Clinical trial NCT03309150
Conditions: Advanced Stage Solid Tumors
Keywords: Ataxia telangiectasia mutated and Rad3-related protein inhibitor (ATRi) M6620 Solid tumors
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-01-10; Completion date: 2024-01-26
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of the study was to monitor the safety of participant receiving long-term treatment of Berzosertib as monotherapy.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Berzosertib
Intervention descriptions: intervention 1: Participants received intravenous infusion of Berzosertib at a dose of 126 milligrams (mg) on Days 1, 8 and 15 until disease progression or unacceptable toxicity occurred.

Protocol documents:
Prot_000.pdf: 
Berzosertib/M6620
ATRi Transition Rollover Study
MS201923-0007
C O N F I D E N T I A L
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Clinical Study Protocol
Clinical Study Protocol Number
MS201923-0007
Title
A Rollover Study to Provide Continued Treatment 
with M6620
Phase
I
IND Number
Not applicable
EudraCT Number
2017-002354-37
Coordinating Investigator
 
 
Telephone: 
Fax: 
E-mail: 
Sponsor
Name 
and 
Legal 
Registered Address
Merck KGaA
Frankfurter Str. 250, 64293
Darmstadt, Germany
Medical Responsible:
General Merck Phone Number: 
General Merck Fax Number: Not Applicable
Clinical Study Protocol Version
01 March 2021 / Version 4.0
Replaces Version
17 November 2020 / Version 3.0
- 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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ATRi Transition Rollover Study
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
17 Aug 2017
2.0
Global
18 Sep 2017
3.0
Global
17 Nov 2020
4.0
Global
01 Mar 2021
Protocol Version 4.0 (01 March 2021)
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union: because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study.
Overall Rationale for the Amendment
The purpose of this amendment is to provide the correct Sponsor name.
Section # and 
Name
Description of Change
Brief Rationale
Cover Page 
and 
Synopsis
Sponsor name modified to:
Merck KGaA, Frankfurter Strasse 250, 
64293 Darmstadt, Germany
To provide correct Sponsor name
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ATRi Transition Rollover Study
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Protocol Table of Contents
Protocol Amendment Summary of Changes........................................................................2
Protocol Table of Contents ..................................................................................................3
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis................................................................................................9
2
Sponsor, Investigators and Study Administrative Structure...............12
3
Background Information.....................................................................12
3.1
Study Rationale...................................................................................13
4
Study Objectives.................................................................................13
4.1
Primary Objective...............................................................................13
4.2
Secondary Objectives .........................................................................13
5
Investigational Plan ............................................................................14
5.1
Overall Study Design and Plan...........................................................14
5.2
Discussion of Study Design................................................................15
5.2.1
Scientific Rationale for the Study Design ..........................................15
5.2.2
Justification for Dose..........................................................................15
5.2.3
Rationale for Endpoints......................................................................15
5.2.4
Inclusion of Special Populations ........................................................15
5.3
Selection of Study Population ............................................................15
5.3.1
Inclusion Criteria ................................................................................16
5.3.2
Exclusion Criteria...............................................................................16
5.4
Criteria for Initiation of Study Treatment...........................................16
5.5
Criteria for Participant Withdrawal ....................................................16
5.5.1
Withdrawal from Study Therapy........................................................16
5.5.2
Withdrawal from the Study ................................................................16
5.6
Premature Termination of the Study...................................................17
5.7
Definition of End of Study .................................................................17
6
Study Intervention ..............................................................................17
6.1
Description of Study Intervention ......................................................17
6.2
Dosage and Administration ................................................................17
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6.3
Assignment to Treatment Groups.......................................................18
6.4
Concomitant Medications and Therapies ...........................................18
6.4.1
Permitted Medicines...........................................................................18
6.4.2
Prohibited Medicines..........................................................................18
6.4.3
Other Interventions.............................................................................19
6.4.4
Special Precautions.............................................................................19
6.4.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................21
6.5
Packaging and Labeling of the Study Intervention.............................21
6.6
Preparation, Handling, and Storage of the Study Intervention...........21
6.7
Study Intervention Accountability......................................................21
6.8
Assessment of Study Intervention Compliance..................................22
6.9
Blinding ..............................................................................................22
6.10
Emergency Unblinding.......................................................................22
6.11
Treatment of Overdose .......................................................................22
6.12
Medical Care of Participants after End of Study................................23
7
Study Procedures and Assessments....................................................23
7.1
Schedule of Assessments....................................................................23
7.1.1
Enrollment ..........................................................................................23
7.1.2
Treatment............................................................................................23
7.1.3
Safety Follow Up................................................................................23
7.2
Demographic and Other Baseline Characteristics ..............................23
7.3
Efficacy Assessments .........................................................................23
7.4
Assessment of Safety..........................................................................23
7.4.1
Adverse Events ...................................................................................24
7.4.2
Pregnancy and In Utero Drug Exposure.............................................29
7.4.3
Clinical Laboratory Assessments .......................................................29
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............30
7.5
Pharmacokinetics................................................................................30
7.6
Biomarkers..........................................................................................30
7.7
Other Assessments..............................................................................30
8
Statistics..............................................................................................30
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.30
8.2
Randomization....................................................................................31
8.3
Endpoints............................................................................................31
8.3.1
Primary Endpoints ..............................................................................31
8.3.2
Secondary Endpoints ..........................................................................31
8.4
Analysis Sets.......................................................................................31
8.5
Description of Statistical Analyses.....................................................31
8.5.1
General Considerations.......................................................................31
8.5.2
Analysis of Primary Endpoints...........................................................31
8.6
Interim and Additional Planned Analyses ..........................................32
9
Ethical and Regulatory Aspects..........................................................32
9.1
Responsibilities of the Investigator ....................................................32
9.2
Participant Information and Informed Consent ..................................33
9.3
Participant Identification and Privacy ................................................33
9.4
Emergency Medical Support and Participant Card ............................34
9.5
Clinical Study Insurance and Compensation to Participants..............34
9.6
Independent Ethics Committee or Institutional Review Board..........34
9.7
Health Authorities...............................................................................35
10
Study Management .............................................................................35
10.1
Case Report Form Handling...............................................................35
10.2
Source Data and Participant Files.......................................................35
10.3
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................36
10.4
Changes to the Clinical Study Protocol..............................................37
10.5
Clinical Study Report and Publication Policy ....................................37
10.5.1
Clinical Study Report .........................................................................37
10.5.2
Publications.........................................................................................37
11
References Cited in the Text...............................................................37
12
Appendices .........................................................................................37
Appendix I: Contraception.................................................................................................38
Appendix II: Signature Pages and Responsible Persons for the Study..............................40
Signature Page –Protocol Lead..........................................................................................41
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Signature Page – Coordinating Investigator ......................................................................42
43
Appendix IV: Prohibited Medication, Food and Activities During the Study ..................50
Appendix V: Protocol Amendment History ......................................................................52
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Table of In-Text Tables
Table 1
Schedule of Assessments for Participants Transitioned from Part 
A1: Single Agent Therapy once weekly.............................................11
Table 2
Laboratory Assessments .....................................................................30
Table of In-Text Figures
Figure 1
Study design diagram of ATR inhibitor Transition Rollover Study...14
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List of Abbreviations
AE
Adverse event
ATM
Ataxia telangiectasia mutated
ATR
Ataxia telangiectasia mutated and Rad3-related protein
ATRi
Ataxia telangiectasia mutated and Rad3-related protein inhibitor
CYP
Cytochrome P450
eCRF
Electronic Case Report Form
EDC
Electronic data capture
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
DDR
DNA damage response
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IR
Ionizing radiation
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
SAE
Serious adverse event
TEAE
Treatment-emergent adverse event
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1
Synopsis
Clinical Study Protocol Number
MS20193-0007
Title
A Rollover Study to Provide Continued Treatment 
with M6620
Study Phase
I
IND Number
Not applicable
FDA covered study
No
EudraCT Number
2017-002354-37
Coordinating Investigator
 
 
Sponsor
Merck KGaA
Frankfurter Str. 250, 64293
Darmstadt, Germany
Study sites/countries
The number and nature of the study sites will be 
determined by the actual need. At the time of 
initiation of this protocol, it is expected that 
participants from a single site in the UK will enter 
this Safety Follow Up study.
Planned study period
(first participant in-last participant
out)
Estimated 5 years
Trial Registry
EudraCT
Objective: 
Primary Objective: 
! To monitor the safety of participants who are on long-term treatment with M6620
(berzosertib).
Methodology: This clinical study enables further treatment with M6620 (referred to as 
berzosertib henceforth) and safety follow up of participants from Vertex clinical study 
VX13-970-002, that was terminated. Therefore, this is a multicohort study not requiring any 
study committees. Participants enrolled in the Merck KGaA-sponsored rollover study will 
continue treatment with berzosertib on the same dose and schedule as the original study. 
Participants receiving combinations of berzosertib with other drugs in the study from which 
the participant is transitioned will continue to receive the same combination drugs in this Safety 
Follow Up study. Combination drugs will be obtained from the local study site pharmacy. The
participants will complete a Safety Follow Up visit to be scheduled 28 (+7) days after the last 
administration of berzosertib.
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Planned number of participants: This is a rollover study to allow the participants to continue 
their treatment. Therefore no sample size considerations were undertaken.
Primary endpoints: Occurrence of adverse events (AEs) and treatment-related AEs in 
participants receiving berzosertib, graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (NCI-CTCAE) (Version 4.03).
Secondary endpoints: Not applicable.
Pharmacokinetics: Not applicable.
Diagnosis and key inclusion and exclusion criteria: Participants on ongoing treatment with 
berzosertib either as monotherapy or in combination with other drugs at the time of 
transitioning will be enrolled in this study.
Study Intervention: dose/mode of administration/dosing schedule:
Berzosertib
mode of administration: intravenous infusion after 
dilution in 
 before intravenous infusion.
Dosage and schedule will be diverse, depending on the details of treatment in the study from 
which the participant transitioned. Participants will continue receiving treatment at the same 
dosage and according to the same schedule from which the participant transitioned.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable.
Planned study and treatment duration per participant: Participants can continue treatment 
until disease progression or unacceptable toxicity is reported. The End of Study is defined by 
the completion of a Safety Follow Up visit to be scheduled 28 (+7) days after the last 
administration of berzosertib.
Statistical methods:
 
Safety: 
All safety data summaries will be based on the safety analysis set. 
Adverse events will be coded according to the latest available version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Severity of AEs will be graded using the NCI-CTCAE 
(Version 4.03) toxicity grades. Adverse events will be summarized by frequency and incidence 
using MedDRA.
Safety data measurements will be summarized by dose group and/or time point using 
descriptive statistics for observed values and change from baseline values (as appropriate). 
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Table 1
Schedule of Assessments for Participants Transitioned from Part A1: Single Agent Therapy once weekly
Event/Assessmenta
Treatment Cycle (21 days)
Follow Upb
Enrollment
Day 1
Day 8
Day 15
28 (+7) days after last 
administration
Safety Assessment
Informed consent
X
Demographic and other Baseline 
Characteristics
X
Concomitant medication/AEs
Continuous from signing Informed Consent Form through Safety Follow Up visit
Study Intervention Administration
Berzosertib dosing
X
X
X
AE = Adverse event
a Physical examination, weight, vital signs, serum chemistry, hematology and urinalysis will be measured as per Standard of Care and institutional guidelines and 
as clinically indicated; only clinically significant values should be reported as AEs.
b Follow Up will include a Safety Follow Up Visit to be scheduled 28 (+7) days following the last administration of berzosertib.
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2
Sponsor, Investigators and Study Administrative Structure
This clinical study will be sponsored by Merck KGaA (Darmstadt, Germany).
The number and nature of study sites will be determined by the actual need. It is expected that 
participants from a single site in the UK will enter this Safety Follow Up study. Further sites and 
countries may be added via amendment(s) to this protocol in the future if new demand for 
participants transitioning into this transition rollover study emerges.
The Coordinating Investigator will provide expert medical input and advice relating to study
design and execution and is responsible for the review and signoff of the clinical study report.
Signature pages for the Medical Responsible and Coordinating Investigator are in Appendix II.
The study will appear 12 months after the last clinical visit of the final study participant, or another 
appropriate date to meet applicable requirements, in the following clinical trial registry: EudraCT.
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Study Leader.
3
Background Information
Chemotherapeutic agents and ionizing radiation that induce DNA damage are an effective and 
common treatment option for patients with many types of solid tumors. However, many cancers, 
despite displaying initial sensitivity and clinical response to these agents, ultimately progress. One 
mechanism that has been proposed to protect tumor cells from DNA damage is the DNA damage 
response (DDR) pathway regulated by the kinases ataxia telangiectasia mutated (ATM) and ataxia 
telangiectasia mutated and Rad3-related protein (ATR). In many malignant cells, ATR assumes a 
crucial role in protecting cancer cells from DNA damage and from subsequent cell death after 
chemotherapy and ionizing radiation (IR). A reliance on ATR can arise from expression of 
oncogenes that drive deregulated proliferation and high levels of replicative stress or from defects 
in ATM/p53 signaling. Thus, small molecule-mediated inhibition of ATR should enhance the 
effect of IR and DNA damaging chemotherapy on cancer cells.
Vertex Inc (Boston, MA, USA) developed a selective inhibitor of ATR protein (Vertex code 
VX-970). Merck KGaA acquired the rights for this compound and will continue the development. 
The Vertex study intervention, VX-970, will be referred to as berzosertib when used in this and 
future clinical studies.
Berzosertib is a potent, selective first-in class inhibitor of ATR. Inhibition of ATR enhances the 
cytotoxic effect of DNA damaging drugs and IR in several cancer cell line derived xenografts and 
primary patient-derived tumors xenografts. In contrast, normal cells seem to tolerate ATR 
inhibition since they can activate compensatory DDR signaling via the ATM/p53 pathway. In 
xenograft models, berzosertib markedly enhances the anticancer activity of numerous DNA 
damaging drugs and IR, often substantially delaying or completely halting tumor progression and 
promoting tumor regression. 
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Consistent with the compensatory role of the ATM/p53 pathway in response to ATR inhibition in 
normal cells, defects in this pathway result in increased cell sensitivity to ATR inhibition. In 
isogenic cell studies it has been shown that loss of ATM or of its principal substrate p53, can 
markedly increase cell sensitivity to ATR inhibition. Similarly, in a large panel of 119 
genetically diverse cancer cell lines, TP53 mutational status was shown to correlate with response 
to ATR inhibition in combination with DNA damaging agents.
In nonclinical experiments, ATR inhibition by berzosertib has been shown to enhance the 
anticancer effects of DNA damaging agents, such as cisplatin and gemcitabine, and has been 
shown to exhibit activity as a single agent in a limited set of tumor lines.
Study VX13-970-002 was a Phase I clinical study initiated by Vertex studying berzosertib. For the 
initial dose escalation period (Parts A1, A2, B1, and B2), eligible participants had advanced stage 
solid tumors that have progressed through at least 1 line of therapy and had no approved treatment 
options. Early signs of clinical efficacy were observed in participants receiving berzosertib in the 
Vertex clinical study VX13-970-002. At the time of VX13-970-002 study completion, there was 
a participant from Part A1 still receiving treatment. This participant transferred to Study 
MS201923-0007 to continue receiving berzosertib. 
Refer to the current berzosertib Investigator’s Brochure (IB) for further information about the 
nonclinical and clinical programs and Guidance for the Investigator.
These clinical studies were conducted in compliance with the clinical study protocol and 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP; hereafter referred to 
as ICH GCP) and any additional applicable regulatory requirements.
3.1
Study Rationale
This study is designed to provide continuous access to treatment with berzosertib for eligible 
participants from Vertex clinical study VX13-970-002 (parent study), and to collect long-term 
safety data. Additional participants may be added via amendment(s) to this protocol in the future 
if new demand for participants transitioning into this rollover study emerges.
4
Study Objectives
4.1
Primary Objective
! To monitor safety of participants that are on long-term treatment with berzosertib.
4.2
Secondary Objectives
None. 
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5
Investigational Plan
5.1
Overall Study Design and Plan
Participants from the Vertex clinical study VX13-970-002 still on active berzosertib treatment at 
the time of termination/transition may be enrolled in the Merck KGaA-sponsored study and 
continue treatment with berzosertib as monotherapy or in combination with other drugs and be 
monitored for safety. A schematic of the study design is presented in Figure 1. A schedule of study 
procedures/assessments is provided in Table 1.
Figure 1
Study design diagram of ATR inhibitor Transition Rollover Study
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Participants enrolled in the Merck KGaA-sponsored rollover study will continue treatment on the 
same dose and schedule as the original study, and will be monitored for safety as specified in Table 
1. The participants will complete a Safety Follow Up visit to be scheduled 28 (+7) days after the 
last administration of berzosertib. Participants who transferred from combination treatment to 
berzosertib monotherapy before enrollment in this study should continue accordingly.
5.2
Discussion of Study Design
This will be a multicohort Safety Follow Up study. Participants will be transitioned from Vertex 
clinical study VX13-970-002. The participants will continue treatment on the same dose and 
schedule as the original study after being transitioned. The number and nature of the cohorts will 
be determined by the treatments in the studies from which participants are transitioning.
5.2.1
Scientific Rationale for the Study Design
To continue treatment and monitoring of safety of participants who are on treatment with 
berzosertib in a study at the time when that study is to be terminated.
5.2.2
Justification for Dose 
Participants in this rollover study will continue to receive the dosage of berzosertib and any other 
study intervention(s) that are being used in the study from which they transitioned. In case of a 
dose/schedule modification in the previous study, participants will continue on the modified 
dose/schedule.
5.2.3
Rationale for Endpoints
This will be a study to monitor the safety of participants who are on long-term treatment receiving 
berzosertib either as monotherapy or combination treatment. Therefore, no other endpoints beyond 
safety monitoring are required.
5.2.4
Inclusion of Special Populations
Not applicable.
5.3
Selection of Study Population
Only participants that are ongoing with treatment in the Vertex study VX13-970-002 may be 
enrolled into this study. Participants will be transitioned from the VX13-970-002 study to enable 
them to continue treatment with berzosertib. Prior to performing any study assessments not part of 
the participant’s routine medical care, the Investigator will ensure that the participant or the 
participant’s legal representative has provided written informed consent following the procedure 
described in Section 9.2.
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5.3.1
Inclusion Criteria
! Ongoing treatment in Vertex clinical study VX13-970-002 (parent study)
! Participant must be able to understand and provide written informed consent
! Participant must be willing and able to comply with the scheduled visits, treatment plan, 
lifestyle, laboratory tests, contraceptive guidelines (as described in Appendix I), and other study 
procedures.
5.3.2
Exclusion Criteria
! Participants experiencing disease progression or unacceptable toxicity at the time of transition
from the VX13-970-002 study into the Safety Follow Up study.
5.4
Criteria for Initiation of Study Treatment
Participants will continue the treatment with berzosertib as monotherapy or in combination with 
other study interventions as administered in the VX13-970-002 study.
5.5
Criteria for Participant Withdrawal
5.5.1
Withdrawal from Study Therapy
A participant must be withdrawn from study treatment if any of the following occur in this Safety 
Follow Up study:
! Participant withdraws consent
! Participant is reported to have disease progression or unacceptable toxicity
! Participation in another clinical study
! Any events that unacceptably endanger the safety of the participant
! Protocol noncompliance (to be discussed on a case-by-case basis with the Sponsor). 
5.5.2
Withdrawal from the Study
Participants may withdraw from the study at any time without giving a reason. Withdrawal of 
consent will be considered withdrawal from the study.
A participant must be withdrawn if any of the following occur during the study:
! Participant withdraws consent
! Participant is lost to follow up
! Participation in another clinical study.
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5.6
Premature Termination of the Study
The clinical study may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for
berzosertib. The Sponsor may discontinue the study if it becomes unjustifiable for medical or 
ethical reasons or because of discontinuation of clinical development of berzosertib. In case of 
termination of the study, the Health Authorities and Independent Ethics Committees 
(IECs)/Institutional Review Boards (IRBs) will be informed about the discontinuation of the study 
in accordance with applicable regulations.
5.7
Definition of End of Study
This rollover study will be ongoing while any participant is receiving berzosertib. The end of the 
study will be the day when the last participant has completed the Safety Follow Up visit to be 
scheduled 28 (+7) days after the last administration of berzosertib.
The Sponsor may terminate the study at any time once access to berzosertib for participants still 
benefiting is provisioned via expanded access, marketed product or another mechanism of access 
as appropriate.
6
Study Intervention
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol.
6.1
Description of Study Intervention
Study intervention dosing and schedule for participants in this rollover study will be identical to 
the dosing and schedule of the study intervention(s) received in the study from which the 
participant transitioned. This implies that participants receiving combinations of berzosertib with 
any other drugs in the study from which the participant is transitioned will continue to receive the 
same study interventions in this Safety Follow Up study. 
The study intervention (berzosertib) administered in this study will be supplied and distributed by 
the Sponsor or designee. Combination drugs will be obtained from the local pharmacies.
Berzosertib will be supplied as 
 
 to be diluted in 
 before intravenous infusion.
6.2
Dosage and Administration
Dosage and schedule of berzosertib administration will depend on the details of treatment in the
VX13-970-002 study from which the participant transitioned.
More general recommendations for study intervention administration and management (e.g.,
details of administration, dose modification for toxicity, missed doses etc.) are given in the 
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VX13-970-002 protocol from which the participants are transitioning. Details of dose preparation 
are provided in the Formulation Preparation Instructions (see Appendix III).
The dose of berzosertib will be infused intravenously over 60 minutes (± 10 minutes). If the total 
volume of the infusion exceeds 600 mL, the infusion time may be extended beyond 60 minutes, as 
tolerated, but no more than 90 minutes. Details of dose preparation for berzosertib will be provided 
in the Pharmacy Manual.
Intravenous administration of berzosertib is independent of food intake. 
To minimize the possibility of phlebitis, berzosertib should be administered through a large bore 
catheter into a large caliber peripheral vein. If any participant develops phlebitis or signs or 
symptoms of inflammation that may progress to phlebitis or that the participant cannot tolerate, 
standard measures should be employed to ameliorate these symptoms (including removal of the 
infusion catheter and resumption of infusion through a different vein).
6.3
Assignment to Treatment Groups
Participants on active treatment will continue receiving treatment at the same dosage and 
frequency as in the study the participant transitioned from.
6.4
Concomitant Medications and Therapies
All concomitant medications taken by the participant during the study, from the date of signature 
of informed consent are to be recorded in the appropriate section of the electronic Case Report 
Form (eCRF), noting the name, dose, duration and indication of each drug. Nondrug interventions
and any changes to a concomitant medication or other intervention should also be recorded in the 
eCRF.
6.4.1
Permitted Medicines
Any medications that are considered necessary to protect participant welfare and will not interfere 
with the study intervention may be given at the Investigator’s discretion.
Premedication with hydrocortisone and chlorphenamine and rescue medications may be 
administered to address anticipated adverse reactions or anticipated emergency situations (see 
Section 6.4.5).
Antiemetics and supportive therapies will be administered or dispensed to participants according 
to individual site Standard of Care.
6.4.2
Prohibited Medicines
In vitro drug metabolism studies suggest that berzosertib is a substrate of cytochrome P450 (CYP) 
3A, and its systemic exposure may be affected by concomitant medications that are strong CYP3A 
inhibitors or inducers. 
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Prior and concomitant medication restrictions during treatment include:
! Grapefruit/grapefruit juice, Seville or blood oranges/marmalade
! Strong CYP3A inhibitors or inducers
! Ototoxic or Nephrotoxic medication for participants receiving carboplatin. 
For a more complete list of study prohibited and cautioned medication/food/activity, see
Appendix IV.
6.4.3
Other Interventions
Not applicable.
6.4.4
Special Precautions
6.4.4.1
Risk of Phototoxicity
All participants should be advised to avoid prolonged or intense sun exposure, sunlamps, and 
tanning beds. Use of sunscreen, clothing, and eyewear that decrease sun exposure is recommended.
6.4.4.2
Contraception
Women of childbearing potential and males must use a highly effective method of contraception 
(i.e., methods with a failure rate of less than 1% per year when used consistently and correctly) as 
detailed below throughout the study and for 6 months after the last dose of assigned treatment. 
All participants must undergo appropriate contraceptive counselling. The Investigator or any 
skilled representative of the study site should counsel participants on the most effective method(s) 
for avoiding pregnancy during the study.
Men
Acceptable contraceptive methods must be used from Screening visit through 6 months after last 
dose of the study intervention, and include the following:
! True abstinence (abstinence of any sexual intercourse, when in line with the preferred and usual 
lifestyle of the participant). Periodic abstinence (e.g., calendar, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception.
! Condom with or without spermicide. In addition, the female partner must use a highly effective 
contraception method as outlined in Appendix I.
! Surgical sterilisation (vasectomy) with a negative sperm post-vasectomy semen analysis; If the 
absence of sperm has not been confirmed, men must use a condom and their female partner 
must use a highly effective contraception method as outlined in Appendix I. 
Men must not donate sperm from Screening visit through 6 months after last dose of the study 
intervention.
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Women of Nonchildbearing Potential
Women in the following categories are not considered women of childbearing potential:
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥ 12 consecutive months and 
increased follicle-stimulating hormone (FSH) > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, a follicle-stimulating hormone will be drawn at Screening.
! Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use one of the non-hormonal highly effective contraception methods if 
they wish to continue their hormone replacement therapy during the study. Otherwise, they 
must discontinue hormone replacement therapy to allow confirmation of postmenopausal 
status before study enrollment.
All other female participants (including participants with tubal ligations and participants who 
do not have a documented hysterectomy) will be considered to be of childbearing potential.
Women of Childbearing Potential
A highly effective contraception as outlined in Appendix I must be used before start of first dose 
of study treatment, during the treatment period and for at least 6 months after the last dose of study 
treatment. 
The following contraception methods are not considered to be highly effective birth control 
methods and must not be used: 
! Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action
! Male or female condom with or without spermicide 
! Cap, diaphragm or sponge with spermicide 
! Combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods).
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6.4.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
Based on the observations made so far, participants experienced significant physical discomfort, 
defined variably by diaphoresis, flushing, dyspnea, nausea, diarrhea, change in mental status, 
and/or hypotension several minutes after administration of their second dose of berzosertib. 
Investigators may prophylactically premedicate all participants with 200 mg hydrocortisone 
approximately 60 minutes before infusion, and 10 mg of chlorphenamine approximately 
30 minutes before infusion.
6.5
Packaging and Labeling of the Study Intervention
Berzosertib will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
6.6
Preparation, Handling, and Storage of the Study Intervention
Berzosertib single use vials must be carefully stored at 
 
, in a location with restricted access, and separately from other drugs. 
Following dilution of the test material, intravenous bags should be covered to protect from light 
and stored in the dark. 
Any deviations from the recommended storage conditions should be immediately reported to the 
Sponsor, and the medication should not be used until authorization has been received from the 
Sponsor. The study interventions must not be used for any purpose other than the study. The 
administration of the study intervention to participants who have not been enrolled into the study 
is not covered by the study insurance.
Disposal of the study interventions should be according to local regulations and institutional 
guidelines.
6.7
Study Intervention Accountability
The Investigator is responsible for ensuring berzosertib accountability, including reconciliation of 
drugs and maintenance of records.
! Upon receipt of study intervention, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
! Study intervention dispensing will be recorded on the appropriate drug accountability forms so 
that accurate records will be available for verification at each monitoring visit.
! Study site study intervention accountability records will include the following:
 Confirmation of study intervention receipt, in good condition and in the defined temperature 
range
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 The inventory of study intervention provided for the clinical study and prepared at the site
 The use of each dose by each participant
 The disposition of any unused study intervention
 Dates, quantities, batch numbers, vial/kit numbers (as applicable), expiry dates, formulation 
(for study intervention prepared at the site), and the individual participant study numbers.
The Investigator site should maintain records, which adequately document that participants were 
provided the doses specified in this protocol, and all study interventions provided were fully 
reconciled.
Unused study intervention must not be discarded or used for any purpose other than the present 
study. No study intervention that is dispensed to a participant may be redispensed to a different 
participant.
A Study Monitor will periodically collect the study intervention accountability forms.
After completion of the study, any study intervention distributed to the site but not administered, 
dispensed to or taken by the participant(s) will be destroyed at the study site. Details will be agreed 
upon between the Sponsor and the Investigator. All unused medications will be carefully recorded 
and documented before destruction.
6.8
Assessment of Study Intervention Compliance
Berzosertib will be administered under the direct supervision of the Investigator or designee. For 
all doses of the study intervention, the number of units administered and missed doses will be 
recorded in the eCRF. All modifications in study intervention dose or interval between dosing, as 
well as the reason for modification, will be recorded in the eCRF. 
6.9
Blinding
Not applicable.
6.10
Emergency Unblinding
Not applicable.
6.11
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical study
protocol or planned for an individual participant enrolled in the study. Even if it does not meet 
other criteria for a serious adverse event (SAE), any overdose must be recorded in the study
medication section of the eCRF and reported to Drug Safety in an expedited manner using the SAE 
Report Form, and following the procedure in Section 7.4.
For dose modification and toxicity, refer to the Dose Modification for Toxicity section from the
VX13-970-002 protocol.
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6.12
Medical Care of Participants after End of Study
After a participant has completed the study or has been withdrawn, further treatment will be 
administered, if required, in accordance with the study site’s Standard of Care and generally 
accepted medical practice depending on the participant’s individual medical needs.
The Sponsor will not provide any additional care to participants after they leave the study because 
such care should not differ from what is normally expected for participants with advanced tumors. 
7
Study Procedures and Assessments
7.1
Schedule of Assessments
Prior to performing any study assessments that are not part of routine medical care for the 
participant, the Investigator will obtain written informed consent as described in Section 9.2.
A detailed Schedule of Assessments is provided in Table 1. 
7.1.1
Enrollment
Participants still on active study intervention at the termination/transition of the VX13-970-002 
will be enrolled in this Safety Follow Up study. 
7.1.2
Treatment
The participant will continue treatment at the same dose and according to the same schedule as in 
the VX13-970-002 study.
7.1.3
Safety Follow Up
Safety Follow Up will include a Safety Follow Up visit to be scheduled 28 (+7) days after the last 
administration of berzosertib. Participants will be treated according to institutional standards of 
care, including monitoring of disease progression. 
7.2
Demographic and Other Baseline Characteristics
At enrollment, the following demographic data will be documented in the eCRF: date of birth, sex
(gender), race, and participant identifier from the parent study.
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of the nature, occurrence, and severity of treatment-emergent adverse events (TEAEs). 
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Physical examination, weight, vital signs, serum chemistry, hematology and urinalysis will be 
measured as per Standard of Care and institutional guidelines and as clinically indicated; only 
clinically significant values should be reported as AEs.
A clinically significant value is a result that a clinician would consider to be medically meaningful. 
Clinically significant values may be more severe than values expected for the participant’s 
condition, age, and gender.
Comprehensive assessment of any apparent toxicity experienced by each participant will be 
performed from the time of giving informed consent and throughout the study. The Investigator 
will report any AEs, whether observed by the Investigator or reported by the participant (see 
Section 7.4.1.2). The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant or clinical investigation participant
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute Common Terminology Criteria for AEs 
(NCI-CTCAE) (Version 4.03), 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 of 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 following 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
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! Grade 5 or Death 
According to Sponsor convention, 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 seriousness criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for e.g., sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to the study 
intervention using the following definitions. Decisive factors for the assessment of causal 
relationship of an AE to the study intervention include, but may not be limited to, temporal 
relationship between the AE and the study intervention, known side effects of the study 
intervention, medical history, concomitant medication, course of the underlying disease, study
procedures.
Unrelated:
Not reasonably related to the study intervention. The AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the study intervention. The AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an 
electrocardiogram [ECG] trace) should not be reported as AEs unless they are associated with 
clinical signs and symptoms, lead to treatment discontinuation or are considered otherwise 
medically important by the Investigator. If a laboratory abnormality fulfills these criteria, the 
identified medical condition (for e.g., anemia or increased alanine aminotransferase) must be 
reported as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. (“Life-threatening” refers to an event in which the participant is at risk of 
death at the time of the event, not an event that hypothetically might have caused death if it was
more severe)
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
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! Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse).
In this clinical study, any late spontaneous abortion, fetal death in utero, ectopic pregnancy, chronic 
fetal distress, stillbirth, neonatal death, or prematurity-related complication more than is typical 
for prematurity should be considered as an SAE (see Section 7.4.2).
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study treatment or study procedures (e.g., an
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression 
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the participant’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the adverse event reporting period (as defined in Section 7.4.1.3).
Adverse Events of Special Interest 
No adverse events of special interest have been identified.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
whether reported by the participant or observed by the Investigator. Adverse events that are 
ongoing during transition from the VX13-970-002 study will be recorded at enrollment to ensure
the outcome and end date of the AE are captured. 
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Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate Report Form as 
described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration, onset and 
resolution dates (and also onset and resolution times when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified and the appropriate seriousness criteria 
documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the participant is initially enrolled in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until 28 days after the last administration of berzosertib.
Any SAE assessed as related to berzosertib must be reported whenever it occurs, irrespective of 
the time elapsed since the last administration of berzosertib.
7.4.1.4
Procedure for Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the electronic SAE report form in the Electronic Data Capture 
(EDC) system. Reporting of SAEs using a paper report form is required as a back-up method 
only for an EDC system failure. Names, addresses, and telephone and fax numbers will be 
included on the paper form. All information from the paper form must be transcribed into the 
electronic form as soon as the system becomes available.
In exceptional circumstances, an SAE (or follow up information) may be reported by telephone; 
in these cases, an electronic SAE form must be completed immediately thereafter.
Relevant pages from the eCRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report). 
The Investigator must respond to any request for follow up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
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reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow up will usually be made via the Study Monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the IEC/IRB that approved 
the study. 
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of participants, impact the conduct of the study or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study.” In particular and in line with 
respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (suspected 
unexpected serious adverse reactions). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/ Suspected unexpected serious adverse reaction/ Safety Issues 
will be carried out in accordance with that Directive and with the related Detailed Guidance
documents.
7.4.1.6
Monitoring of Participants with Adverse Events
Adverse events are recorded and assessed continuously throughout the study (see Section 7.4.1.3) 
and are assessed for final outcome at Safety Follow Up visit to be scheduled 28 (+7) days after the 
last administration of berzosertib. All SAEs ongoing at the Safety Follow Up visit must be 
monitored and followed up by the Investigator until stabilization or until the outcome is known, 
unless the participant is documented as “lost to follow up”. Reasonable attempts to obtain this 
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information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to the study intervention (e.g.,
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same 
rule applies to pregnancies in female participants and to pregnancies in female partners of male 
participants. The Investigator must notify the Sponsor/designee in an expedited manner of any 
pregnancy using the Pregnancy Report Form, which must be transmitted according to the same 
process as described for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the course of the study, the participant
must be discontinued from study medication immediately. The Sponsor/designee must be notified 
without delay and the participant must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected as per Standard of Care and institutional guidelines and 
as clinically indicated; only clinically significant values should be reported as AEs.
Laboratory assessments are summarized in Table 2.
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Table 2
Laboratory Assessments
Hematology
White blood cell count, red blood cell count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, platelet count, neutrophils (absolute and percentage), 
lymphocytes (absolute and percentage), monocytes (absolute and percentage), 
eosinophils (absolute and percentage), basophils (absolute and percentage)
Biochemistry
Sodium, potassium, blood urea nitrogen, creatinine, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, creatine kinase, gamma-
glutamyl transferase, lactate dehydrogenase, albumin, calcium, phosphate, 
glucose, total bilirubin, total protein, cholesterol, triglycerides, uric acid, chloride
Urinalysis
Leukocytes, protein, bilirubin, urobilinogen, ketones, red blood cells, pH, nitrite, 
specific gravity, glucose, microscopy when indicated by abnormal dipstick results
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs will be measured as per Standard of Care and institutional guidelines and as clinically 
indicated. 
7.4.4.2
Physical Examination
Physical examinations will be performed as per Standard of Care and institutional guidelines and 
as clinically indicated. Symptom directed physical examinations will be performed as clinically 
indicated at the Investigator’s judgment.
7.5
Pharmacokinetics
Not applicable.
7.6
Biomarkers
Not applicable.
7.7
Other Assessments
Not applicable.
8
Statistics
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8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoints
! Occurrence of AEs and treatment-related AEs in participants receiving berzosertib, graded 
according to NCI-CTCAE (Version 4.03).
8.3.2
Secondary Endpoints
Not applicable.
8.4
Analysis Sets
For the purposes of analysis, the following populations are defined: 
Enrolled analysis set: All participants who sign informed consent for this study.
Safety analysis set: All participants who receive at least 1 dose of study intervention in this study. 
Participants will be analyzed according to the actual treatment they receive. 
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Continuous measurements will be summarized by means of descriptive statistics (i.e., number of 
observations (n, both available and missing), mean, standard deviation, minimum, median, 
maximum), and categorical data will be summarized by means of frequency tables (i.e., count and 
percentages), if not stated otherwise. 
If not otherwise specified, “Baseline” refers to the last available measurement before 
administration of the first study intervention for each dose group from the VX13-970-002 study, 
as appropriate.
Depending on the number of participants enrolled, no summary statistics will be provided, and the 
data will be presented in listings only. Details will be provided in the Integrated Analysis Plan.
8.5.2
Analysis of Primary Endpoints
All safety data summaries will be based on the safety analysis set by dose group as from the 
VX13-970-002 study.
Adverse events will be coded according to the latest available version of the Medical Dictionary 
for Regulatory Activities (MedDRA). Severity of AEs will be graded using the NCI-CTCAE 
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(Version 4.03) toxicity grades. Adverse events will be summarized by frequency and incidence 
using MedDRA.
Treatment-emergent adverse events (after transition) are defined as AEs that were reported or 
worsened after signing the Informed Consent Form of this rollover study up to the Safety Follow
Up visit (28 [+7] days after the last administration of berzosertib).
Only TEAEs will be summarized in the tables. All summaries of TEAEs will be presented by the 
severity of the AE and relationship to the study intervention. Some rules that will apply to the 
summarization of AEs are: 
! A participant with multiple occurrences of the same AE or continuing AEs will only be counted 
once
! Only the maximum severity level will be presented in the severity summary
! Only the worst relationship level will be presented in the relationship summary. 
Treatment-emergent AEs leading to study intervention modification or permanent discontinuation 
will be summarized. 
Adverse events leading to death, SAEs, dose interruption of the study, or permanent 
discontinuation of the study intervention, and SAEs will be listed separately. Pretreatment AEs 
and TEAEs will be listed in individual participant data listings. Unresolved, ongoing AEs reported 
at the Safety Follow Up visit (28 [+7] days after the last administration of berzosertib) will be 
listed separately in an individual participant data listing. 
Laboratory and vital signs measurements will be summarized by dose group and/or time point 
using descriptive statistics for observed values and change from baseline values (as appropriate). 
Laboratory values outside the normal ranges will be identified in individual data listings. Shift 
from baseline according to normal range criteria may also be presented if deemed appropriate.
All clinical laboratory data will be stored in the database in the units in which they are reported 
and using the laboratory reference ranges as well as in the International System of Units.
Participant listings and summary statistics at each assessment time will be presented using the 
International System of Units.
8.6
Interim and Additional Planned Analyses
Not applicable.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at the site and will ensure that the study
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
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Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that only 
participants who have given informed consent are enrolled in the study.
9.2
Participant Information and Informed Consent
An unconditional prerequisite for each participant prior to participation in the study is written 
informed consent, which must be given before any study-related activities are carried out.
Adequate information must therefore be given to the participant by the Investigator or an 
appropriate designee (if local regulations permit) before informed consent is obtained. 
A participant information sheet must be prepared in the local language in accordance with ICH
GCP and will be provided by the Sponsor for the purpose of obtaining informed consent. In 
addition to providing this written information to a potential participant, the Investigator or a
designate will inform the participant verbally of all pertinent aspects of the study, using language 
chosen so that the information can be fully and readily understood by laypersons. The participant
will be given sufficient time to read the information and the opportunity to ask questions and to 
request additional information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the participant
about the study and sign the Informed Consent Form (ICF), as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
participant and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing and 
inspection purposes. A copy of the signed and dated information and ICF should be provided to 
the participant prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the participant information sheet and any other written information to 
be provided to the participants and submit them to the IEC/IRB for review and opinion. Using the 
approved revised participant information sheet and other written information, The Investigator will 
explain the changes to the previous version to each study participant and obtain new written 
consent for continued participation in the study. The participant will be given sufficient time to 
read the information and the opportunity to ask questions and to request additional information 
and clarification about the changes.
9.3
Participant Identification and Privacy
A unique number will be assigned to each participant, immediately after informed consent has 
been obtained. This number will serve as the participant’s identifier in the study as well as in the 
clinical study database, and will be linked to the identifier assigned to the participant in the 
VX13-970-002 study. All participant data collected in the study will be stored under the 
appropriate participant number. Only the Investigator will be able to link study data to an 
individual participant via an identification list kept at the site. For each participant, original medical 
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data will be accessible for the purposes of source data verification by the Monitor, audits and 
regulatory inspections, but participant confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing participant data. Participants will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Participant Card
Participants will be provided with Emergency Medical Support cards supplied by the Sponsor for 
use during study participation in order to provide clinical study participants with a way of 
identifying themselves as participating in a clinical study and to give health care providers access 
to any information about this participation that may be needed to determine the course of medical 
treatment for the participant.
The first point of contact for all emergencies will be the clinical study Investigator caring for the 
affected participant. The Investigator agrees to provide his or her emergency contact information 
on the card for this purpose. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the study site 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.
9.5
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating to the study. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the study at a given site, this clinical study protocol will be submitted 
together with its associated documents (ICF, IB, Participant Information, and study specific 
material) to the responsible IEC or IRB for its favorable opinion or approval, which will be filed 
in the Investigator Site File. A copy will be filed in the Sponsor Trial Master File at the Sponsor 
or contract research organization. 
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the study, the clinical study protocol version 
and the Participant Information and ICF version reviewed should be provided. Where possible, 
copies of the meeting minutes should be obtained.
Amendments to this clinical study protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.4). Relevant safety information will 
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be submitted to the IEC or IRB during the course of the study in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical study protocol and any applicable documentation (e.g., study intervention Dossier, 
Participant Information and ICF) will be submitted or notified to the Health Authorities in 
accordance with all local and national regulations for each site.
10
Study Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical study protocol in a 
complete, accurate, legible and timely manner. The data in the eCRF should be consistent with the 
relevant source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
study is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any participant names.
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures have been completed. PDF files 
of the eCRFs will be provided to the Investigators at the completion of the study.
10.2
Source Data and Participant Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every participant in the study. It must be possible to identify each participant by using this 
participant file. This file will contain the demographic and medical information for the participant
listed below and should be as complete as possible. 
! Participant’s full name, date of birth, sex, height, and weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identification, that is, the Sponsor study number for this clinical study, and participant
number
! Dates for entry into the study (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in this clinical study protocol
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! All AEs
! Date that the participant left the study including any reason for withdrawal from the study or 
study intervention (if applicable).
All documents containing source data must be filed, including, laboratory results. Such documents 
must bear the participant number and the date of the procedure. If possible, this information should 
be printed by the instrument used to perform the assessment or measurement. As necessary, 
medical evaluation of such records should be performed; all evaluations should be documented,
signed, and dated by the Investigator.
Electronic participant files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site. Printing the files will not be necessary if the monitor is permitted to access
and review electronic participant files or other electronic study records at Investigator sites,
provided that they are given their own unique access and is “Read Only.”
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File 
containing all necessary study documents, which will be completed throughout the study and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor audits 
and for inspection by Health Authorities during and after the study, and must be safely archived 
for at least 15 years (or longer, per local requirements or as otherwise notified by the Sponsor) 
after the end of the study. The documents to be archived include the Participant Identification List 
and the signed participant ICFs. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee.
All original participant files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.3
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This study will be monitored in accordance with the ICH GCP and any other applicable 
regulations. The site Monitor will perform visits to the study site at regular intervals.
The clinical study protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical study report, will be participant to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the study to ensure the validity and 
integrity of the study data. Representatives of the Quality Assurance unit from the Sponsor or a 
designated organization, as well as Health Authorities, must be permitted to access all study
documents and other materials at the site, including the Investigator Site File, the completed 
eCRFs, all study intervention and study intervention accountability records, and the original 
medical records or files for each participant.
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10.4
Changes to the Clinical Study Protocol
Changes to the clinical study protocol will be documented in writing. Substantive amendments 
will usually require submission to the Health Authorities and to the relevant IEC/IRB for approval 
or favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the participant’s 
agreement to participate in the study requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.5
Clinical Study Report and Publication Policy
10.5.1
Clinical Study Report
After completion of the study, a clinical study report will be written by the Sponsor in consultation 
with the Coordinating Investigator following the guidance in ICH Topic E3.
10.5.2
Publications
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require review by the Sponsor before submission. The Sponsor will not 
suppress publication, but maintains the right to delay publication in order to protect intellectual 
property rights.
Posting data on EUDRA-CT is planned and will occur 12 months after the last clinic visit of the 
final study participant or another appropriate date to meet applicable requirements.
11
References Cited in the Text
Not applicable.
12
Appendices
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Appendix I: Contraception
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., Müllerian 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.
!
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in a female not using hormonal contraception or 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 nonestrogen 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, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea 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 II: Signature Pages and Responsible Persons for the Study
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Signature Page –Protocol Lead
Study Title:
A Rollover Study to Provide Continued Treatment 
With M6620
IND Number:
Not applicable
EudraCT Number:
2017-002354-37
Clinical 
Study
Protocol 
Date/Version:
01 March 2021/Version 4.0 
Protocol Lead:
I approve the design of the clinical study:
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Senior Medical Director
Institution:
Global Clinical Development Center - Oncology
Address:
Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany
Telephone number:
Fax number:
Not applicable
E-mail address:
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Signature Page – Coordinating Investigator
Study Title
A Rollover Study to Provide Continued Treatment With 
M6620
IND Number
Not applicable
EudraCT Number
2017-002354-37
Clinical Study Protocol 
Date/Version
01 March 2021/Version 4.0 
I approve the design of the clinical study, am responsible for the conduct of the study at this site 
and understand and will conduct it per the clinical study protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Coordinating Investigator
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Appendix IV: Prohibited Medication, Food and Activities During the Study
Study prohibited Medication
Generic Name
Brand Name
Notes
Boceprevir
Victrelis
Bosentan
Tracleer
Inducer
Carbamazepine 
Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, 
Stazepine, Telesmin, Teril, Timonil, Trimonil, Epimaz and others 
Inducer
Chloramphenicol 
Chloramycetin 
Ciclosporin 
Neoral, Cicloral and others 
Clarithromycin 
Biaxin, Klaricid, Klabax, Claripen, Claridar, Fromilid and others 
Conivaptan 
Vaprisol 
Cyproterone 
Androcur, Cyprostat, Cyproteron, Procur, Cyprone, Cyprohexal
Delavirdine 
Rescriptor 
Dexamethasone 
Decadron, Dexasone, Hexadrol 
Inducer
Dihydroergotamine 
DHE 45 
Efavirenz 
Sustiva, Stocrin 
Inducer
Ergotamine 
Ergormar, Cafergot 
Etravirine 
Intelence 
Inducer
Felbamate
Felbatol
Gestodene
Griseofulvin
Grisovin
Inducer
Indinavir
Crixivan
Inducer
Itraconazole 
Sporanox 
Indinavir 
Crixivan 
Ketoconazole 
Nizoral 
Mibefradil 
Posicor 
Mifepristone 
Mifeprex 
Modafinil 
Provigil, Alertec, Modavigil 
Nafcillin 
Unipen, Nallpen 
Nefazodone 
Serzone, Nefadar 
Nelfinavir 
Viracept 
Nevirapine 
Viramune 
Inducer 
Oxcarbazepine 
Trileptal 
Phenobarbital 
Solfoton, Luminal 
Inducer 
Phenytoin, 
Fosphenytoin 
Phenytek, Dilantin and others 
Cerebyx, Prodilantin and others 
Inducer 
Posaconazole 
Noxafil 
Primidone 
Mysoline 
Inducer 
Quinupristin/dalfopristin 
Synercid 
Rifabutin 
Mycobutin 
Inducer 
Rifampin 
Rifidin, Rimactane 
Inducer 
Rifapentine 
Priftin 
Inducer 
Ritonavir 
Norvir 
Nitonavir/darunavir 
Prezista 
Ritonavir/lopinavir 
Kaletra 
Saquinavir 
Invirase, Fortovase 
Telaprevir 
Incivek 
Telithromycin 
Ketek 
Tofisopam 
Emandaxin, Grandaxin 
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Troglitazone 
Rezulin, Resulin, Romozin 
Troleandomycin 
TAO 
Voriconazole 
Vfend 
Study Prohibited Food and Herbal Supplements
Name
Notes/Description
Grapefruit juice
Included sodas that contain concentrated grapefruit juice
Hyperforin
Inducer – constituent of St. Johns Wort
Pomelos
Seville Oranges
St Johns Wort
Inducer
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Appendix V: Protocol Amendment History
The information for the current amendment is on the title page.
The following information provides a high-level summary of previous amendments with the most 
recent amendment listed first.
Amendment 2 (17 November 2020)
Section # and Name
Description of Change
Brief Rationale
Synopsis
Table 1
Section 7.4.3 Clinical 
Laboratory Assessment
Section 7.4.4.1 Vital signs
Section 7.4.4.2 Physical 
Examination
Laboratory assessments (serum chemistry, 
hematology, and urinalysis), vital sign 
measurements, and physical examination 
will be only performed according to 
Standard of Care and institutional 
guidelines and as clinically indicated; only 
clinically significant changes will be 
recorded as adverse events (AEs).
To reduce the study assessments for
the participant and clinical site, 
leveraging them according to the 
clinical site Standard of Care. The 
study requires any clinically significant 
values to be collected as AEs to ensure 
patient’s safety throughout the study 
treatment.
Synopsis
Planned study period changed to“ 
estimated 5 years”
For clarity.
Synopsis
Section 8.3.1 Primary 
Endpoints
Primary endpoint updated to “Occurrence 
of adverse events (AEs) and 
treatment-related AEs in participants 
receiving berzosertib, graded according to 
the National Cancer Institute Common 
Terminology Criteria for AEs (NCI-CTCAE) 
(Version 4.03)”
To align with current Merck KGaA 
endpoint library.
Table 2 
Removed Table 2 (VX13-970-002 Part B2) 
SoA.
Since VX13-970-002 study was 
completed and no participants from 
Part B2 were transitioned to this study.
Section 3 Background 
Information
Section 3.1 Study 
Rationale
Description of VX13-970-002 study was 
updated and description of VX12-970-001 
study was deleted.
Since VX13-970-002 study was 
completed and no participants were 
transitioned to this study from Study 
VX12-970-001.
Figure 1 
Updated and simplified Figure 1 
For clarity.
Section 5.7 Definition of 
End of Study
Added the statement “The Sponsor may 
terminate the study at any time once 
access to berzosertib for participants still 
benefiting is provisioned via expanded 
access, marketed product or another 
mechanism of access as appropriate”.
For flexibility and clarity.
Section 6.2 Dosage and 
Administration
Section 6.4 
Noninvestigational 
Medicinal Products to be 
Used(deleted)
Section 6.4.1 Permitted 
Medicines
Text regarding infusion of berzosertib after 
chemotherapy (carboplatin and paclitaxel) 
removed
Since participant not receiving any 
chemotherapy agents (paclitaxel and 
carboplatin).
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Section # and Name
Description of Change
Brief Rationale
Section 7.4 Assessment 
of Safety
Added the statement “Physical 
examination, weight, vital signs, serum 
chemistry, hematology and urinalysis will 
be measured as per Standard of Care and 
institutional guidelines and as clinically 
indicated; only clinically significant values 
should be reported as AEs. 
A clinically significant value is a result that 
a clinician would consider to be medically 
meaningful. Clinically significant values 
may be more severe than values expected 
for the participant’s condition, age, and 
gender”.
For clarity.
Section 7.4.1 Adverse 
Events
Section updated and text added to specify 
that “In this clinical study, any late 
spontaneous abortion, fetal death in utero, 
ectopic pregnancy, chronic fetal distress, 
stillbirth, neonatal death, or prematurity-
related complication more than is typical for 
prematurity should be considered as an 
SAE.”
To align with current Merck KGaA 
standard.
Section 7.4.1.4 Procedure 
for Reporting Serious 
Adverse Events
Specified that serious adverse events to be 
reported using Electronic Data Capture 
(EDC) and paper reports required only in 
case of EDC system failure.
This study will use electronic Case 
Report Forms.
Section 8.5.1 General 
Considerations
Specified that depending on the number of 
participants enrolled, no summary statistics 
will be provided and the data will be 
presented in listings only.
Only one participant was enrolled in 
this study to date. All other participants 
completed berzosertib study 
intervention within the initial study 
protocol.
Section 10.1 Case Report 
Form Handling
Removed text about paper Case Report 
Forms.
This study will use electronic Case 
Report Forms.
Section 10.2 Source Data 
and Participant Files
Added a clarification statement regarding 
when printing files is not necessary.
To add flexibility to study data 
management.
Appendix I Contraception 
Contraception information updated.
To align with current Merck KGaA 
standard.
Appendix III Vertex 
VX13-970-002 Clinical 
Study Protocol
Removed previously appended Vertex 
protocol.
To align with Merck standard not to 
append a protocol with standalone 
documents.
Appendix IV Protocol 
Amendment History
The protocol amendment history 
information was moved to the front of the 
document.
To align with current Merck standards 
and style of reporting.
Throughout
Minor editorial and document formatting 
revisions
Minor; therefore, not summarized.
Amendment 1 (18 September 2017)
Section # and Name
Description of Change
Brief Rationale
Table 1 header and vital signs/footnote
Deleted 28 days in treatment 
cycle and added vital signs 
at Day 15. 
For clarification and to 
update to company 
standards for vital sign 
measurements.
Document No. 0900babe815bc205v1.0
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Section # and Name
Description of Change
Brief Rationale
Table 2 (VX13-970-002 Part B2) footnote
Vital sign measurements 
clarified in table footnote.
To update to company 
standards for vital sign 
measurements.
Table 2 (VX13-970-002 Part B2) footnote
The following footnote was 
added:
“The participants who are not 
able to tolerate combination 
therapy 
due 
to 
toxicity 
associated with carboplatin 
and/or 
paclitaxel 
and 
continue on single agent 
M6620 should be assessed 
according to Schedule of 
Assessments for Participants 
Transitioned from Part A1: 
Single Agent Therapy once 
weekly (see Table 1)”
To provide for a plan in case 
of combination tolerability 
issues.
Section 5.1 Overall Study Design and Plan
Added sentence specifying 
that participants who 
transferred from combination 
treatment to M6620 
monotherapy before 
enrollment in this rollover 
study should continue 
accordingly in this protocol.
For clarification.
Throughout
Minor editorial and 
document formatting 
revisions
Minor; therefore, have not 
been summarized
Document No. 0900babe815bc205v1.0
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SAP_001.pdf: 
M6620 
 
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MS201923-0007 Version 1 
 
 
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Integrated Analysis Plan 
Clinical Trial Protocol 
Identification No. 
MS201923-0007 
Title 
A Rollover Study to Provide Continued Treatment with M6620 
Trial Phase 
I 
Investigational Medicinal 
Product(s) 
M6620 
Clinical Trial Protocol 
Version 
08 September 2017 / Version 2.0 
Integrated Analysis Plan 
Author 
Coordinating Author 
 
, Merck 
 
Function 
Author(s) / Data Analyst(s) 
 
 
 
 
 
Integrated Analysis Plan 
Date and Version 
28 January 2019 / Version 1 
Integrated Analysis Plan 
Reviewers 
 
Function 
Name 
 
 
, Merck 
 
, Merck 
 
 
 
 
 
 
 
 
Confidential 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies. 
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without 
express permission of Merck KGaA, Darmstadt, Germany or its affiliate.  
Copyright © 2018 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 
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Approval Page 
 
Integrated Analysis Plan: MS201923-0007 
 
A Rollover Study to Provide Continued Treatment with M6620 
 
Merck responsible 
Date 
Signature 
 
Via ELDORADO approval process 
 
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1 
Table of Contents 
Integrated Analysis Plan ......................................................................................................1 
Approval Page 
2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................4 
3 
Modification History ............................................................................5 
4 
Purpose of the Integrated Analysis Plan ...............................................5 
5 
Objectives and Endpoints .....................................................................5 
6 
Overview of Planned Analyses .............................................................5 
7 
Changes to the Planned Analyses in the Clinical Trial Protocol ..........5 
8 
Protocol Deviations and Analysis Sets .................................................5 
9 
General Specifications for Data Analyses ............................................6 
10 
Trial Subjects ........................................................................................6 
10.1 
Disposition of Subjects and Discontinuations ......................................6 
10.2 
Protocol Deviations ..............................................................................6 
11 
Demographics and Other Baseline Characteristics ...............................6 
12 
Concomitant Medications/Procedures ..................................................6 
13 
Treatment Compliance and Exposure ...................................................6 
14 
Efficacy Analyses .................................................................................6 
15 
Safety Analyses ....................................................................................6 
15.1 
Adverse Events .....................................................................................7 
15.2 
Clinical Laboratory Evaluation .............................................................7 
15.3 
Vital Signs ............................................................................................7 
16 
References .............................................................................................7 
17 
Appendices ...........................................................................................7 
 
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2 
List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
eCRF 
Electronic Case Report Form 
ENR 
Enrolled Analysis Set 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SDTM 
Study Data Tabulation Model 
WHO-DD 
World Health Organization-Drug Dictionary 
 
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3 
Modification History 
Unique 
Identifier for 
Version 
Date of 
IAP Version 
Author 
Changes from the Previous Version 
1.0 
28Jan2019 
 
Initial version. 
4 
Purpose of the Integrated Analysis Plan 
The purpose of this Integrated Analysis Plan (IAP) is to document technical and detailed 
specifications for the presentation of data collected for protocol MS201923-0007.  
The IAP is based upon Section 8 (Statistics) of the trial protocol and protocol amendments and is 
prepared in compliance with International Conference on Harmonization (ICH) E9. 
5 
Objectives and Endpoints 
 
 
Objective 
Endpoint 
IAP 
section 
Primary 
Objective 
To monitory safety of subjects that are on 
long-term treatment with M6620. 
Occurrence adverse events (AEs) in 
subjects receiving M6620, graded 
according to National Cancer Institute 
Common Terminology Criteria for AEs 
(NCI-CTCAE) (Version 4.03), 28 days 
after the last administration of M6620. 
15.1 
6 
Overview of Planned Analyses 
There are no interim analyses planned for this study.  All final, planned analyses identified in the 
Clinical Trial Protocol and in this IAP will be performed only after the last subject has completed 
the study with all trial data in-house, all data queries resolved, and the database locked.  
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved. 
7 
Changes to the Planned Analyses in the Clinical Trial Protocol 
Due to the small number of subjects on the study, no statistical analysis will be conducted, and the 
data will be presented in listings only. 
8 
Protocol Deviations and Analysis Sets 
The following populations are defined per protocol. 
Enrolled analysis set (ENR): All subjects who sign informed consent for this study. 
Safety analysis set (SAF): All subjects who receive at least 1 dose of study drug in this study. 
Subjects will be analyzed according to the actual treatment they receive. 
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9 
General Specifications for Data Analyses 
All data will be listed as collected, and no derived datasets will be produced.  All listings will be 
based upon the Study Data Tabulation Model (SDTM) datasets.  Subjects will be listed according 
to the cohort in which they were continued from the previous study. 
10 
Trial Subjects 
10.1 
Disposition of Subjects and Discontinuations 
Subject disposition and treatment/trial discontinuation data will be listed as collected on the 
electronic case report form (eCRF). 
10.2 
Protocol Deviations 
All important deviations from inclusion/exclusion criteria will be listed. 
11 
Demographics and Other Baseline Characteristics 
All demographic and baseline characteristics data will be listed as collected on the eCRF. 
12 
Concomitant Medications/Procedures 
Concomitant medications, as reported on the eCRF, will be listed according to the Anatomical 
Therapeutic Class (ATC) Level 2 text and preferred term as given from the current version of the 
World Health Organization-Drug Dictionary (WHO-DD) dictionary at time of database lock and 
noted as to whether they were ongoing at the time of study transition. 
Concomitant procedures will be listed according to the reported name and standardized name as 
given from the current version of the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary at the time of database lock.   
13 
Treatment Compliance and Exposure 
All exposure data will be listed, as collected on the eCRF, by the drug administered. 
14 
Efficacy Analyses 
Not applicable. 
15 
Safety Analyses 
All safety data will be listed as collected on the eCRF.  
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15.1 
Adverse Events 
All adverse events (AEs) will be listed according to the preferred term as given from the current 
version of the MedDRA dictionary at the time of database lock.  All serious adverse events (SAEs) 
will be noted in the main AE listing, and a separate SAE listing will be produced. 
15.2 
Clinical Laboratory Evaluation 
Clinical laboratory results will be listed with the applicable normal ranges along with flags for 
above/below normal range.   
15.3 
Vital Signs 
All vitals sign results and subject weights will be listed as collected on the eCRF. 
16 
References 
Not applicable. 
17 
Appendices 
Not applicable. 
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