline is the Day 1 pre-dose value in each 
cycle)
!
Worst on-treatment grade (Period 2 only)
Vital Signs
! Summary statistics for baseline and on-treatment values
ECGs
! Summary statistics of all measurements by scheduled time point
Tertiary/Exploratory
Not applicable
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.
9.4.3
Other Analyses
Baseline characteristics will be analyzed on the SAF. Summary statistics will be provided as 
described for continuous/categorical variables in Section 9.4.
For demographic (e.g., age, sex, race, etc.), baseline and safety assessments, continuous 
measurements will be summarized by means of descriptive statistics (i.e. number and percentage 
of observations, number and percentage of missing observations, mean, standard deviation [SD], 
median, the first and third quartile [Q1 and Q3], minimum [Min], and maximum [Max]) and 
categorical data will be summarized by means of frequency tables (i.e., count and percentages), 
if not stated otherwise. 
Analysis of Pharmacokinetics
PK parameters (e.g. Cmax, AUC, t1/2, CL, Vz, and Vss of berzosertib and Cmax, AUC, t1/2 of total 
radioactivity in plasma; Cmax, AUC, t1/2 of total radioactivity in blood) will be calculated using 
noncompartmental methods based on the actual sampling times, listed and tabulated with 
descriptive statistics. The noncompartmental analysis will be outsourced under the supervision 
of the Sponsor and will be performed by PRA – Early Development Services (EDS) using 
Phoenix® WinNonlin® version 8.1 or higher (Certara, L.P., Princeton, NJ, 08540 US). 
Individual plasma concentrations of berzosertib and radioactivity, and amounts excreted in 
urine/feces will be tabulated using the nominal sampling times with descriptive statistics at all 
time points. Excretion of total radioactivity will be calculated based on the administered 
radioactive dose and the relative amount of radioactivity recovered in urine and feces. Graphical 
displays will be produced where appropriate.
Details on the PK analyses will be in the IAP that will be finalized before database lock. 
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9.4.4
Sequence of Analyses
After all participants have completed Period 1, the primary report for the study will be generated 
once all data queries are resolved, and the primary database will be soft-locked for Period 1. The 
primary analysis will include all data collected in Period 1 and all planned analyses identified in 
the Clinical Study Protocol, in particular the analysis of the mass balance data. Data from 
Period 2 will be added to the report as an addendum, upon end of study as described in 
Section 4.4, with all study data in-house, all data queries resolved, and the database locked.
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10
References 
Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, et al. Berzosertib plus gemcitabine 
versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, 
open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:957-68.
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):1594-602.
Thomas A, Takahashi N, Rajapakse VN, et al. Therapeutic targeting of ATR yields durable 
regressions in small cell lung cancers with high replication stress. Cancer Cell. 2021;39:566-79.
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11
Appendices
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Appendix 1
Abbreviations
AE(s)
Adverse Event(s)
ALT
Alanine aminotransferase
AMS
Accelerator mass spectrometry
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
BLQ
Below lower limit of quantification
BOI
Beginning of infusion
C
Cycle
CIOMS
Council for International Organizations of Medical Sciences
CRO
Clinical Research Organization
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed tomography
CTFG
Clinical Trial Facilitation Group
CYP
Cytochrome P450
D
Day
DDI
Drug-drug interaction
DDR
DNA damage response
DRE
Disease-related events
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EDC
Electronic data capture
EDS
Early Development Services
EMA
European Medicines Agency
EOI
End of infusion
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EORTC
European Organization for the Research and Treatment of Cancer
EOT
End of treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GMP
Good Manufacturing Practice
Hb
Hemoglobin 
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HRT
Hormonal replacement therapy
IAP
Integrated Analysis Plan
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product 
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LAM
Lactational amenorrhea method
MedDRA
Medical Dictionary for Regulatory Activities
MetID
Metabolite identification
MIST
Metabolites in Safety Testing
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NIMP
Noninvestigational Medicinal Product
OATP
Organic anion-transporting polypeptide
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PD
Progressive disease
PET-CT
Positron emission tomography computed tomography
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKAS
Pharmacokinetics Analysis Set
PR
Partial response
PRA
PRA Health Sciences
QTL
Quality Tolerance Limit
RECIST 1.1
Response Evaluation Criteria in Solid Tumor Version 1.1
SAE(s)
Serious Adverse Event(s)
SAF
Safety Analysis Set
SCLC
Small Cell Lung Cancer
SCR
Screening (Analysis Set)
SD
Stable disease; standard deviation
SmPC
Summary of product characteristics
SoA
Schedule of Activities
SoC
Standard of care
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent Adverse Event
TR
Total radioactivity
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper Limit of Normal
US
United States
WHO
World Health Organization
WOCBP
Woman of Childbearing Potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
! The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally-authorized representative (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; local regulations; 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.
! Participants who are rescreened are required to sign a new ICF (see Section 5.4 for details).
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.
! 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.
! Certain tasks listed above can be delegated to PRA
Study Administrative
The Principal Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Principal Investigator will provide expert medical 
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input and advice on the study design and execution and is responsible for the review and signoff 
of the clinical study report.
Details of structures and associated procedures will be defined in a separate Project Management 
Plan.
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
! Applicable laws and regulations
! The protocol, protocol amendments (if applicable), ICF, Investigator’s Brochure, and other 
relevant documents (e.g., advertisements) will be submitted to an IRB/IEC for review and 
approve before the study is initiated.
! Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities.
! The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
! The Sponsor or designee will provide Emergency Medical Support cards to participants for 
use during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the participant. The information on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
! The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators.
When the Investigator is not available, the Phase I facility will provide the appropriate means to 
contact a physician. This includes the provision of a 24-hour contact number at the facility, 
whereby the health care providers will be given access to an appropriate physician to assist with 
the medical emergency and to provide support for the potential unblinding of the participant 
concerned.
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Clinical Study Insurance and Compensation to Participants
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 the 
Principal Investigator, or other relevant study-appointed committees or groups. This task may be 
delegated to PRA.
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.
! Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
! Study results will be shared with study participants
! Merck-sponsored study information and tabular study results will be published on 
www.ClinicalTrials.gov once the drug is approved or the program has been terminated, 
whichever occurs first.
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 Data Management Plan.
! 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.
! Quality Tolerance Limits (QTLs) will not be pre-defined in this study because of the 
impracticality of applying QTLs in the limited number of planned participants in this trial.
! 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 
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monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan or 
contracts.
! 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, 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.
Source Documents
! Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
! The Investigator will maintain source documents that support the data recorded in the eCRFs.
! Data recorded on 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.
! Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the Sponsor’s 
written approval.
! Definition of what constitutes source data is found in the eCRF guidelines.
Study and Site Start and Closure
The study start date is when the first participant signs the ICF.
Study and Site Closure
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended closure.
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
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! 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 third-party service 
providers 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 and Barrier Requirements
Definitions:
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 (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
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
!
Oral
!
Intravaginal
!
Transdermal
!
Injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulation
!
Oral
!
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.
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 (CTFG) 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 (LAM) 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
AE Definition
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 and are judged to be more severe than 
expected for the participant’s condition are considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease, but may be leading to study intervention discontinuation).
!
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 within the expectedness for participant’s condition, as judged by the 
Investigator.
!
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
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!
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.
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.
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 8.3.4.
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.
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!
However, all events leading to unplanned hospitalizations or unplanned prolongation 
of an elective hospitalization must be documented and reported as SAEs.
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 
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 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.
Assessment of Intensity
Investigators will reference the NCI-CTCAE, Version 5.0 (publication date: 27 Nov 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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!
The Investigator will also consult the IB 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.
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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.
!
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor/designee with a copy of any post-mortem 
findings including histopathology.
!
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.
Reporting of SAEs
SAE Reporting by an Electronic Data Collection Tool
!
The primary mechanism for reporting an SAE in multicenter studies 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 form, specified 
below, to report the event within 24 hours. This applies for this study.
!
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 may be used in single center studies in addition to 
the standard eCRF and as a back-up method for an electronic data capture (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.
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!
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.
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
Eastern Cooperative Oncology Group Performance Status
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
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Appendix 6
Clinical Laboratory Tests
The protocol-required clinical laboratory assessments are in the following table:
Table 14
Clinical Laboratory Assessments
Laboratory Assessments1
Parameters
Hematology
Platelet count
MCV
White Blood Cell 
Count with 
Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Hemoglobin
MCH
Hematocrit
Coagulation
Prothrombin time/INR
Activated partial thromboplastin time
Biochemistry2
BUN or 
Urea3
Potassium
Aspartate 
aminotransferase
Bilirubin (i.e., total)
Direct bilirubin
Creatinine
Sodium
Alanine 
aminotransferase
Protein4
Glucose
Calcium
Alkaline phosphatase
Albumin
Magnesium
Phosphate
Notes:
1
Laboratory assessments, e.g. hematology, chemistry, etc., will be performed locally.
2
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. 
3
Urea can be performed only when BUN cannot be done; the same test should be performed consistently for 
each participant for the duration of the study.
4
A measurement of the total protein.
Other Screening Tests
!
FSH and estradiol (as needed if not a woman of childbearing potential 
only).
!
Serum and urine human chorionic gonadotropin pregnancy test (as needed 
for women of childbearing potential).
!
Covid 19 PCR testing will be performed at D-1 during Period 1.
!
Urine cotinine testing will be performed at Screening and at D-1.
BUN = blood urea nitrogen; FSH = follicle-stimulating hormone; INR = international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCV = mean corpuscular volume; PCR = polymerase chain reaction
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Appendix 8
Protocol Amendment History
Not applicable
Document No. 0900babe815fff85v3.0
Object No. 0900babe81670c46
Global Version ID: 78691_1309431_6418641

Berzosertib
Human Mass Balance Study
MS201923_0008
C O N F I D E N T I A L
I N F O R M A T I O N
84/85
Appendix 9
Sponsor Signature Page
Study Title:
Phase I study to evaluate the mass balance, 
pharmacokinetics (PK), metabolism and excretion of 
berzosertib 
(intravenous) 
containing 
microtracer 
[14C]berzosertib in participants with advanced solid 
tumors
Regulatory Agency Identifying 
Number:
EudraCT: 2021-002226-24
Clinical Study Protocol Version:
15 June 2021/Version 1.0
I approve the design of the clinical study:
___________
_______________
____________________________
Signature
Date of Signature
Name, academic degree:
, MD
Function/Title:
Institution:
, Merck KGaA
Address:
Telephone number:
E-mail address:
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