Conditions: Locally Advanced Rectal Cancer
Keywords: DNA-PK inhibitor Peposertib capecitabine
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The main purpose of the study was to define maximum tolerated dose (MTD), recommended Phase II dose (RP2D) safety and tolerability of Peposertib in combination with capecitabine and radiotherapy (RT).

Detailed description:

Arms:
arm 1: Participants received peposertib 50 milligram (mg) once daily in combination with capecitabine 825 milligram per square meter (mg/m\^2) twice daily 5 days per week and radiotherapy (RT) of 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. arm 2: Participants received peposertib 100 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. arm 3: Participants received peposertib 150 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period. arm 4: Participants received peposertib 250 mg once daily in combination with capecitabine 825 mg/m\^2 twice daily 5 days per week and RT of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks treatment period.

Interventions: intervention 1: Peposertib 50 mg intervention 2: Peposertib 100 mg intervention 3: Peposertib 150 mg intervention 4: Peposertib 250 mg intervention 5: Capecitabine intervention 6: Radiotherapy (RT)
Intervention descriptions: intervention 1: Participants received peposertib 50 milligram (mg) once daily 5 days per week up to 5.5 weeks. intervention 2: Participants received peposertib 100 mg once daily 5 days per week up to 5.5 weeks. intervention 3: Participants received peposertib 150 mg once daily 5 days per week up to 5.5 weeks. intervention 4: Participants received peposertib 250 mg once daily 5 days per week up to 5.5 weeks. intervention 5: Participants received capecitabine at a dose of 825 milligram per square meter (mg/m\^2) twice daily 5 days per week up to 5.5 weeks. intervention 6: Participants received RT 50 to 50.4 Gray (Gy) to the tumor area and 45 Gy to the electively irradiated tissues in 25 to 28 fractions up to 5.5 weeks.

Protocol document:
Prot_000.pdf: 




Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Section # and Name
Description of Change
Brief Rationale
Title Page
Removed the details of Medical 
Responsible and Medical 
Monitor.
Removed the row for protocol 
previous version.
Required and/or 
recommended changes per 
Merck Protocol Template 
version 15.
Section 5 Study Population
Appendix 2 Study Governance
Included mandatory text 
regarding participant’s legal 
representative.
Removed the definition of “legally 
authorized representative” from 
Appendix 2.
Section 1.1 Synopsis
Section 1.2 Schema
Section 1.3 Schedule of Activities
Section 2.3 Benefit/Risk Assessment
Section 3 Objectives and Endpoints
Section 3.1 Definitions of Pathological 
Complete Response and Clinical Complete 
Response, and Derivation of the Composite 
Endpoint
Section 4.1 Overall Design
Section 4.1.2 Treatment Period
Section 4.1.3 Follow-up Periods
Section 4.2 Scientific Rationale for Study
Design
Section 5.4 Screen Failures
Section 6.1 Study Intervention(s) Administration
Section 6.3.1 Study Intervention Assignment
Section 6.3.2 Blinding
Section 6.3.3 Emergency Unblinding (Section 
removed)
Section 6.6 Dose Selection and Modification
Section 6.6.2 Dosing Instructions (and 
subsections)
Section 8 Study Assessments and Procedures
Section 8.1.1 Pathological Complete Response
Section 8.1.2 Tumor Evaluation Methods and 
Response Assessment
Section 8.1.3 Quality of Life (Section removed)
Section 8.2.3 Electrocardiograms
Section 8.5 Pharmacokinetics
Section 9.3 Population for Analyses
Section 9.4 Statistical Analyses
Section 9.4.1 Efficacy Analyses
Section 9.4.2 Safety Analyses
Section 9.4.3 Other Analyses
Section 9.4.4 Sequence of Analyses
Appendix 2 Study Governance
Appropriate details of Phase II 
part of the study removed from 
the protocol in the respective 
sections.
Study will be prematurely 
discontinued. Participants in 
Phase Ib will only be 
followed for 1 year, Phase II 
will not be started (see 
overall rationale above).
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
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radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 1.2 Schema
Section 1.3 Schedule of Activities
Section 3 Objectives and Endpoints
Section 4.1 Overall Design
Section 4.1.3 Follow-up Periods
Section 6.5 Concomitant Therapy
Section 8.1.2 Tumor Evaluation Methods and 
Response Assessment
Section 8.1.2.2 Tumor Response Evaluation
Section 8.2 Safety Assessments and
Procedures
Section 8.3.1 Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse 
Event Information
Section 8.3.3 Follow-up of Adverse Events and 
Serious Adverse Events
Appendix 5 Tumor Response Criteria
Long-term Safety Follow-up 
period shortened to 1 year 
(previously 2 years) and 
removed Survival Follow-up.
Safety Follow-up is reduced 
to 1 year since this will 
provide a sufficient 
timeframe to address any 
possible late toxicities due to 
radiotherapy that normally 
develop in the first year after 
treatment.
Section 1.1 Synopsis
Section 3 Objectives and Endpoints
Section 9.4.1 Efficacy Analyses
Removed the endpoints of 
“overall survival” and “best 
overall response”.
Overall survival removed as 
the Safety Follow-up period 
is reduced to 1 year. 
Section 1.1 Synopsis
Section 3 Objectives and Endpoints
Section 9.4.1 Efficacy Analyses
Added endpoint of “neoadjuvant 
rectal score”.
Due to discontinuation of 
Phase II, data on the 
neoadjuvant rectal score of 
Phase Ib will be analyzed to 
obtain more comprehensive 
data on antitumor activity.
Section 6.1 Study Intervention(s) Administration
Added that “for Spain, 
capecitabine will be provided by 
local vendor”.
To clarify the Supplier 
details of capecitabine in 
Spain.
Throughout
Minor editorial and document 
formatting revisions.
Minor; therefore, have not 
been summarized.
- Confidential –
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................5
List of Tables
..............................................................................................................9
List of Figures
..............................................................................................................9
1
Protocol Summary ..............................................................................11
1.1
Synopsis..............................................................................................11
1.2
Schema................................................................................................13
1.3
Schedule of Activities.........................................................................14
2
Introduction.........................................................................................31
31
2.2
Background.........................................................................................31
2.3
Benefit/Risk Assessment ....................................................................33
3
Objectives and Endpoints ...................................................................35
3.1
Definitions of Pathological Complete Response and Clinical 
Complete Response, and Derivation of the Composite Endpoint ......36
4
Study Design.......................................................................................38
4.1
Overall Design....................................................................................38
4.1.1
Screening Period.................................................................................38
4.1.2
Treatment Period ................................................................................38
4.1.3
Follow-up Periods...............................................................................39
4.2
Scientific Rationale for Study Design ................................................39
4.3
Justification for Dose..........................................................................40
4.4
End of Study Definition......................................................................41
5
Study Population.................................................................................41
5.1
Inclusion Criteria ................................................................................42
5.2
Exclusion Criteria...............................................................................44
5.3
Lifestyle Considerations .....................................................................45
5.3.1
Meals and Dietary Restrictions...........................................................45
5.3.2
Caffeine, Alcohol, and Tobacco .........................................................45
5.3.3
Activity ...............................................................................................46
5.4
Screen Failures....................................................................................46
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Phase Ib/II study of peposertib in combination with capecitabine and
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6
Study Intervention(s) ..........................................................................46
6.1
Study Intervention(s) Administration.................................................46
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................47
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................49
6.3.1
Study Intervention Assignment ..........................................................49
6.3.2
Blinding ..............................................................................................49
6.4
Study Intervention Compliance..........................................................49
6.5
Concomitant Therapy .........................................................................50
6.5.1
Prohibited Medicines..........................................................................50
6.6
Dose Selection and Modification........................................................51
6.6.1
Definition of Dose Limiting Toxicity.................................................51
6.6.2
Dosing Instructions.............................................................................52
6.6.2.1
Peposertib ...........................................................................................52
6.6.2.2
Capecitabine .......................................................................................53
6.6.2.3
Radiotherapy.......................................................................................54
6.6.2.4
Administration of the Combination Therapy......................................54
6.6.3
Management of Toxicities..................................................................55
6.6.3.1
Diarrhea ..............................................................................................55
6.6.3.2
Capecitabine Management for Toxicities Other Than Diarrhea.........55
6.6.3.3
Peposertib and Radiotherapy..............................................................57
6.6.3.4
Radiotherapy Treatment Delay...........................................................59
6.7
Study Intervention After the End of the Study...................................59
6.8
Special Precautions.............................................................................59
6.9
Management of Adverse Events of Interest........................................59
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................60
7.1
Discontinuation of Study Intervention................................................60
7.1.1
Temporary Discontinuation................................................................60
7.1.2
Rechallenge.........................................................................................60
7.2
Participant Discontinuation/Withdrawal from the Study ...................61
7.3
Lost to Follow-up ...............................................................................61
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Phase Ib/II study of peposertib in combination with capecitabine and
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8
Study Assessments and Procedures....................................................62
8.1
Efficacy Assessments and Procedures................................................63
8.1.1
Pathological Complete Response .......................................................63
8.1.2
Tumor Evaluation Methods and Response Assessment.....................64
8.1.2.1
Evaluation Methods............................................................................64
8.1.2.2
Tumor Response Evaluation...............................................................65
8.1.2.3
Neoadjuvant Rectal Score...................................................................65
8.2
Safety Assessments and Procedures ...................................................66
8.2.1
Physical Examinations........................................................................66
8.2.2
Vital Signs ..........................................................................................67
8.2.3
Electrocardiograms.............................................................................67
8.2.4
Clinical Safety Laboratory Assessments ............................................67
8.2.5
Suicidal Risk Monitoring....................................................................68
8.3
Adverse Events and Serious Adverse Events.....................................68
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................68
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...68
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............68
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....69
8.3.5
Pregnancy ...........................................................................................69
8.4
Treatment of Overdose .......................................................................70
8.5
Pharmacokinetics................................................................................70
72
72
73
8.9
Health Economics...............................................................................74
74
9
Statistical Considerations....................................................................74
9.1
Statistical Hypotheses.........................................................................74
9.2
Sample Size Determination ................................................................74
9.3
Populations for Analyses ....................................................................74
9.4
Statistical Analyses.............................................................................75
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
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9.4.1
Efficacy Analyses ...............................................................................75
9.4.2
Safety Analyses ..................................................................................76
9.4.3
Other Analyses....................................................................................78
9.4.4
Sequence of Analyses.........................................................................79
10
References...........................................................................................80
11
Appendices .........................................................................................83
Appendix 1
Abbreviations......................................................................................84
Appendix 2
Study Governance...............................................................................86
Appendix 3
Contraception......................................................................................93
Appendix 4
Radiation Therapy ..............................................................................95
Appendix 5
Tumor Response Criteria....................................................................98
Appendix 6
Pathology Assessments.....................................................................100
Appendix 7
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................103
Appendix 8
Clinical Laboratory Tests .................................................................107
.108
Appendix 10
Model for Bayesian Dose Escalation................................................109
Appendix 11
Protocol Amendment History...........................................................112
Appendix 12
Sponsor Signature Page....................................................................120
Appendix 13
Coordinating Investigator Signature Page........................................121
Appendix 14
Principal Investigator Signature Page...............................................122
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Figure 4
Prior Distribution..............................................................................110
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Phase Ib/II study of peposertib in combination with capecitabine and
MS100036-0020
radiotherapy in rectal cancer
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I N F O R M A T I O N
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1
Protocol Summary
1.1
Synopsis
Protocol Title: A multicenter study with an open-label Phase Ib part followed by a randomized, 
placebo-controlled, double-blind, Phase II part to evaluate efficacy, safety, tolerability, and 
pharmacokinetics of the DNA-PK inhibitor peposertib (M3814) in combination with capecitabine 
and radiotherapy in participants with locally advanced rectal cancer.
Short Title: Phase Ib/II study of peposertib in combination with capecitabine and radiotherapy in 
rectal cancer.
Phase II of this study will not be performed and was therefore deleted from this protocol.
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Endpoints (Outcome Measures) 
Timeframe
Primary
To define a maximum tolerated 
dose (MTD) and recommended 
Phase II dose (RP2D) of 
peposertib in combination with 
capecitabine and RT
Occurrence of dose limiting 
toxicities (DLTs)
Time from first study intervention 
to the end of chemoradiotherapy
with a final assessment at 
4 weeks after surgery
Secondary
To evaluate safety and tolerability 
of peposertib in combination with 
capecitabine and RT
!
Occurrence of 
treatment-emergent adverse 
events (TEAEs) and 
treatment-related adverse 
events according to the National 
Cancer Institute (NCI)-Common 
Terminology Criteria of Adverse 
Events (CTCAE) version 5.0
!
Occurrence of abnormalities 
(Grade ≥3) in laboratory test 
values, markedly abnormal vital 
sign measurements, and 
clinically significantly abnormal 
electrocardiograms (ECGs)
including clinically important 
increases in QT interval (QTcF)
Time from first study intervention 
to final assessment at 1 year
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and
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radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Objectives
Endpoints (Outcome Measures)
Endpoints (Outcome Measures) 
Timeframe
To explore antitumor activity of 
peposertib in combination with 
capecitabine and RT
!
Composite endpoint of pCR/cCR
!
Pathology evaluation of
specimen after surgery (pCR) 
and clinical evaluation 
1 to 2 weeks prior to surgery 
(cCR)
!
Disease-free Survival
!
Time from first study
intervention to final
assessment at 1 year
!
pCR
!
Pathology evaluation of
specimen after surgery
!
cCR
!
Time from first study
intervention until clinical 
evaluation 1 to 2 weeks prior 
to surgery
!
Local recurrence and/or distant
metastasis
!
Time from surgery to final
assessment at 1 year
!
Neoadjuvant rectal score
!
Pathology evaluation of 
specimen after surgery
To assess the pharmacokinetics
(PK) of peposertib
Pharmacokinetic profile of 
peposertib in terms of PK parameter 
estimates (e.g. Cmax, AUC0-t, tmax, 
CL/f, Vz/f, and t1/2)
Fraction day (FD)1 and FD9
Overall Design: This is a multicenter, open-label, single arm, dose escalation study in participants 
with locally advanced rectal cancer.
The study will consist of a Screening period of 4 weeks, a Treatment period of 5 to 5.5 weeks (25 
or 28 FD) (DLT period), a Short-term Safety Follow-up period of 13.5 weeks (including 30 days 
after surgery), a Long-term Safety Follow-up period until 1 year after the start of study 
intervention/randomization.
Number of Participants: The planned cohort size is 3 participants. The total sample size will 
depend on the number of cohorts to be evaluated. It is anticipated that 18 to 30 evaluable 
participants will be required.
Study Intervention Groups and Duration: Participants will be assigned to peposertib given in 
combination with capecitabine 825 mg/m2 twice daily 5 days/week and RT of 50 to 50.4 Gy to the 
tumor area and 45 Gy to the electively irradiated tissues in 25 or 28 fractions (corresponding to 5
to 5.5 weeks). The starting dose of peposertib for the first cohort will be 50 mg once daily
5 days/week. The peposertib dose for the next cohorts will be determined by the Safety Monitoring 
Committee (SMC) guided by a Bayesian 2-parameter logistic regression model with overdose 
control.
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Phase Ib/II study of peposertib in combination with capecitabine and
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radiotherapy in rectal cancer
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Premature Discontinuation: As of 06 May 2021, in the Phase Ib dose escalation part, 19 
participants have been treated with doses ranging from 50 to 250 mg peposertib once daily plus 
capecitabine and RT. Preliminary clinical data from 16 participants that have finished the study up 
to Week 19 as well as changing treatment landscape in locally advanced rectal cancer indicate that 
the ability to generate a meaningful proof of concept under the current protocol is low. Therefore, 
the dose escalation in the Phase Ib part will be prematurely discontinued after completing the 
Cohort 5 of 150 mg, and the Phase II part of the study will not be initiated.
Involvement of Special Committee(s): Yes
1.2
Schema
Figure 1 shows a schematic overview of the study design.
Figure 1
Study Design Diagram
DLT=dose limiting toxicity, Gy=Gray, FU=follow-up, RP2D=recommended Phase II dose, RT=radiotherapy.
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Phase Ib/II study of peposertib in combination with capecitabine and
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radiotherapy in rectal cancer
C O N F I D E N T I A L
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1.3
Schedule of Activities
The treatment period will include 25 or 28 RT fractions, depending on local practice.
!
The Schedule of Activities (SoA) is provided in Table 1.
!
The SoA for the Long-term Safety Follow-up is provided in Table 2.
!
!
The PK sampling schedule is provided in Table 4.
!
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Table 2
Schedule of Activities – Long-term Safety Follow-up Period
Study Periods
Long-term Safety FU
Notes
Visit Weeks
19 to 52
Visit Week
21 and 27 wk after start of study intervention/ 
randomization: Wk 21 and 27; thereafter every 
3 mo in Yr 1: Wk 39 and 52
Participants followed-up until 1 year after start of study 
intervention/randomization, or earlier due to any reason whereby tumor 
assessments are no longer applicable (e.g. if new treatment is started, study 
discontinued, withdrawal of consent). Adjuvant chemotherapy is allowed as 
per local standards (see Section 6.5). Participants receiving adjuvant 
chemotherapy will continue to follow the schedule of activities as per 
protocol. If adjuvant chemotherapy is given any additional safety 
evaluations/laboratory tests will be as per local practice.
Reason for early discontinuation should be captured in source documents. If 
EOT occurs before Wk 52, all assessments must be done as planned for 
Wk 52. 
Visit Windows (Week)
± 1 for Wk 21;
± 2 for other visits
Participants who have already been followed up for more than 1 year (Long-term Safety or Survival Follow-up) will be discontinued from the study after the 
approval of protocol amendment version 4.0 by the respective Health Authority and Ethics Boards. Participants will be informed of the discontinuation by the 
Investigator via a phone call. No further study visits or assessments are planned.
Assessment and Procedures
Vital Signs
X
Pulse rate, DBP, SBP, body temperature, and body weight.
Physical Examination
X
Physical examination (including body weight) will report findings in the 
irradiated area during Short- and Long-Term FU periods.
ECOG PS
X
Adverse Event 
Assessment
X
Evaluation of ongoing or new AEs assessed as related to study intervention 
until resolution or permanent outcome. New SAE assessed as unrelated to 
study intervention only up to Wk 27.
Concomitant Therapy
X
Adjuvant Chemotherapy
X
Adjuvant chemotherapy if given, according to local guidelines, must start 
between 1 and 3 mo after surgery.
Hematology
X
Serum Chemistry and 
Coagulation
X
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Study Periods
Long-term Safety FU
Notes
Visit Weeks
19 to 52
Visit Week
21 and 27 wk after start of study intervention/ 
randomization: Wk 21 and 27; thereafter every 
3 mo in Yr 1: Wk 39 and 52
Participants followed-up until 1 year after start of study 
intervention/randomization, or earlier due to any reason whereby tumor 
assessments are no longer applicable (e.g. if new treatment is started, study 
discontinued, withdrawal of consent). Adjuvant chemotherapy is allowed as 
per local standards (see Section 6.5). Participants receiving adjuvant 
chemotherapy will continue to follow the schedule of activities as per 
protocol. If adjuvant chemotherapy is given any additional safety 
evaluations/laboratory tests will be as per local practice.
Reason for early discontinuation should be captured in source documents. If 
EOT occurs before Wk 52, all assessments must be done as planned for 
Wk 52. 
Visit Windows (Week)
± 1 for Wk 21;
± 2 for other visits
Participants who have already been followed up for more than 1 year (Long-term Safety or Survival Follow-up) will be discontinued from the study after the 
approval of protocol amendment version 4.0 by the respective Health Authority and Ethics Boards. Participants will be informed of the discontinuation by the 
Investigator via a phone call. No further study visits or assessments are planned.
Assessment and Procedures
Carcinoembryonic 
Antigen
X
MRI/CT
X (starting Wk 27)
T2 weighted and diffusion weighted, without gadolinium. No MRI/CT at 
Wk 21.
AE=adverse event, CT=computerized tomography, ctDNA=circulating tumor DNA, DBP=diastolic blood pressure, ECOG PS=Eastern Cooperative Oncology 
Group Performance Status, EOT=End of Trial, FU=Follow-up, MRI=magnetic resonance imaging, SAE=serious adverse event, SBP=systolic blood pressure.
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Table 4
Pharmacokinetic Sampling Schedule of Peposertib and Capecitabine
Study 
Day
Sampling Time Point 
(Peposertib)
Sampling Window
Phase Ib
Notes
FD1
Predose
Within 60 min prior to 
peposertib 
administration
X
Predose samples should be taken before capecitabine and 
peposertib administration. All other sampling times are 
related to peposertib administration; sampling for 
capecitabine/metabolite PK is done at the same time as the 
blood is drawn for peposertib PK analysis
1 h
± 10 min
X
2 h
± 10 min
X
3 h
± 20 min
X
4 h
± 20 min
X
6 h
± 30 min
X
FD2
Predose
Within 60 min prior to 
peposertib 
administration
X
Predose samples should be taken before capecitabine and 
peposertib administration.
FD9
Predose
Within 60 min prior to 
peposertib 
administration
X
Predose samples should be taken before capecitabine and 
peposertib administration. All other sampling times are 
related to peposertib administration; sampling for 
capecitabine/metabolite PK is done at the same time as the 
blood is drawn for peposertib PK analysis
1 h
± 10 min
X
2 h
± 10 min
X
3 h
± 20 min
X
4 h
± 20 min
X
6 h
± 30 min
X
FD10
Predose
Within 60 min prior to 
peposertib 
administration
X
Predose samples should be taken before capecitabine and 
peposertib administration.
FD=fraction day, PK=pharmacokinetics.
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completed the single dose escalation part where 31 participants were treated with dose levels 
between 100 mg once daily and 400 mg twice daily. The maximum tolerated dose (MTD) was not 
reached at 400 mg twice daily; however, further dose escalation was not done, per Safety 
Monitoring Committee (SMC) decision. There were no dose limiting toxicities (DLTs) reported 
at the 400 mg twice daily dose level. The recommended Phase II dose (RP2D) for peposertib
monotherapy was established as 400 mg twice daily and confirmed in an additional 6 aspirin-naïve 
participants (aspirin-naïve participants were included to test for alterations in platelet aggregation). 
The efficacy data did not support further development of peposertib in monotherapy due to the 
lack of clear clinical activity in this setting.
The second study with peposertib (EMR100036-002) is currently ongoing and is a combined 
Phase Ia/Ib, open label, dose escalation and dose-expansion study designed to explore the safety, 
tolerability, PK,
 and clinical activity of peposertib in 
combination with RT/chemoradiotherapy (CRT), and to determine the MTD and a RP2D for 
peposertib in combination with RT/CRT.
!
The Arm A-Phase Ia part of the study includes previously treated participants with locally 
advanced disease (any tumor or metastases including lymphomas) localized in the head and 
neck region or thorax that is not amenable to surgical therapy or with standard systemic therapy 
with an indication for palliative RT (30 Gy in 10 fractions) over 2 weeks. 
!
The Arm B-Phase Ia part includes treatment naïve SCCHN participants who are eligible for 
fractionated RT (66 to 70 Gy in 33 to 35 fractions) with concurrent cisplatin.
!
In ancillary clinical proof-of-principle part of the study, participants with at least 
2 cutaneous/subcutaneous tumors/metastasis are included to evaluate alterations in 
phosphorylated-DNA-PK expression induced by RT (Lesion 1), as compared with expression 
induced by RT after administration of peposertib (Lesion 2).
A third study (MS100036-0022) investigated peposertib in combination with etoposide and 
cisplatin in participants with treatment naïve extensive disease SCLC. Two participants were 
treated with peposertib (capsule and tablet formulation). One participant received a single dose of 
the tablet, and the capsule for the remainder of the study. No DLTs or deaths were reported, and 
none of the participants discontinued due to an adverse event (AE). Enrollment in the study was 
prematurely terminated due to recruitment challenges and not due to concerns of safety for the 
subjects. 
The Investigator’s Brochure provides a more detailed overview of the nonclinical and clinical 
information on peposertib.
Rectal cancer is a subset of colorectal cancer, which is the third most common diagnosed cancer. 
An estimated 40,000 new cases of rectal cancer were diagnosed in 2017 in the USA with an 
increase in incidence rates in the younger population (Siegel 2017). In the European Union the 
incidence of rectal cancer is 15 to 25 cases/100,000 population per year resulting in approximately 
125,000 new cases per year, and mortality is 4-10/100,000 population per year 
(Glynne-Jones 2017). Rectal cancer is a distal large bowel adenocarcinoma tumor located at or 
below the peritoneal reflection. The standard of care (SoC) for locally advanced rectal cancers is 
neoadjuvant CRT, with or without sequential chemotherapy followed by surgical intervention (e.g.
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total mesorectal excision [TME]), with the aim to remove the irradiated tumor and decrease the 
risk of local recurrence and mortality (National Comprehensive Cancer Network® [NCCN] 
Guidelines for Patients® Rectal Cancer 2019; Glynne-Jones 2017). This methodology has resulted 
in a decrease in local recurrence and an improvement in mortality rates (Shahab 2017). However, 
one-third of patients with locally advanced rectal cancer will later develop distant metastases and 
will subsequently die from the disease. In addition, most survivors experience significant 
impairment in their QoL, due primarily to removal of the rectum. Consequently, the current 
challenges in the treatment of locally advanced rectal cancer are how to improve survival by 
reducing the risk of distant metastases, and how to improve QoL in surviving patients by 
preserving the rectum. There is an unmet need to improve long-term outcomes and QoL and so the 
development of new therapeutic strategies to further increase these aspects is of key importance.
2.3
Benefit/Risk Assessment
The benefit-risk relationship has been carefully considered in the planning of this study. 
Nonclinical data show that peposertib potently and selectively inhibits DNA DSB repair induced 
by IR and other DNA damaging agents.
As of 18 December 2019 (Investigator’s Brochure, Version 8.0), the important potential risks with
peposertib identified for the purpose of the study based on nonclinical studies are as follows:
!
Lymphoid depletion with risk of infection
!
Stomatitis, mucositis
!
Rash
!
Increased radiation dermatitis
!
Reproductive toxicity
!
Increase in liver enzymes: aspartate aminotransferase, alanine aminotransferase and glutamate 
dehydrogenase
!
Drug-drug interactions
Further, the following not important potential risks have been identified:
!
Vomiting
!
Diarrhea 
There are no other important potential risks from completed/ongoing studies that are considered 
relevant for this rectal study population.
Recommendations for the clinical use of peposertib include the monitoring of adverse effects in 
the digestive tract and radiation side effects, as well as monitoring of hematological parameters 
and liver enzymes. In addition, precautionary measures to mitigate the risks of other treatments 
and treatment recommendations of known adverse reactions, need to be respected when given in 
combination with peposertib.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of peposertib may be found in Section 4.2 (Scientific Rationale for Study Design)
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and the Investigator’s Brochure, Participant Information Leaflet, or Development Safety Update 
Report.
The purpose of this study is to determine whether peposertib can be safely administered in 
combination with the current neoadjuvant SoC for rectal cancer, capecitabine in combination with 
RT, and whether the combination with peposertib shows a relevant antitumor efficacy advantage 
compared with SoC. Improved rates of clinical complete response (cCR) should translate into 
higher rates of organ preservation in patients with locally advanced rectal cancer. It is hypothesized
that this will improve long-term QoL outcomes.
In this study, appropriate precautionary measures to mitigate the potential risks are implemented. 
The safety will be monitored on an ongoing basis by the SMC. The study will be discontinued in 
the event of any new findings that indicate a relevant deterioration of the benefit-risk balance for 
the participants, which would render continuation of the study unjustifiable.
The SoC CRT has a known and well-established toxicity profile. Nausea, vomiting, diarrhea, 
mucositis, hand-foot syndrome, radiation dermatitis, and decreases in hemoglobin, leucocytes, and 
platelets, are the most frequently reported Grade 3 AEs in clinical studies with capecitabine and 
RT (Liu 2016). These potential toxicities can be readily monitored with clinical laboratory, AE,
and clinical assessments.
It is known that RT can cause acute toxicities in the form of, e.g. radiation dermatitis and mucositis. 
Late toxicities arising 3 months or later after the end of RT can be seen in the form of, e.g.
mucositis, fibrosis, and bowel perforation. This must be evaluated by appropriate means including 
physical examination, imaging and endoscopy when indicated. Potentially, acute and late toxicities 
can be more severe when RT is given in combination with peposertib. This will be evaluated on 
an ongoing basis.
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable.
The starting dose of 50 mg once daily peposertib in combination with RT and capecitabine is 
considered appropriate to mitigate possible AEs by overlapping or unexpected toxicities of the 
combination, and possible higher formulation-dependent fraction absorbed.
Peposertib has a nonclinical safety profile adequate for the treatment of patients with 
life-threatening advanced malignancies, and the safety profile does not raise concerns about further 
investigation of peposertib in participants with cancer. In addition, the available clinical safety data
for peposertib when given as a single agent forms a basis for the clinical study in combination with 
RT, as well as chemotherapy, and supports the investigation also in the neoadjuvant setting.
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In conclusion, emerging clinical safety data from studies EMR100036-001 and EMR100036-002, 
and supportive results of a comprehensive series of nonclinical safety pharmacology, PK, and 
toxicology studies, as well as primary and secondary PD findings support continued clinical 
development of peposertib in combination with RT, and/or chemotherapy.
3
Objectives and Endpoints
Study objectives and endpoints are provided in Table 6. Statistical analysis of the endpoints is 
described in Section 9.4.
Table 6
Study Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
Endpoints (Outcome Measures) 
Timeframe
Primary
To define an MTD and RP2D of 
peposertib in combination with 
capecitabine and RT
Occurrence of dose limiting toxicities
Time from first study intervention to 
the end of CRT with a final 
assessment at 4 weeks after 
surgery
Secondary
To evaluate safety and tolerability 
of peposertib in combination with 
capecitabine and RT
!
Occurrence of TEAEs and 
treatment-related adverse events 
according to the NCI-CTCAE 
version 5.0
!
Occurrence of abnormalities 
(Grade ≥3) in laboratory test 
values, markedly abnormal vital 
sign measurements, and clinically 
significantly abnormal ECGs 
including clinically important 
increases in QT interval (QTcF)
Time from first study intervention to 
final assessment at 1 year
To explore antitumor activity of 
peposertib in combination with 
capecitabine and RT
!
Composite endpoint of pCR/cCR
!
Pathology evaluation of
specimen after surgery (pCR) 
and clinical evaluation 
1 to 2 weeks prior to surgery 
(cCR)
!
Disease-free Survival
!
Time from first study
intervention to final assessment 
at 1 year
!
pCR
!
Pathology evaluation of
specimen after surgery
!
cCR
!
Time from first study
Intervention until clinical 
evaluation 1 to 2 weeks prior to 
surgery
!
Local recurrence and/or distant
metastasis
!
Time from surgery to final
assessment at 1 year
!
Neoadjuvant rectal score
!
Pathology evaluation of 
specimen after surgery
To assess the PK of peposertib
PK profile of peposertib in terms of
PK parameter estimates (e.g. Cmax, 
AUC0-t, tmax, CL/f, Vz/f, t1/2)
FD1 and FD9
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cCR=Clinical Complete Response, CRT=chemoradiotherapy, 
 
 ECG=electrocardiogram, FD=fraction day, MTD=maximum tolerated dose, NCI-CTCAE=National Cancer 
Institute Common Terminology Criteria of Adverse Events,
, 
pCR=Pathological Complete Response, PK=pharmacokinetic(s), RP2D=recommended Phase II dose, 
RT=radiotherapy, TEAE=treatment-emergent adverse event.
The definition of pathological complete response (pCR) and cCR, and derivation of the pCR/cCR 
composite endpoint are described in Section 3.1. Statistical aspects of other endpoints are 
described in Section 9.4.
3.1
Definitions of Pathological Complete Response and Clinical 
Complete Response,
and Derivation of the Composite 
Endpoint
Pathological Complete Response
Participants are considered to have a pCR if they undergo surgery and no residual cancer is found 
on histological examination of the removed specimen (ypT0N0).
The assessment of pCR will be based on local review of the histology slides.
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Clinical Complete Response
Participants are considered to have a cCR if all the criteria below are fulfilled:
!
Absence of any residual tumor in the primary site and draining lymph nodes on imaging with 
magnetic resonance imaging (MRI; T2 weighted and diffusion weighted) as defined in the 
Appendix 5, which is based on a modification of tumor evaluation as described by Maas 2015.
!
No visible lesion at endoscopy except a flat scar, telangiectasia, and/or whitening of the mucosa
(documented by photography)
!
Absence of any palpable tumor or irregularity on digital rectal examination (DRE) and 
endoscopic ultrasonography (EUS) (if indicated or if performed)
!
If a biopsy is taken, it must be negative.
Composite Endpoint of Pathological Complete Response/Clinical Complete Response
Participants are considered as responders to the composite endpoint pCR/cCR if 1 of the following 
2 criteria is fulfilled (Figure 2):
!
Participant had surgery and has pCR
!
Participant did not undergo surgery but has cCR (defined above).
Participants who are not operated on and do not undergo the procedures to define cCR will be 
regarded as nonresponders.
Figure 2
Derivation of Composite Endpoint
cCR=Clinical Complete Response, CR=Complete Response, pCR=Pathological Complete Response, MRI=Magnetic 
Resonance Imaging. See Section 9.4 for the statistical aspects of the endpoints.
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4
Study Design
4.1
Overall Design
This is a multicenter open-label, single arm, dose escalation study in participants with locally 
advanced rectal cancer.
The study will consist of a Screening period of 4 weeks, a Treatment period of 5 to 5.5 weeks (25 
or 28 fraction days [FDs]) (DLT period, see Section 6.6.1), a Short-term Safety Follow-up period 
of 13.5 weeks including 30 days after surgery, a Long-term Safety Follow-up period until 1 year
after the start of study intervention/randomization.
A schematic overview of the study is shown in Section 1.2. A detailed SoA is provided in 
Section 1.3.
4.1.1
Screening Period
Screening will be performed within 4 weeks prior to FD1 and first day of study intervention 
administration. Participants will be assessed for eligibility to participate in the study, and will 
undergo clinical evaluations to ensure compliance with the inclusion and exclusion criteria
(Section 5.1 and Section 5.2, respectively). Details of tumor evaluation methods at Screening are 
provided in Section 8.1.2. Details of rescreening are provided in Section 5.4. For participants who 
received induction chemotherapy prior to the study, a DRE and endoscopy (and EUS if indicated 
or if performed per local practice) will need to be done to determine current stage before starting 
CRT, in compliance with the inclusion criteria (Section 5.1).
4.1.2
Treatment Period
The starting dose of peposertib for the first cohort will be 50 mg once daily (Section 4.3). 
Participants for next cohorts will be assigned to an peposertib dose determined by the SMC. The 
SMC dose recommendations will be guided by a Bayesian 2-parameter logistic regression model 
with overdose control (Appendix 10). The planned cohort size is 3 participants. Peposertib will be 
given in combination with capecitabine at a dose of 825 mg/m2 twice daily and RT of 50 to 50.4 Gy 
to the tumor area and 45 Gy to the electively irradiated tissues in 25 or 28 fractions (corresponding 
to 5 to 5.5 weeks). Full details of the dosing regimens are provided in Section 6.6.2.
After each cohort has completed the 5 to 5.5-week treatment period (DLT period), the SMC will 
review safety, including DLT data, tolerability, and PK data if available, and will recommend the 
peposertib dose for the next cohort. In addition, any toxicities observed during the Short-term 
Safety Follow-up will be reviewed and considered by the SMC for the overall evaluation of the 
safety and proposal of dose escalation of peposertib. Dose limiting toxicities are defined in 
Section 6.6.1. If the SMC decides to escalate the dose for the next cohort, it is in exceptional cases 
at discretion of the study team (medical lead and safety lead with input from statistician) to include
up to 3 further participants in parallel, on a dose level that has already been tested in a previous
cohort.
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Participants will receive CRT until treatment completion after 25 or 28 RT fractions or disease 
progression, unacceptable toxicity or participant refusal to continue.
4.1.3
Follow-up Periods
The study follow-up will include:
!
Short-term Safety Follow-up: the duration of the Short-term Safety Follow-up is 
approximately 13.5 to 14 weeks after treatment completion, including 30 days after surgery, 
with an optional 1 visit per week from Week 7 to Week 14 in case of acute toxicities until 
recovery to Grade 1 or to baseline. For all participants, a mandatory visit will be performed at 
Week 14, approximately 1 to 2 weeks prior to surgery, including a tumor assessment with MRI
(T2 weighted and diffusion weighted) needed for restaging and evaluation. Additional details 
on tumor evaluation methods and response assessments are provided in Section 8.1.2.
!
Surgical intervention must be performed 15 weeks (± 14 days) after start of study 
intervention/randomization (i.e. approximately 9.5 weeks after stopping RT), unless there are 
contraindications for surgery, or if the participant refuses. The last Short-term Safety Follow-up 
visit 
is 
scheduled 
for 
Week 19, 
approximately 
4
to
6 weeks 
after 
surgical 
intervention/imaging/biopsy, as per SoC. During this visit, all safety information since the last 
visit, including surgical and/or biopsy morbidities/toxicities will be collected.
!
Long-term Safety Follow-up: participants will be followed-up at 21 and 27 weeks after start 
of study intervention/randomization; every 3 months until 1 year after start of study 
intervention/randomization. Details on tumor evaluation methods and response assessments are 
provided in Section 8.1.2. Adjuvant chemotherapy is allowed as per local standards (see 
Section 6.5). Participants receiving adjuvant chemotherapy will continue to follow the schedule 
of activities (SoA) as per protocol. If adjuvant chemotherapy is given, any additional safety 
evaluations/laboratory tests will be as per local practice.
!
Participants who have already been followed up for more than 1 year (Long-term Safety or 
Survival Follow-up) will be discontinued from the study after the approval of protocol 
amendment version 4.0 by the respective Health Authority and Ethics Boards. Participants will 
be informed of the discontinuation by the Investigator via a phone call. No further study visits 
or assessments are planned.
4.2
Scientific Rationale for Study Design
Study Interventions:
!
In this study, peposertib will be used in combination with capecitabine and RT. Peposertib is a 
potent and selective, ATP-competitive inhibitor of DNA-PK and blocks a major DSB repair 
pathway (nonhomologous end joining pathway). Inhibitors of DNA-PK are expected to 
synergistically enhance the therapeutic effect of DSB-inducing anticancer modalities.
!
The current SoC for locally advanced rectal cancer is capecitabine, a prodrug of 5-fluorouracil
(5FU), in combination with RT (NCCN 2019, Glynne-Jones 2017). The mechanism of 5FU
cytotoxicity has been attributed to the mis-incorporation of fluoronucleotides into RNA and 
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as this study intervention is in the neoadjuvant setting and therefore potentially curative, the 
starting dose will be 50 mg to increase the probability that participants can complete the study 
intervention as per protocol.
Peposertib tablets will be given once daily and on RT days only. Peposertib has an apparent
terminal half-life (t1/2) of approximately 5.5 h. Therefore, once daily dosing will give adequate 
exposure for the timeframe in which the DSB caused by RT are repaired (Kwok 1989,
Schulz 2017).
Capecitabine will be administered at a twice daily dose of 825 mg/m2 and RT will be given at a
total dose of 50 to 50.4 Gy to the tumor area and 45 Gy to the electively irradiated tissues in 25 or
28 fractions. These doses are in accordance with current medical guidelines (NCCN 2019,
Glynne-Jones 2017).
See Section 6.6 for dosing instructions and the procedures for selecting and modifying each 
participant’s dose.
4.4
End of Study Definition
A participant has completed the study if he/she has completed all study visits, interventions, and 
procedures, including the last scheduled activity shown in the SoA (Section 1.3). No further data 
will be collected from a participant after completion of the respective follow-up period (refer to 
Section 4.1.3). 
The end of the study is defined as the date of the last scheduled activity, shown in the SoA 
(Section 1.3), for the last participant in the study globally.
The Sponsor reserves the right to close the study site or terminate the study at any time and for any 
reason (Appendix 2).
5
Study Population
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to enroll 
only participants who are appropriate for the study; thereby ensuring the study fulfills its 
objectives. All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative (where 
allowed by local laws and regulations) has provided written informed consent, as indicated in 
Appendix 2 (Study Governance).
Participants will be recruited based on referrals to study sites and local site review of participant 
profiles.
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1.
Are ≥18 years of age, at the time of signing the informed consent
Type of Participant and Disease Characteristics
2.
Have an Eastern Cooperative Oncology Group Performance Status ≤1
3.
Have histologically confirmed and localized resectable rectal cancer (Stage II or Stage III at 
original staging). Participants who received induction chemotherapy are allowed to be 
enrolled to this study except if this induction is resulting in cCR or tumor progression (see 
Section 8.1.2 and Appendix 5). Participants who received induction chemotherapy should be 
evaluated by MRI, endoscopy and DRE before start of study intervention/randomization 
(peposertib and CRT), see Appendix 5. The following induction chemotherapies prior to 
screening for the current study are allowed: FOLFOX (folic acid, 5-FU, and oxaliplatin) and 
CAPEOX (capecitabine and oxaliplatin) as per NCCN 2019 guidance.
4.
Have lower edge of the tumor located in rectum
5.
Have evaluable disease in MRI
6.
Have adequate hematological function: hemoglobin ≥9 g/dL, neutrophils ≥1.5 × 109/L and 
platelets ≥100 × 109/L
7.
Have adequate renal function: serum creatinine ≤1.5 × upper limit of normal (ULN) or 
creatinine clearance ≥50 mL/min (Cockcroft 1976)
8.
Have adequate liver function: aspartate aminotransferase, alanine transaminase, alkaline 
phosphatase ≤3 × ULN, and bilirubin ≤1.5 × ULN
Sex
9.
Are male or female
!
Male participants:
Agree to the following during the study intervention period and for at least 12 weeks after 
the last dose of study intervention:
o
Refrain from donating sperm
Plus, either: 
o Abstain from any activity that allows for exposure to ejaculate.
OR
o
Use a male condom:
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
When having sexual intercourse with a woman of childbearing potential, 
who is not currently pregnant, and advise her to use a highly effective 
contraceptive method with a failure rate of < 1% per year, as described in 
Appendix 3, since a condom may break or leak.

When engaging in any activity that allows for exposure to ejaculate.
!
Female Participants: 
o Are not pregnant or breastfeeding, and at least one of the following conditions 
applies:

Not a woman of childbearing potential
OR

If a woman of childbearing potential, use a highly effective contraceptive 
method (i.e. with a failure rate of < 1% per year), preferably with low user 
dependency, as described in Appendix 3 for the following time periods:
o
Before the first dose of the study intervention(s), if using hormonal contraception:

Has completed at least one 4-week cycle of an oral contraception pill and
either had or has begun her menses
OR

Has used a depot contraceptive or extended-cycle oral contraceptive for 
least 28 days and has a documented negative pregnancy test using a highly 
sensitive assay.
AND

A barrier method, as described in Appendix 3.
o
During the intervention period
o
After the study intervention period (i.e. after the last dose of study intervention is 
administered) for at least 12 weeks, after the last dose of study intervention and 
agree not to donate eggs (ova, oocytes) for reproduction during this period.
The Investigator evaluates the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
o
Have a negative serum pregnancy test, as required by local regulations, within 4 
weeks before the first dose of study intervention. Additional requirements for 
pregnancy testing during and after study intervention are in Section 8.2.4.
!
The Investigator reviews the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female with an early undetected pregnancy.
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Informed Consent
10.
Can give signed informed consent, as indicated in Appendix 2 (Study Governance), which 
includes compliance with the requirements and restrictions listed in an informed consent 
form (ICF) and this protocol.
Details of rescreening are provided in Section 5.4.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History of any other significant medical disease or psychiatric conditions that might in the 
assessment of the Investigator preclude safe participation in the study
2.
History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease or 
conditions that may hamper compliance and/or absorption of the study intervention
3.
Unstable cardiovascular function within 6 months prior to enrollment (i.e. ischemia,
symptomatic angina, congestive heart failure, Class III to IV New York Heart Association
uncontrolled conduction abnormalities including a history of long QTc syndrome 
[QTcF > 480 ms] and/or pacemaker, or myocardial infarction)
4.
Hypertension uncontrolled by medication (i.e. systolic blood pressure ≥150 mmHg and 
diastolic blood pressure ≥90 mmHg)
5.
History of other malignant disease within the past 5 years, other than successfully treated 
basal carcinoma of the skin or carcinoma in situ of the cervix
6.
Known human immunodeficiency virus positivity, known active viral hepatitis, current 
alcohol abuse, or cirrhosis
7.
Ongoing active infection or treatment with a live attenuated vaccine within 4 weeks of 
dosing.
Prior/Concomitant Therapy
8.
Previous radiation therapy to the pelvis
9.
Concurrent use of other anticancer therapy
10.
Major surgical intervention within 4 weeks prior to the first dose of study intervention. 
Biopsy(s) to establish the diagnosis for rectal cancer is permitted. Diverting ostomy is 
permitted
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11.
Concomitant or prior use of medications or herbal supplements, known to be strong 
inhibitors of cytochrome P450 (CYP) 3A and/or CYP2C19, unless use can be discontinued 
1 week prior to receiving the first dose of study intervention. Concomitant or prior use of 
medications or herbal supplements, known to be strong inducers of CYP3A and/or
CYP2C19, unless use can be discontinued at least 3 weeks prior to receiving study 
intervention. Concomitant or prior therapy use of medications or herbal supplements mainly 
metabolized by CYP3A with a narrow therapeutic index must be stopped at least 1 day prior 
to receiving study intervention
12.
Concomitant use of H2-blocker or proton pump inhibitors (PPIs) (or unable to stop at least 
5 days prior to the first treatment). Note that calcium carbonate is acceptable
13.
Treatment with sorivudine or its chemically related analogues, such as brivudine
Prior/Concurrent Clinical Study Experience
14.
Participation in any interventional clinical study within 28 days prior to Screening or during 
participation in this study
Diagnostic Assessments
15.
Contraindications to MRI imaging
Other Exclusions
16.
Pregnant or nursing (lactating) women
17.
Known dihydropyrimidine dehydrogenase deficiency
18.
History of severe and unexpected reactions to fluoropyrimidine therapy
19.
Hypersensitivity to capecitabine or to any of the excipients or fluorouracil.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
The timing of meals relative to dosing of study interventions and fasting requirements are detailed 
in the SoA (Section 1.3) and Section 6.6.2.
Participants will be instructed to refrain from consumption of red wine, Seville oranges, grapefruit 
or grapefruit juice, Seville orange marmalade, star fruit, or other products containing grapefruit, 
Seville oranges or star fruit from 7 days before the start of study intervention until after the final 
dose because its potential to interfere with the PK of peposertib.
5.3.2
Caffeine, Alcohol, and Tobacco
No restrictions on caffeine, modest alcohol, or tobacco use apply during this study, with the 
exception of red wine (Section 5.3.1).
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5.3.3
Activity
Electrocardiograms (ECG) will be obtained after the participant has been in a semi-supine position 
for at least 5 min (Section 8.2.3).
Participants will abstain from strenuous exercise for 2 h before each blood collection for clinical 
laboratory tests. Participants may participate in light recreational activities.
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (potential participants who 
failed screening) may be rescreened. Rescreened participants will be assigned a new participant 
number. Retesting before baseline will be permitted only once, and the test for the specific 
abnormal value must be repeated within the timeframe of the Screening period. The last value of 
the previously questioned test result must meet the study criteria before start of study intervention.
In the case of a rescreen and the screening CT scan is > 28 days from the previous screening scan, 
the screening CT must be repeated.
6
Study Intervention(s)
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. For this study, 
peposertib is the investigational intervention, and the study interventions include peposertib, 
capecitabine, and RT. Peposertib and capecitabine will be administered on an outpatient basis, 
except on dosing days requiring predose PK samples (Table 4, Table 7).
6.1
Study Intervention(s) Administration
Study interventions are summarized in Table 7.
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Table 7
Description of Study Interventions
Study Intervention 
Name:
Peposertib
Capecitabine
Dose Formulation:
Film-coated tablet
Film-coated tablet
Unit Dose Strengths:
50 mg
150 mg/500 mg
Route of Administration:
Oral
Oral
Dosing Instructions:
Administered at home (except on days 
requiring predose PK sample), once daily 
and on RT days only. Take 1 h after 
meal, and fast 1 h post peposertib intake. 
On days when predose PK sample is 
drawn (Fraction Days 1, 2, 9, and 10), 
dose should be taken at the clinic after 
the predose PK blood draw.
See Section 6.6 for dose selection
Administered at home (except for the 
morning dose on days requiring 
predose PK sample) and on RT days 
only. Take within 30 min after meal 
(breakfast/dinner). On days when 
predose PK sample is drawn (Fraction 
Days 1, 2, 9, and 10), morning dose 
should be taken at the clinic after the 
predose PK blood draw.
See Section 6.6 for dose selection
Packaging and Labeling
Study intervention will be provided in 
aluminum/aluminum blisters.
Each blister will be packaged and labeled 
per all applicable regulatory requirements 
and Good Manufacturing Practice 
Guidelines
Study intervention will be provided as a 
marketed product. It will be prepared in 
accordance with its product labeling
PK=pharmacokinetics, RT=radiotherapy.
!
Capecitabine is administered as part of the study. General guidance on the use of capecitabine 
is provided. However, Investigators must follow and instruct participants to follow the package 
insert, the Product Information, the Summary of Product Characteristics (SmPC), and their 
site’s specific policies/instructions for the final use of capecitabine.
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability
!
Peposertib will be supplied as formulated film-coated tablets intended for ready-to-use oral 
administration. The aluminum ‘ALU/ALU’ blisters are used as the container closure system for 
peposertib film-coated tablets. 
 
!
The preparation, handling and storage of capecitabine at the study site will be in accordance 
with its product label. Investigators or assigned staff should instruct participants on proper 
handling and storage.
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e. receipt, 
reconciliation, and final disposition records).
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After completion of the study, any study intervention distributed to the site but not administered, 
dispensed to or taken by the participant will be destroyed at the site. Details will be agreed upon 
between the Sponsor and the Investigator. All unused medications will be carefully recorded and 
documented before destruction. The Investigator will ensure the supplied study intervention is not 
used for any purpose other than this study.
!
Upon receipt of the study intervention(s), the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate document and returning 
it to the location specified. A copy will be archived for the Investigator Site File.
!
Any temperature excursion during shipment or damaged receipt must be properly documented 
in the Interactive Voice/Web Response System (IVRS/IWRS) and the sending site must be 
informed.
!
Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) must be stored in a secure, 
environmentally-controlled, and monitored (manual or automated) area, in accordance with the 
labeled storage conditions, and with access limited to the Investigator and authorized site staff.
!
Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
!
Each study site must ensure that the study intervention(s) is not used:
o
After the expiry date, or
o
After the retest date unless the study intervention is reanalyzed and its release date 
extended.
This is to be closely monitored by the study monitor.
!
Study intervention(s) accountability records at the study site will include the following:
o
Confirmation of receipt, in good condition and in the defined temperature range.
o
The inventory provided for the clinical study and prepared at the site.
o
The dose(s) each participant used during the study.
o
The disposition (including return, if applicable) of any unused study 
intervention(s).
o
Dates, quantities, batch numbers, kit numbers, expiry/use-by dates, and the 
participant numbers.
!
The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled.
!
Unused study intervention(s) 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.
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!
A Study Monitor will periodically collect the study intervention(s) accountability forms.
!
Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Clinical Operations Plan.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
!
The IVRS/IWRS will be used to assign unique participant numbers, and study intervention to 
participants at each study intervention visit.
!
Before the study is initiated, the telephone number and call-in directions for the IVRS and/or 
the log-in information and directions for the IWRS will be provided to each site. The site will 
contact the IVRS/IWRS prior to starting study intervention administration for each participant. 
The site will record the study intervention assignment in the applicable Case Report Form 
(CRF).
6.3.2
Blinding
Blinding is not applicable as this is an open-label study.
6.4
Study Intervention Compliance
!
Acceptable compliance for this study will be defined in the Monitoring Plan.
!
Measures to monitor and document participants’ compliance with study intervention will 
include: 
o
Patient diaries used to document the dates and times of study intervention 
administration and to support the participant in planning the correct times to take 
study intervention(s)
o
Compliance will be captured in the source documents using electronic data capture,
reviewed by the study monitor and documented in the Monitoring Report.
!
Participants must be withdrawn from the study intervention in the event of noncompliance that 
is deemed by the Investigator or Sponsor to compromise participant safety or study integrity 
(Section 7.1 and Section 8.4).
!
The following procedures will be used for increasing compliance:
o
Use of patient diaries
o
Regular review of dosing with the participant.
Further details of procedures used for increasing compliance will be included in the Monitoring 
Plan.
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6.5
Concomitant Therapy
!
Adjuvant chemotherapy is allowed during the Long-term Safety Follow-up period if initiated 
within 1 to 3 months after surgery. The following adjuvant chemotherapies are allowed: 
FOLFOX and CAPEOX or capecitabine as per NCCN 2019 guidance.
!
Drugs mainly metabolized by CYP3A with a narrow therapeutic index are to be used with 
caution. 
Examples 
of 
drugs 
are 
found 
on 
the 
following 
page: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm. The Investigator may decide not to include a participant in 
the study, if the participant cannot withdraw the drugs that have a narrow therapeutic index and 
that are known to be metabolized via CYP3A; if the Investigator decides to enroll a participant 
who is treated with one of these drugs, close safety monitoring is advised.
!
Record in the electronic Case Report Form (eCRF) all concomitant therapies (e.g. medicines or 
nondrug interventions) used from the time the participant signs the informed consent until 
completion of the study, including any changes. For prescription and over-the-counter 
medicines, record the name, reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Prohibited Medicines
!
Participants must not have received any prior anticancer therapy for locally advanced rectal 
cancer including experimental agents,
except induction chemotherapy. Use of
any 
investigational agent within 28 days prior to the first study intervention administration is 
prohibited.
!
During the treatment period and up to 30 days after last study intervention administration, any 
other investigational agent, or any other anticancer therapy (i.e. chemotherapy, RT, biologics,
other targeted therapy, or immunotherapies) are prohibited. Use of any investigational agent 
during the entire study duration is not permitted.
!
Medications or herbal supplements known to be strong inhibitors or inducers of CYP3A or 
CYP2C19, 
are 
prohibited. 
A 
list 
is 
provided
on 
the 
following 
page: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm, although this list may not be exhaustive.
!
The solubility of peposertib is pH dependent; therefore, antacid drugs, H2-blocker and PPIs 
might affect absorption. PPIs should be stopped 5 days prior to the first study intervention and 
avoided during the entire study intervention period. Antacid drugs should not be taken 1 h 
before and until 2 h after peposertib administration. H2 blockers may be allowed at least at 2 h 
after peposertib dose and 1 h after RT dose but it should be stopped at least 4 h before the 
evening dose of capecitabine and 8 h before peposertib dose in the next morning.
!
Capecitabine must not be administered concomitantly with sorivudine or its chemically related 
analogues, such as brivudine. Concomitant use of allopurinol with capecitabine should be 
avoided. Caution is required with concomitant use of leucovorin with capecitabine as per 
standard practice.
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If prohibited concomitant therapy becomes necessary during the treatment period, e.g. due to AEs, 
the participant should be interrupted for a safe duration of time.
6.6
Dose Selection and Modification
Physician discretion may be used if monitoring or dose modification outside of the guidelines is 
considered necessary.
If participants vomit after taking their dose of peposertib and/or capecitabine, they should be given 
an antiemetic but the dose(s) will not be replaced. Prophylactic antiemetics should then be 
considered prior to subsequent doses of peposertib and/or capecitabine. Any change from dosing 
schedule, dose interruptions, or dose reductions should be recorded in the eCRF.
In general, each participant will stay on the peposertib, and capecitabine dose level assigned in the 
study unless treatment needs to be interrupted, modified or stopped. If peposertib dosing 
interruptions are necessary, the SMC may decide to start the next cohort at a lower dose level or 
at a lower dosing intensity (e.g. three times weekly or twice weekly).
If 1 study intervention must be withheld, that study intervention’s dose should be skipped rather 
than delayed, and the other study intervention (capecitabine or peposertib) should be given alone.
If hemoglobin is < 8 g/dL then appropriate measures according to standard clinical practice must 
be taken prior to any further dose administration.
The SMC will be responsible for dose escalation decisions and will provide input into the selection 
of a RP2D. Details of SMC decision making processes are provided in Appendix 2. The DLT 
definition is provided in Section 6.6.1.
6.6.1
Definition of Dose Limiting Toxicity
A DLT is defined as any of the following TEAEs considered possibly related to peposertib and/or 
capecitabine and/or RT by the Investigator and/or the Sponsor up to completion of the assigned 
CRT treatment (25 FD or 28 FD) (DLT period). A DLT must be confirmed by the SMC:
1. An adverse drug reaction that, in the opinion of the SMC, is of potential clinical 
significance such that further dose escalation would expose participants to unacceptable 
risk
2. Any occurrence of drug-induced liver injury (DILI) meeting the Hy’s law criteria (i.e.
defined as aminotransferases > 3 × ULN, alkaline phosphatase < 2 × ULN, total bilirubin 
≥2 × ULN, with no other reason to account for these abnormalities)
3. Any Grade 3 toxicity, excluding:
a) Diarrhea (< 7 days duration) despite early, adequate and optimal antidiarrhea 
therapy
b) Neutropenia lasting for ≤5 days and not associated with fever
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c) Isolated Grade 3 lymphocytopenia without clinical correlate
d) Grade 3 radiation dermatitis that resolves to Grade ≤2 with supportive measures 
within 5 weeks
e) Nausea and vomiting (< 3 days duration) with adequate and optimal therapy
f)
Fatigue or headache (< 7 days duration) following initiation of adequate supportive 
care
g) Any other single laboratory values out of the normal range that have no clinical 
significance as confirmed by the Investigator, and that resolve to Grade 2 or less 
with adequate measures within 7 days
h) Grade 3 thrombocytopenia without bleeding
4. All Grade ≥4 AEs at least possibly related to study intervention, irrespective of duration, 
excluding:
a) Isolated Grade 4 lymphocytopenia without clinical symptoms
b) Neutropenia lasting for ≤5 days and not associated with fever
5. Any toxicity related to study intervention that causes the participant to receive less than 
80% of the planned peposertib, capecitabine or RT dose
6.6.2
Dosing Instructions
See Table 7.
6.6.2.1
Peposertib
The participants will take peposertib orally once daily in the morning for 5 days a week (on all 
FDs) throughout the RT course in combination with capecitabine (Figure 3).
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 (	) = ℎ () × ℎ ()
3131
If there is a change in body weight of at least 10% from baseline, the individual capecitabine doses 
should be recalculated. Otherwise the initial body surface area should be utilized for subsequent 
doses.
Capecitabine will be administered orally at a dose of 825 mg/m2 twice daily 5 days a week 
throughout the RT course. The total daily dose, calculated in terms of mg/m2, will be rounded to 
the nearest 500 mg, to allow for tablet size, and then divided into 2 doses. If this results in an 
uneven number of tablets (e.g. 7 tablets daily), then then the larger number will be taken with the 
morning dose (i.e. 4 tablets in the morning and 3 tablets in the evening). Capecitabine tablets are 
not to be split.
In addition, participants will be instructed to:
!
Take capecitabine tablets in 2 daily doses: a morning dose and an evening dose
!
Swallow capecitabine tablets with water within 30 min after a meal (breakfast and dinner).
6.6.2.3
Radiotherapy
Radiotherapy will be given at a total dose of 50 to 50.4 Gy to the tumor area and 45 Gy to the 
electively irradiated tissues in 25 or 28 fractions, concomitant integrated boost is allowed based 
on local guidelines (NCCN 2019, Glynne-Jones 2017). Radiotherapy will be given 5 days a week. 
Radiotherapy will be given using intensity modulated RT or volumetric modulated arc therapy, 
using gold standard for dose planning and rigorous constraints for organs at risk (OAR).
Participants must be treated with fields that at least include the tumor, presacral nodes, mesorectal 
region, and internal iliac nodes. In addition, quality assurance on the delivered dose and fields will 
be mandated. Details are provided in Appendix 4.
6.6.2.4
Administration of the Combination Therapy
The regimen for the study consists of once daily administration of peposertib together with 
capecitabine and RT:
!
Capecitabine should be given within 30 min after a meal in 2 daily doses (a morning dose and 
an evening dose)
!
Peposertib should be given 1 h after a meal
!
Radiotherapy should be given 1.5 h (± 30 min) after peposertib dosing.
The combination therapy follows the SoC therapy schedule, which is generally administered over 
25 or 28 FDs.
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6.6.3
Management of Toxicities
Participants should be reviewed at least weekly during CRT when acute toxicity assessments are 
performed. 
The following guidance should be followed for the management of acute toxicity and dose 
modifications:
!
AEs should be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 5.0 (CTCAE v5.0)
!
In the event of overlapping toxicities, dose modification should be based on the worst toxicity 
grade observed.
!
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken in the case report and in the medical notes.
!
If a participant experiences a toxicity, then dose modifications should be applied as per protocol, 
even if the toxicity has resolved by the time the participant is next seen.
6.6.3.1
Diarrhea
It is particularly important to assess and monitor participants who experience diarrhea during CRT. 
Recommendation for participants who experience diarrhea during concurrent CRT is given in the 
diarrhea management charter. 
6.6.3.2
Capecitabine Management for Toxicities Other Than 
Diarrhea
Investigators must follow the package insert, the product information, the SmPC, and their site’s 
specific policies/instructions for the final use of capecitabine.
Toxicity due to capecitabine administration may be managed by symptomatic treatment and/or 
modification of the dose (treatment interruption or dose reduction). Once the dose has been 
reduced, it should not be increased at a later time. For those toxicities considered by the treating 
physician to be unlikely to become serious or life-threatening, e.g. alopecia, altered taste, nail 
changes, treatment can be continued at the same dose without reduction or interruption. 
Participants taking capecitabine should be informed of the need to interrupt treatment immediately 
if moderate or severe toxicity occurs. Doses of capecitabine omitted for toxicity will not be
replaced.
Hematological Toxicity
Participants with baseline neutrophil counts of < 1.5 × 109/L and/or platelet counts of 
< 100 × 109/L should not be treated with capecitabine. If these counts drop during treatment, doses 
of capecitabine are modified as shown in Table 8.
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Table 8
Dose Adjustment for Capecitabine for Absolute Neutrophil Count 
and/or Platelet Counts
Cell Count
Order of 
Occurrence
Action
Dose Resumed at (% 
of Starting Dose)
ANC ≥1.0 × 109/L and platelets
≥75 × 109/L
Maintain capecitabine dose
100%
ANC < 1.0 × 109/L and/or 
platelets < 75 × 109/L
First occurrence
Interrupt treatment until 
ANC ≥1.0 × 109/L and platelets
≥75 × 109/L
100%
ANC < 1.0 × 109/L and/or 
platelets< 75 × 109/L
Second 
occurrence
Interrupt treatment until 
ANC ≥1.0 × 109/L and platelets
≥75 × 109/L
75%
ANC < 1.0 × 109/L and/or 
platelets < 75 × 109/L
Third 
occurrence
Interrupt treatment until 
ANC ≥1.0 × 109/L and platelets
≥75 × 109/L
50%
ANC < 1.0 × 109/L and/or 
platelets < 75 × 109/L
Fourth 
occurrence
Discontinue capecitabine 
treatment
Not applicable
ANC=absolute neutrophil count.
Nonhematological Toxicity
For nonhematological toxicity due to capecitabine, doses are to be modified in line with Table 9.
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Table 9
Dose Adjustment for Capecitabine According to Common Terminology 
Criteria of Adverse Events Version 5.0 – Nonhematological Toxicity
Order of 
Occurrence
Grade 2
Grade 3
Grade 4
First 
Occurrence
Interrupt treatment until 
resolved to Grade 0/1, then 
continue at 100% or original 
capecitabine dose
Interrupt treatment until 
resolved to Grade 0/1, then 
continue at 75% or original 
capecitabine dose
Discontinue capecitabine 
treatment
Second 
Occurrence
Interrupt treatment until 
resolved to Grade 0/1, then 
continue at 75% or original 
capecitabine dose
Interrupt treatment until 
resolved to Grade 0/1, then 
continue at 50% or original 
capecitabine dose
Third 
Occurrence
Interrupt treatment until 
resolved to Grade 0/1, then 
continue at 50% or original 
capecitabine dose
Discontinue capecitabine 
treatment
Fourth 
Occurrence
Discontinue capecitabine 
treatment
Source: EU Summary of Product Characteristics Version 02 February 2006.
6.6.3.3
Peposertib and Radiotherapy
The criteria for peposertib and RT dose modification in the study are included in Table 10.
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Table 10
Dose Modifications of Peposertib and Radiotherapy During the Study
for toxicities other than Diarrhea
Dose Modifications
Toxicity
Peposertiba
Radiotherapyb
Toxicities in Radiation Field Grade 4
!
Radiation dermatitis.
Temporarily interrupt peposertib. 
Resume treatment once severity 
resolves to Grade ≤3. Maximum delay 
of up to and including 7 days; otherwise 
permanently discontinue study 
intervention.
Temporarily interrupt 
treatment. Resume 
treatment once severity 
resolves to Grade ≤3
and dose distribution 
may be adjusted to 
spare skin.
Systemic Toxicities
Hematologic Toxicities:
Any Grade ≥3 toxicity, excluding:
!
Neutropenia lasting for ≤5 days and not 
associated with fever
!
Isolated Grade 4 lymphocytopenia 
without clinical correlate
!
Grade 3 thrombocytopenia without 
bleeding.
Temporarily interrupt peposertib. 
Resume treatment (at the same dose) 
once severity resolves to Grade ≤1 or 
baseline. Maximum delay of 7 days; 
otherwise permanently discontinue 
peposertib. If there is a second 
recurrence at the same grade, 
permanently discontinue peposertib.
No action to be taken.
Nonhematologic Toxicities:
Any Grade ≥3 toxicity, excluding:
!
Nausea and vomiting (< 3 days 
duration) with adequate and optimal 
therapy
!
Fatigue or headache (< 7 days duration) 
following initiation of adequate 
supportive care
!
Any other single laboratory values out of 
the normal range that have no clinical 
significance, and that resolve to 
Grade ≤2 with adequate measures 
within 7 days.
Temporarily interrupt peposertib. 
Resume treatment (at the same dose) 
once severity resolves to Grade ≤1 or 
baseline. Maximum delay of 7 days; 
otherwise permanently discontinue 
study intervention. If there is a second 
recurrence, permanently discontinue 
peposertib.
If Grade ≥3 liver enzyme values, the 
participant must be monitored at least 
every 4 days until recovery to 
Grade ≤2.
No action to be taken.
Treatment-related hepatocellular damage 
for more than 3 days, such as 
Grade ≥3 ALT or AST with or without 
elevation of serum total bilirubin to 
> 2 × ULN, without initial findings of 
cholestasis (elevated serum alkaline 
phosphatase) or other apparent clinical 
causality.
ALT=alanine aminotransferase, AST=aspartate aminotransferase, ULN=upper limit of normal.
a
As all treatments with peposertib will be given in combination with radiotherapy, an interruption in the 
administration of radiotherapy would lead to an interruption in treatment with peposertib.
b
A maximum radiotherapy delay of up to and including 7 days in total is allowed within the complete treatment 
period. If radiotherapy and peposertib treatment have to be delayed by more than 7 days, the participant must be 
discontinued from peposertib.
Severity of adverse events will be graded using the Common Terminology Criteria for Adverse Events (version 5.0) 
toxicity grades.
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6.6.3.4
Radiotherapy Treatment Delay
Within this study, a maximum delay of up to and including 7 days in total is allowed within the 
complete Treatment period (Table 10). If RT and study intervention must be delayed by more than 
7 days, the participant must be permanently discontinued from study intervention.
As all treatments with peposertib will be given in combination with RT, an interruption in the 
administration of RT would lead to an interruption in treatment with peposertib. Capecitabine can 
be continued or discontinued according to local guidelines.
If a participant misses RT administration, then the missed RT day will be made up (i.e. the missed 
RT dose is not skipped); participants should receive a total of 25 or 28 RT fractions.
6.7
Study Intervention After the End of the Study
After a participant has completed the study or has withdrawn prematurely, usual treatment will be 
administered, if required, in accordance with the study site’s SoC and generally accepted medical 
practice and depending on the participant’s individual medical needs.
6.8
Special Precautions
!
Participants should be carefully monitored for ophthalmological complications such as keratitis 
and corneal disorders according to local guidelines.
!
Caution should be exercised with the intake of anticoagulants, phenytoin and/or leucovorin, and 
of drugs mainly metabolized by CYP3A with a narrow therapeutic index.
!
Care should be exercised when capecitabine is coadministered with CYP2C9 substrates, e.g.
phenytoin. Participants taking phenytoin concomitantly with capecitabine should be regularly 
monitored for increased phenytoin plasma concentrations.
!
Participants taking coumarin-derivative anticoagulants concomitantly with capecitabine should 
be monitored regularly for alterations in their coagulation parameters (prothrombin time or 
international normalized ratio) and the anticoagulant dose adjusted accordingly.
!
Capecitabine dosing should be discontinued in the event of severe mucocutaneous reactions. 
Capecitabine dosing should be interrupted in the event of hand-and-foot syndrome, 
hyperbilirubinemia, and low neutrophil or platelet counts.
Further details of special precautions for capecitabine
are available in the Product 
Information/SmPC.
See Section 5.3.1 for dietary restrictions.
6.9
Management of Adverse Events of Interest
For peposertib no AEs of special interest have been defined so far. Specific toxicities identified 
during the conduct of the study will be closely monitored and specific instructions for monitoring 
and management of expected toxicities will be incorporated into the protocol and the Investigator’s 
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Brochure. When further safety data for this study intervention combination become available, risk 
assessment and mitigation activities will be reviewed to assess the continued appropriateness.
The management of toxicity due to capecitabine administration is described in Section 6.6.3.2.
Toxicities related to RT will be managed according to the local institute’s guidelines.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
The participant must be withdrawn from the study intervention in the event of any of the following:
!
Therapeutic failure requiring urgent additional medication, such as administration of new 
anticancer therapy that is considered more suitable according to the Principal Investigator
!
Discontinuation of RT if participant is unable to tolerate < 80% of the planned RT dose
!
Adverse events that cause RT delays of > 7 days
!
Occurrence of AEs, if discontinuation of study intervention is desired or considered necessary 
by the Investigator, or if after temporary treatment interruption the AE does not resolve or 
worsens in severity
!
Pregnancy of participant
!
Prohibited concomitant therapy (as defined in Section 6.5.1) where the predefined consequence 
is withdrawal from the study intervention
!
Noncompliance that is deemed by the Investigator or the Sponsor to compromise participant 
safety or study integrity.
The SoA (Section 1.3) specifies the data to collect at study intervention discontinuation and 
follow-up, and any additional evaluations that need to be completed. Participants who discontinue 
study intervention must be followed on study including completion of study assessments, including 
at minimum tumor assessments until disease progression, until resolution of toxicity or 
discontinuation from study.
7.1.1
Temporary Discontinuation
Formal criteria for the dose modification, including temporary interruption where applicable, for 
capecitabine are provided in Section 6.6.3.2, and for peposertib and RT are provided in 
Section 6.6.3.3.
7.1.2
Rechallenge
Not applicable.
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7.2
Participant Discontinuation/Withdrawal from the Study
!
A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons.
!
At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the SoA. The SoA specifies the data to collect at study discontinuation 
and follow-up, and any additional evaluations that need to be completed.
!
If the participant withdraws consent for future involvement in the study, any data collected up 
to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed.
!
A participant has the right at any time to request destruction of any biological samples taken. 
The Investigator must document this in the site study records.
Participants should be explicitly asked at time of discontinuation of study if they would allow 
survival information to be collected including verification of medical/public records as permitted 
by local regulations. These responses should accordingly be captured in the participant’s source 
data and reported in the eCRF accordingly.
The SoA (Section 1.3) specifies the data to collect at study discontinuation and follow-up, and any 
additional evaluations that need to be completed.
Participants who are discontinued/withdrawn from the study will not be replaced.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule, 
and ascertain if the participant wants to or should continue in the study.
!
Before a participant is deemed “lost to follow-up”, the Investigator or designee must make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be documented 
in the participant’s medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study.
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8
Study Assessments and Procedures
!
Study assessments and procedures and their timing are summarized in the SoA (Section 1.3).
!
No protocol waivers or exemptions are allowed.
!
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.
!
Adherence to the study design requirements, including those specified in the SoA (Section 1.3), 
is essential and required for study conduct.
!
All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all participants screened, to confirm eligibility, and if applicable, record reasons for 
screening failure.
!
Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2 (Study 
Governance).
!
Procedures conducted as part of the participant’s routine medical care (e.g. blood count) and 
obtained before signing of the ICF may be used for Screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA (Section 1.3).
!
Regarding the visits from Week 7 to 14 during the short-term safety follow-up (Table 1). The 
Week 14 visit is mandatory as this is needed for restaging and evaluation. All other visits in this 
period are optional and needed only in case of acute toxicities until recovery to Grade 1 or 
baseline.
!
A maximum of 255 mL of blood will be collected in any one-month period from each 
participant in the study, including any extra assessments that may be required.
Screening:
Participants will be screened between Days -28 and -1, prior to first dosing on Day 1. Assessments 
and procedures to be performed at Screening are detailed in the SoA (Section 1.3). 
Screening-specific procedures include:
!
Demography: date of birth, sex (gender), race, and ethnicity.
!
Medical history: disease history, previous illness and surgeries (e.g. all during the past year 
and only major ones prior to that), concomitant illness, relevant medication, allergies, therapies 
stopped or changed at entry into the study, tobacco use including pack years, and alcohol use.
!
Eastern Cooperative Oncology Group Performance Status: assessed at Screening to assess 
eligibility (Section 5.1) and then assessed according to the SoA (Section 1.3).
!
Chest-abdominal computerized tomography (CT): A CT scan of the chest and abdomen will 
be performed prior to the beginning of study intervention to document the baseline status of the 
participant. Computerized tomography will be performed with intravenous iodinated contrast 
unless contraindicated. Evaluation up to 28 days prior to start of study intervention is allowed.
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In the case of a rescreen and the screening CT scan is > 28 days from the previous screening 
scan, the screening CT will need to be repeated.
!
DRE and endoscopy (and EUS if indicated or if performed): for participants who have 
received induction chemotherapy prior to start of study
Surgery
Participants will undergo surgery using TME 15 weeks (± 14 days) after start of RT according to 
a standardized technique, unless there are contraindications for surgery (Ridgway 2003, 
Parfitt 2007), if the participant refuses, or if the participant has a cCR and is eligible for organ 
preservation.
The choice of the surgical procedure, abdominoperineal resection or low anterior resection, is at 
the surgeon’s discretion. Further details will be described in a dedicated surgical charter.
8.1
Efficacy Assessments and Procedures
8.1.1
Pathological Complete Response
The pathologic specimens after TME will be evaluated using standard pathological guidelines as 
described in the Appendix 6. All surgical and pathology reports for the TME resection must be 
submitted. 
The American Joint Committee on Cancer (AJCC) 8th edition (Amin 2017) will be used to 
categorize the completeness of the TME resection.
Reports must contain information about microscopic involvement and surgical resection margins.
If there is residual macroscopic tumor, standard pathological examination will be carried out with 
3 to 5 sections to investigate the deepest invasion in the bowel wall. If no macroscopic tumor is 
present and only a small ulcer is observed, the ulcer with a 2 cm margin will be examined for 
residual tumor and deepest invasion in the bowel wall. All lymph nodes will be examined 
according to standard procedures and the circumferential resection margin (CRM) will be 
measured (Washington 2009). The status of the surgical CRM will be defined as involved if there 
is tumor within 1 mm of the CRM.
The extent of residual tumor in the resected specimen will be classified according to the Tumor 
Node Metastases staging system of the 8th edition AJCC, with the prescript “y” to indicate that 
the tumor had been treated before surgical resection. After preoperative CRT, residual tumor 
masses will be semi-quantitatively evaluated according to the 4-point regression grading scale 
Modified Ryan scheme for tumor regression score (see Appendix 6).
A pCR will be defined as the absence of viable tumor cells in the primary tumor and lymph nodes 
(ypT0N0).
Standard data on pathology, completeness of resection, and the response to neoadjuvant 
chemotherapy will be collected. The slides will be locally reviewed to record whether there was 
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macroscopic clearance of the tumor. Assessments of the pathology must be according to 
international guidelines and will be further described in Appendix 6.
8.1.2
Tumor Evaluation Methods and Response Assessment
Rectal cancer staging, and measurement at baseline and after chemoradiation should be performed 
as per NCCN Guidelines for Patients Rectal Cancer 2019. For participants who received induction 
treatment the baseline assessments will be based on MRI, endoscopy and DRE and biopsy, if 
required. For participants without induction treatment, the baseline assessment will consist of MRI 
only. For all participants the assessments after chemoradiation (Week 14) will include MRI, 
endoscopy and DRE and biopsy, if required. This is all based on a modification of tumor evaluation 
as described by Maas 2015. Tumor assessments done during long-term Safety Follow-up will only 
include MRI (T2 weighted and diffusion weighted) or CT scans (Table 1 and Table 2).
Baseline assessments are to be taken not earlier than 4 weeks prior to study intervention 
start/randomization. After study intervention start/randomization, tumor assessments will be 
performed at 14 weeks (± 7 days) after study intervention start/randomization (i.e. before surgery) 
and 27 weeks (± 2 week) after study intervention start/randomization, every 3 months thereafter 
(± 2 weeks) until 1 year after study intervention start/randomization.
8.1.2.1
Evaluation Methods
MRI: A standard and diffusion-weighted MRI sequences will be obtained in 1.5T or 3T units by 
using a phased array body coil. All images will be interpreted by expert radiology staff at the 
participant primary treatment center for participant eligibility, clinical staging, according to 
standard clinical criteria, including extramural vascular invasion and CRM assessment. For all 
participants, evaluation up to 28 days prior to start study intervention/randomization is allowed.
If induction chemotherapy was given, an MRI must be done to evaluate tumor changes after 
chemotherapy. It should be done as described above and within 2 weeks after the last day of 
chemotherapy but before starting study intervention/randomization.
Endoscopy with photography: Is to be done along with DRE and MRI. The length of the tumor 
is defined as the difference between the distance of the proximal and distal margins of the lesion 
in relation to the anal verge. 
If participant received induction chemotherapy, endoscopy will be performed 2 weeks (± 14 days) 
after the last day of chemotherapy but before starting study intervention/randomization to evaluate 
tumor changes after chemotherapy.
Digital Rectal Exam: If the tumor cannot be reached on digital rectal exam, this should be noted 
on the checklist and evaluation. The digital rectal exam criteria are applicable to participants with 
palpable tumor only. 
In case induction chemotherapy was given, a DRE must be done to evaluate tumor changes after 
chemotherapy. It should be done within 2 weeks (± 14 days) after the last day of chemotherapy 
but before starting study intervention/randomization.
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Biopsy: Only to be done during the endoscopy if required and as per institutional guidelines.
8.1.2.2
Tumor Response Evaluation
After induction chemotherapy: Response evaluation after induction chemotherapy and restaging 
before study intervention with peposertib and CRT are provided in Appendix 5. The evaluation 
with MRI, endoscopy, and DRE is to be done before starting treatment/randomization (peposertib 
and CRT). Overall response is evaluated as progressive disease, stable disease, partial response, 
nearly complete response, or complete response. Participants who present with stable disease, 
partial response, or nearly complete response may enter the study, participants who present with 
tumor progression or cCR should be treated according to standard practice per institutional 
guidelines.
After peposertib and CRT: Response evaluation criteria after treatment and restaging before 
surgery are provided in Appendix 5. The evaluation with MRI, endoscopy, and DRE is to be done 
at Week 14 (± 7 days). Overall response is evaluated as progressive disease, incomplete response, 
nearly complete response, or complete response.
During Long-term Safety Follow-up: Response evaluation is provided in Appendix 5. 
If a scan shows progressive disease, it will be indicated whether it is local recurrence, distant 
recurrence, or both.
Tumor assessments are performed until progressive disease or the participant withdrawal of 
consent. Tumor assessments will be stopped on subsequent start of new anticancer therapy, with 
the exception of starting adjuvant treatment described in Section 6.5.
8.1.2.3
Neoadjuvant Rectal Score
The neoadjuvant rectal score (NAR) was developed by George and colleagues to serve as a 
short term clinical study surrogate endpoint (George 2015). The Valentini nomograms 
(Valentini 2011) to predict overall survival in rectal cancer patients after neoadjuvant treatment 
are the basis of the NAR score. Its score ranges from 0 to 100, whereas a score close to 100 is 
indicative of a poorer prognosis. 
The NAR formula includes the clinical tumor (cT) stage, pathologic tumor (pT), and node (pN) 
stage according to the tumor, node, metastasis classification system for colorectal cancers. The 
NAR formula is as follows:
NAR = [5pN – 3(cT – pT) + 12]2
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8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, and 
laboratory tests.
The safety observation is divided into the following periods:
!
Baseline: safety evaluation before the initiation of study intervention
!
Treatment Period: during study intervention
!
Short-term Safety Follow-up: evaluations after the Treatment Period, including the 
perioperative and postoperative observation (until Week 19)
!
Long-term Safety Follow-up: up to 1 year.
Participants who have already been followed up for more than 1 year (Long-term Safety or 
Survival Follow-up) will be discontinued from the study after the approval of protocol amendment 
version 4.0 by the respective Health Authority and Ethics Boards.
Frequency of visits and specific procedures are described in Table 1 and Table 2.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information).
8.2.1
Physical Examinations
A complete physical examination will be performed at Screening and a brief physical examination 
will be performed at all other time points indicated in the SoA (Section 1.3).
!
A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems. Height (at Screening) 
and weight will also be measured and recorded.
!
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen.
!
Investigators should pay special attention to clinical signs related to previous serious illnesses.
!
Investigators will report findings in the irradiated area during the Short- and Long-term Safety 
Follow-up periods.
For participants with a change in body weight of at least 10% from baseline, individual 
capecitabine doses should be recalculated. See Section 6.1 for details.
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8.2.2
Vital Signs
!
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
!
Blood pressure and pulse measurements will be assessed in a semi-supine position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
!
Blood pressure and pulse measurements should be preceded by at least 5 min of rest for the 
participant in a quiet setting without distractions (e.g. television, cell phones).
!
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 min). The average of the 3 blood pressure readings will be recorded on 
the CRF.
8.2.3
Electrocardiograms
Digital ECGs for all participants will be recorded at the site. Triplicate ECGs will be obtained for 
participants according to the Schedules of Activities (Table 1).
Electrocardiograms will be documented by recording date and time of collection. All ECG results 
must be reviewed at the site by the Investigator or a medically qualified designee for clinical 
management of the participant. The Investigator will judge the overall interpretation as normal or 
abnormal. If abnormal, it will be decided if the abnormality is clinically significant or not clinically 
significant and the reason for the abnormality will be recorded on the eCRF. 
8.2.4
Clinical Safety Laboratory Assessments
!
In woman of childbearing potential, pregnancy testing (serum β-human chorionic 
gonadotropin) will be performed at the visits specified in the SoA (Section 1.3). Participants 
after menopause (age-related amenorrhea ≥12 consecutive months) or participants who have 
undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.
!
Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 8, 
at the time points listed in the SoA (Section 1.3). All samples should be clearly identified.
!
Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations.
!
The tests will be performed by the local laboratory.
!
The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study must be forwarded to the Sponsor 
or designated organization.
!
The Investigator must review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents.
!
Analyte results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.
Nonfasting blood samples are acceptable for this study.
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See Appendix 8 for a full list of clinical laboratory assessments that will be performed. Further 
details will be provided in the Laboratory Manual.
8.2.5
Suicidal Risk Monitoring
Not applicable.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a serious adverse event (SAE) are in Appendix 7.
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until the final assessment at 1 year. Any AE assessed as not related to study 
intervention will be recorded only up to the short-term safety follow-up period. Any AE assessed 
as related to study intervention will be recorded up to resolution or permanent outcome, 
irrespective of the time elapsed since the last administration of study intervention.
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 7, whenever it occurs, irrespective of the time elapsed since the last administration of 
study intervention. Any SAE assessed as not related to study intervention must be recorded and 
reported, as indicated in Appendix 7, only up to Week 27 in the long-term safety follow-up period.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 7.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator.
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the CRF. 
All SAEs must be additionally documented and reported using the appropriate Report Form as 
specified in Appendix 7.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
Adverse events are recorded and assessed continuously throughout the study, as specified in 
Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information) and are assessed for their outcome at the final assessment at 1 year. All SAEs 
ongoing at the final assessment at 1 year must be monitored and followed-up by the Investigator 
until stabilization or until the outcome is known, unless the participant is documented as “lost to 
follow-up”. Reasonable attempts to obtain this information must be made and documented. It is 
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also the responsibility of the Investigator to ensure that any necessary additional therapeutic 
measures and follow-up procedures are performed. Further information on follow-up procedures 
is given in Appendix 7 (Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reports).
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) that approved the study.
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), 
the Sponsor/designee will inform the Investigator of findings that could adversely affect the safety 
of participants, impact the conduct of the study or alter the IEC’s/IRB’s approval/favorable opinion 
to continue the study. In line with respective regulations, the Sponsor/designee will inform the 
Investigator of AEs that are both serious and unexpected and considered to be related to the 
administered product (“suspected unexpected serious adverse reactions” or SUSARs). The 
Investigator should place copies of Safety Reports in the Investigator Site File. National 
regulations regarding Safety Report notifications to Investigators will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
8.3.5
Pregnancy
Only pregnancies the Investigator considers to be related to the study intervention (e.g. resulting 
from a drug interaction with a contraceptive method) are AEs. However, all pregnancies with an 
estimated conception date during the period defined in Section 8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and Serious Adverse Event Information) must be recorded in the AE 
page/section of the CRF for both pregnancies in female participants and 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 by the 
same process specified for SAE reporting in Appendix 7, section on Reporting Serious Adverse 
Events, Adverse Events of Special Interest, and Dose Limiting Toxicities.
Investigators must actively follow-up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
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The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. Any abnormal outcome (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) must be reported in an expedited manner, as specified in 
Section 8.3.1, while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay and 
the participant must be followed as indicated above.
8.4
Treatment of Overdose
For this study, any dose of peposertib greater than 100% of the planned dose will be considered an 
overdose.
The Sponsor does not recommend specific treatment for an peposertib overdose. The Investigator 
should use clinical judgment to manage any overdose considering the presenting symptoms and 
standard evaluation results.
For this study, any dose of capecitabine greater than 100% of the planned dose will be considered 
an overdose.
Overdose of capecitabine generally results in severe forms of normally occurring adverse 
reactions. Investigators are asked to check the respective information in the Product 
Information/SmPC for further advice.
Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and reported 
to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, following 
the procedure in Appendix 7, section on Reporting Serious Adverse Events, Adverse Events of 
Special Interest, and Dose Limiting Toxicities.
8.5
Pharmacokinetics
!
The following PK parameters will be calculated, when appropriate:
Symbol
Definition
Cmax
Maximum observed concentration.
Tmax
The time to reach the maximum observed concentration collected during a dosing interval (unless 
otherwise defined, take the first occurrence if multiple/identical Cmax values).
AUC0-t
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration 
is at or above the lower limit of quantification. Calculated using the mixed log linear trapezoidal rule 
(linear up, log down).
AUC0-24
The AUC from time zero (= dosing time) to 24 h post dose. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down).
AUC0-∞
The AUC from time zero (= dosing time) to infinity post dose. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down).
T1/2
Apparent terminal half-life. T1/2 = ln (2)/λz
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Symbol
Definition
CL/f
The apparent total body clearance of study intervention following extravascular administration on 
FD1, taking into account the fraction of dose absorbed.
CL/f = Dose p.o./AUC0-∞. The predicted AUC0-∞should be used.
Vz/f
The apparent volume of distribution during the terminal phase following extravascular 
administration, based on the fraction of dose absorbed. Vz/f = Dose/(AUC0-∞*λz) following single 
dose. Vz/f = Dose/(AUC∀*λz) following multiple dose.
Racc(Cmax)
The accumulation factor to assess the increase in maximum concentration from FD1 to FD9. 
Racc(Cmax) = (Cmax FD9)/(Cmax FD1).
Racc(AUC0-24) The accumulation factor to assess the increase in exposure from FD1 to FD9 during time 0 to 24 h. 
Racc(AUC0-24) = (AUC0-24 FD9)/(AUC0-24 FD1).
Racc(AUC0-t)
The accumulation factor to assess the increase in exposure from FD1 to FD9 during time 0 to t h. 
Racc(AUC0-t) = (AUC0-t FD9)/(AUC0-t FD1).
LI
The linearity index after repeated administration calculated as LI= (AUC0-24 after multiple dose (at 
steady state)) / (AUC0-∞after single dose)
AUC=area under the concentration-time curve, FD=fraction day.
!
Whole blood samples of approximately 2 mL will be collected for measurement of plasma
concentrations of peposertib (and/or metabolites), capecitabine, and capecitabine metabolites.
Collection times are specified in the SoA (Table 4). PK sampling should be performed 
within ± 10 min for the first 2 h of sample collection, within ± 20 min for the 3 h and 4 h 
sample, and within ± 30 min for the 6 h sample. The predose sample(s) should be collected 
prior to capecitabine and peposertib administration but within 60 min prior to the peposertib
administration. A maximum of 3 samples per participant may be collected at additional time 
points during the study if warranted and agreed upon between the Investigator and the Sponsor. 
The actual date and time (24 h clock time) of each sample will be recorded to calculate actual 
time elapsed since prior dose administration. The sampling timing may be altered during the 
study based on newly available data (e.g. to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.
!
The quantification of peposertib, capecitabine and capecitabine metabolites in plasma will be 
performed using a validated liquid chromatography-tandem mass spectrometry method. 
Concentrations will be used to evaluate PK of peposertib (and/or metabolites) and capecitabine.
!
Remaining samples collected for analyses of peposertib and capecitabine (whole blood) 
concentration may also be used to evaluate safety and efficacy aspects related to concerns 
arising during or after the study.
!
Details on processes for collection and shipment of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF.
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8.9
Health Economics
Not applicable.
8.10
Immunogenicity Assessments
Not applicable.
9
Statistical Considerations
All analyses will be described in detail in the Integrated Analysis Plan.
9.1
Statistical Hypotheses
No formal statistical hypothesis tests will be performed, as the study is designed to be exploratory. 
Any p-values indicated are to be considered exploratory.
9.2
Sample Size Determination
A Bayesian 2-parameter logistic regression model with overdose control is applied to assist the 
SMC in dose recommendations. The planned cohort size is 3 participants. The total sample size 
will depend on the number of cohorts to be evaluated. It is anticipated that 18 to 30 evaluable 
participants are required.
9.3
Populations for Analyses
The analysis populations are specified below (Table 11).
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Table 11
Definition of Populations
Population
Description
Enrolled 
All participants who sign informed consent.
DE
The DE Analysis Set will include all participants treated in dose escalation cohorts, who 
receive at least 80% of peposertib, 50% of capecitabine, and 80% of RT planned dose 
and complete the DLT period. The DE set will also include participants treated in dose 
escalation cohorts who experience a DLT during the DLT period regardless of the 
amount of each study intervention received/completion of the DLT period.
FAS/SAF
The FAS/SAF will include all participants who are enrolled in the study and received at 
least 1 dose of study intervention.
PK
The PK Analysis Set is defined as all participants who receive at least 1 dose of 
peposertib and have at least 1 quantifiable plasma concentration at a scheduled PK time 
point postdose.
cCR=Clinical Complete Response, DE=Dose Escalation, DLT=dose limiting toxicity, FAS=Full Analysis Set, 
PK=Pharmacokinetic, RT=radiotherapy, SAF=Safety.
9.4
Statistical Analyses
The following statistics will be used to summarize the study data (e.g. Baseline characteristics) 
unless otherwise specified:
!
Continuous variables: number of nonmissing observations, mean, standard deviation, median, 
minimum, and maximum, 95% CIs for the mean, as appropriate.
!
Categorical variables: frequencies and percentages.
9.4.1
Efficacy Analyses
Statistical analysis methods for efficacy endpoints are described in Table 12.
Table 12
Statistical Analysis Methods for Efficacy Endpoints
Endpoint
Statistical Analysis Methods
Secondary
Composite endpoint of 
pCR/cCR
Derivation of the pCR/cCR composite endpoint (pCR based on local review) is 
described in Section 3.1.
The proportion of participants with pCR/cCR is indicated together with the 
95%-Clopper-Pearson CI. The analysis will be performed on the FAS.
Disease-Free Survival
Disease-free Survival time, defined as the time from first treatment day to the date of 
the first documentation of objective progressive disease or death due to any cause, 
whichever occurs first.
The analysis will be performed as described below for time-to-event endpoints.
pCR
The definition of pCR is provided in Section 3.1.
pCR will be analyzed once on the local review of the histology slides.
The proportion of participants with pCR will be reported together with the 
corresponding 95% CIs. 
The analysis will be performed on the FAS
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Endpoint
Statistical Analysis Methods
cCR
The definition of cCR is provided in Section 3.1.
The proportion of participants with cCR will be reported together with the 
corresponding 95% CIs. 
The analysis will be performed on the FAS
Local/distant recurrence
The following analyses will be performed:
!
Time from surgery to local recurrence
!
Time from surgery to distant recurrence.
The analyses will be performed as described below for time-to-event endpoints.
Neoadjuvant Rectal 
Score
The neoadjuvant rectal score will be presented in terms of summary statistics (such 
as mean, median, standard deviation, and quartiles) and graphically.
The analysis will be performed on the FAS Population.
cCR=Clinical Complete Response, CI=confidence interval, CR=complete response, FAS=Full Analysis Set, 
pCR=Pathological Complete Response.
In addition to analyses specified in Table 12, for the primary and main secondary endpoints 
subgroup analyses on baseline variables such as gender, tumor stage, etc. will be performed. 
Analysis of Time-to-event Endpoints
Kaplan-Meier estimates will be presented together with a summary of associated statistics (median 
survival time and survival rate estimates) including the corresponding 2-sided 95% CIs. 
Confidence intervals for the median will be calculated according to Brookmeyer and Crowley 
(Brookmeyer 1982) and CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (Kalbfleisch 1980). The estimate of the 
standard error will be computed using Greenwood’s formula.
9.4.2
Safety Analyses
Statistical analysis methods for safety endpoints are described in Table 13.
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Table 13
Statistical Analysis Methods for Safety Endpoints
Endpoint
Statistical Analysis Methods
Primary
Occurrence of DLTs
The number and proportion of participants experiencing a DLT confirmed by the SMC 
during the DLT period will be reported by dose level.
Analysis will be based on the DE Analysis Set.
Secondary
Occurrence of TEAEs
and treatment-related 
AEs according to the 
CTCAE version 5.0
All AEs will be coded according to the MedDRA, version 21.0 or higher. The severity 
of AEs will be graded using NCI-CTCAE v5.0 toxicity grades.
Adverse events related to study intervention will be defined as any AE considered 
related to any study intervention. In addition, missing classifications concerning study 
intervention relationships will be considered related to the study intervention(s).
Adverse events observed from the first dose until 30 days after last study intervention
administration (i.e. TEAEs) will be summarized according to MedDRA system organ 
classes and preferred terms. The incidence and type of the following will be analyzed:
!
TEAEs and SAEs
!
TEAEs and SAEs related to study intervention
!
TEAEs with NCI-CTCAE Grades ≥3
!
TEAEs related to study intervention with NCI-CTCAE Grades ≥3
!
AEs leading to withdrawal, dose modifications, or permanent study intervention
discontinuation
!
Deaths and reasons for death will be tabulated. In addition, deaths within 30 days 
from last dose administration and deaths beyond this period up to 90 days 
follow-up and reasons for death will be tabulated.
Analyses will be based on the Safety Analysis Set.
Occurrence of 
abnormalities 
(Grade ≥3) in laboratory 
test values and markedly 
abnormal vital sign 
measurements, and
clinically significantly 
abnormal ECGs 
including clinically 
important increases in 
QT interval (QTcF)
Laboratory results will be classified by grade according to NCI-CTCAE v5.0. The 
worst on-study grades after the first study intervention will be summarized.
Shifts in toxicity grades from first treatment to highest grade will be displayed. Results 
for variables that are not part of NCI-CTCAE will be presented as below, within, or 
above normal limits. Only participants with postbaseline laboratory values will be 
included in these analyses.
Physical examination, including vital signs (body temperature, respiratory rate, pulse
rate, and blood pressure), and 12-lead ECG, recorded at baseline and after 
administration of study intervention.
Analyses will be based on the Safety Analysis Set.
AE=adverse event, DLT=dose limiting toxicity, ECG=electrocardiogram, MedDRA=Medical Dictionary for Regulatory 
Activities, NCI-CTCAE=National Cancer Institute Common Terminology Criteria of Adverse Events, SAE=serious 
adverse event, SMC=Safety Monitoring Committee, TEAE=treatment-emergent adverse event.
Analyses for SMC Meetings:
During dose escalation the analysis will focus on safety and available PK data.
The Bayesian escalation approach will be applied to assist the SMC in the choice of the next dose 
level. The SMC will receive results of a Bayesian 2-parameter dose-toxicity model with overdose 
control, updated with the observed DLT data. The recommended next dose level will minimize the 
Bayesian Risk among all considered dose levels, while at the same time limiting the risk of 
overdose or excessive toxicity (Neuenschwander 2008). The target toxicity is 30%. Details of the 
model including the prior distribution and toxicity regions are described in Appendix 10.
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The following peposertib dose levels will be considered for escalation decisions: 30, 50, 100, 200, 
400, 600, and 800 mg; 50 mg is the starting dose. Dose increases will not exceed 100% of the 
highest dose level considered safe at the time of escalation decision. The SMC may decide to 
deviate from the suggestion of the Bayesian escalation approach. Also, the SMC may decide to 
change the dosing regimen. In such a case the model will be extended, or a separate model will be 
set up.
Analyses for the Bayesian dose escalation will be performed on the DE Analysis Set. Usually 
decisions on dose escalation are taken once all participants of the most recent cohort have 
completed the DLT period or dropped out. In exceptional cases, however, the SMC may decide on 
the next cohort earlier, i.e. before the last participant of a cohort has finished the DLT period 
(considering the model recommendation and risk of overdose). Per definition of the DLT analysis, 
participants who have not completed the DLT period are not included for update of the model, 
unless they experienced a DLT. However, such participants will be included at next SMC (if 
criteria for the DE Analysis Set are fulfilled).
Details on analyses for SMCs/CSR will be described in the corresponding SAP.
9.4.3
Other Analyses
Baseline Characteristics
Baseline characteristics will be tabulated as described in Section 9.4.
The PK, 
 analyses will be specified in the Integrated Analysis Plan 
finalized before database lock. Integrated analyses across studies, such as the population PK 
analysis 
 will be presented separately from the main CSR.
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9.4.4
Sequence of Analyses
The following analyses will be performed:
To decide on dose escalation, safety and PK analyses will be provided for the purpose of SMC 
meetings. The cut-off for dose escalation assessments by the SMC will usually be triggered by the 
completion of the DLT period (or dropout) of the last participant in the respective dose escalation 
cohort of usually 3 participants. In addition, once a participant completed the Short-term Safety 
Follow-up period at approximately 19 weeks after starting treatment, data of the participant will 
be reviewed. In the event of severe toxicity, an ad-hoc SMC meeting will be scheduled to decide 
on potential dose adjustment.
The cut-off for the primary analysis of the safety and preliminary antitumor activity data from the 
complete dose escalation will be triggered when the last participant enrolled in dose escalation 
reaches the end of the Short-term Safety Follow-up period or dies or prematurely discontinues the 
study for any reason, whichever occurs first.
Additional analyses might be performed, e.g. for publication purposes.
Follow-up analyses to report further efficacy and safety data will be done at the End of Study.
More details will be described in the Integrated Analysis Plan.
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10
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Appendices
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Appendix 1
Abbreviations
AE
Adverse event
AJCC
American Joint Committee on Cancer
ATP
Adenosine triphosphate
cCR
Clinical Complete Response
CI
Confidence interval
CRF
Case Report Form
CRM
Circumferential resection margin
CRT
Chemoradiotherapy
CSR
Clinical Study Report
CT 
Computerized tomography
CTCAE
Common Terminology Criteria of Adverse Events
ctDNA
Circulating tumor DNA
CTV
Clinical target volume
CYP
Cytochrome
DLT
Dose limiting toxicity
DNA-PK
DNA-protein kinase
DRE
Digital rectal examination
DSB
Double-strand break
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EUS
Endoscopic ultrasonography
FD
Fraction day
Gy
Gray
GCP
Good Clinical Practice
HRT
Hormonal replacement therapy
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IR
Ionizing radiation
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IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NAR
Neoadjuvant rectal score
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
OAR
Organs at risk
pCR
Pathological Complete Response
PK
Pharmacokinetic(s)
PPI
Proton pump inhibitor
PTV
Planning target volume
QoL
Quality of life
RP2D
Recommended Phase II dose
RT
Radiotherapy
SAE
Serious adverse event
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SoC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TME
Total mesorectal excision
ULN
Upper limit of normal
5FU
5-fluorouracil
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
!
The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative (where allowed by local laws and regulations) and 
answer all questions on the study.
!
Participants must be informed that their participation is voluntary.
!
Participants or their legally authorized representative (where allowed by local laws and 
regulations) will be required to sign a statement of informed consent that meets the requirements
of 21 CFR 50; local regulations; ICH guidelines; Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable; and the IRB/IEC or study center.
!
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
!
If the ICF is updated during their participation in the study, participants must be re-consented 
to the most current, approved version.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.
!
The original signed and dated consent will remain at the Investigator’s site and must be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes.
!
Participants who are rescreened are required to sign a new ICF.
Data Protection
!
The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the identifier 
only; participant names or any identifiable information will not be transferred.
!
The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant.
!
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality.
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!
The Investigator will complete the participant
registration using the IVRS/IWRS 
(Section 6.3.1). If the participant meets all inclusion criteria and does not meet any of the 
exclusion criteria, the participant will be registered by IVRS/IWRS. If the participant is 
ineligible for the study, a participant number will be allocated and documented.
Study Administrative
This clinical study will be sponsored by Merck KGaA, Germany (in all countries except the USA
and Canada) and EMD Serono Research & Development Institute, Inc. (EMD Serono R&D), USA, 
for sites in the USA and Canada.
Site and country selection will be based on historic enrollment data and the results of a feasibility 
assessment. It is planned to open the dose escalation part in approximately 10 sites in the US and 
Europe. Sites will include clinical centers and academic centers, mostly in an outpatient setting.
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the CSR.
The study will appear in the following clinical studies registries: EudraCT (2018-002275-18) and 
ClinicalTrials.gov.
An SMC will be formed in this study and will review all available safety data on a regular basis 
during the study. The SMC consists of Sponsor representatives (including, but not limited to the 
Medical Responsible, the Patient Safety Strategy Lead, the Biostatistician, and the PK expert) and 
Investigators. The Medical Monitor from the Contract Research Organization will be a SMC 
member.
The SMC will be responsible for dose escalation decisions, continuous safety assessment, and will 
provide input into the selection of a RP2D. The full membership, mandate, and processes of the 
SMC will be detailed in the SMC charter.
After each cohort has finished the peposertib treatment period (DLT period), the SMC will review 
the safety, tolerability, and PK data and will provide recommendations for the next cohort, move 
to the next dose level, stay on the actual dose level, de-escalate to a lower dose level, or explore 
alternative schedules of peposertib. In addition, the SMC will review safety, tolerability, and PK 
data when each cohort has finished the 30-day follow-up period after surgery to provide further 
recommendations on dose escalation.
Details of structures and associated procedures will be defined in separate SMC charters. 
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Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and the following:
o
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH GCP Guidelines
o
Applicable laws and regulations.
!
The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents to an IRB/IEC and the IRB/IEC must 
review and approve them before the study is initiated.
!
Any protocol amendments (i.e. changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities.
!
The Investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently per the IRB’s/IEC’s requirements, policies, and procedures
o
Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures
o
Providing oversight of the study conduct at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), and all other applicable local regulations.
!
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
!
The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable).
!
The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g. unblinding) will follow the standard process 
established for Investigators.
!
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor physician. This includes provision of a 24-h contact number at a call center, whereby 
the health care providers will be given access to the appropriate Sponsor physician to assist with 
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the medical emergency and to provide support for the potential unblinding of the participant 
concerned.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
Clinical Study Report
After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator, and other relevant committees or groups.
Publication
!
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments.
!
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a Coordinating 
Investigator will be designated by agreement.
!
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
!
Procedures for publication planning and the use of professional writers are not yet known. 
Questions may be directed to the Sponsor Medical Responsible.
Dissemination of Clinical Study Data
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3, and will be submitted in 
accordance with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff as have 
been made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study.
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study intervention and therefore may be 
disclosed as required to other clinical Investigators, to the US Food and Drug Administration, and 
to other government agencies. The Investigator also understands that, to allow for the use of the 
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information derived from the clinical study, the Investigator has the obligation to provide the 
Sponsor with complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement.
Data Quality Assurance
!
All participant study data will be recorded on printed or eCRFs or transmitted to the Sponsor 
or designee electronically (e.g. laboratory data). The Investigator is responsible for verifying 
that data entries are complete, accurate, legible, and timely by physically or electronically 
signing the CRF. Details for managing CRFs are in the Clinical Operations Manual and the 
Data Management Guidelines.
!
The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF.
!
The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data.
!
Monitoring details describing strategy (e.g. risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan or 
contracts.
!
The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. PDF files of the CRFs will be 
provided to the Investigators at study completion.
!
Study monitors will perform ongoing source data verification to confirm that data in the CRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be destroyed 
during the retention period without the Sponsor’s written approval. No records may be 
transferred to another location or party without the Sponsor’s written notification.
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
!
The Investigator must keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file must identify each participant, contain the 
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following demographic and medical information for the participant, and should be as complete 
as possible:
o
Participant’s full name, date of birth, sex, height, and weight
o
Medical history and concomitant diseases
o
Prior and concomitant therapies (including changes during the study)
o
Study identifier (i.e. the Sponsor’s study number) and participant’s study number
o
Dates of entry into the study (i.e. signature date on the informed consent) and each 
visit to the site
o
Any medical examinations and clinical findings predefined in the protocol
o
All AEs
o
Date that the participant left the study, including any reason for early withdrawal 
from the study or study intervention, if applicable.
!
All source data must be filed (e.g. CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed and dated by the Investigator.
!
Data recorded on printed or electronic CRFs that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
!
The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator, and kept in the study file.
!
Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures
that no destruction of medical records is performed without the Sponsor’s written approval.
!
Definition of what constitutes source data is found in the eCRF guidelines.
Study Start and Site Start and Closure
First Act of Recruitment
!
The first act of recruitment is the signing of the ICF and will be the study start date.
Study Closure and Site Termination
!
The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a site closure visit has 
been completed.
!
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
!
Reasons for the early closure of a study site by the Sponsor or Investigator may include:
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o
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines
o
Inadequate recruitment of participants by the Investigator
o
Discontinuation of further development of the Sponsor’s compound.
!
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator will promptly inform the participants 
and assure appropriate participant therapy and/or follow-up.
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential
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 woman of childbearing potential is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the above, 
(e.g. mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry.
3. A postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in a female not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, more than 1 FSH measurement is required in the postmenopausal range.
!
A female on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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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 woman of childbearing potential 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.
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, male condoms must be used in addition to hormonal 
contraception.”. 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 4
Radiation Therapy
Radiation therapy general techniques
Linear accelerators with a minimum energy of 6MV photons will be used. A multiple-field 
technique using intensity modulated RT is highly recommended. Radiation will be delivered 5 
business days/week, once per day, at 1.8 Gy/day. 
Radiation simulation and immobilization
Prior to RT, simulation utilizing CT-based planning with ≤3 mm slice thickness will be 
performed. If possible, participants will be treated in the prone position on a belly board. If prone 
positioning is not tolerable for the participant, the supine position should be considered but with 
full bladder technique, if tolerable (participants drink 500 mL of water 1 h prior to scanning and 
1 h prior to daily treatment). A suitable immobilization device (such as Aquaplast mold or 
Alphacradle) should be used with supine positioning.
Oral contrast is recommended to help aid in the identification of the small bowel.
Intravenous contrast can be administered to participants without contrast allergy or compromised 
kidney function, depending on the clinical scenario.
A radio-opaque marker should be placed at the anal verge. 
Contouring and target volume delineation 
The following areas should be contoured:
!
GTV-P primary gross tumor volume
!
GTV-N nodal gross tumor volume
!
Clinical target volume (CTV) (50 or 50.4) should include the gross tumor volume (GTV)
with up to a 2 to 3 cm superior and inferior margin including the entire rectum, mesorectum, 
and presacral space.  
!
CTV45 should include the entire rectum, mesorectum, perirectal nodes, presacral nodes, 
internal iliac nodes, and common iliac nodes below the L5-S1 junction. 
o In participants with T4 disease with anterior involvement of an adjacent organ (i.e. prostate, 
cervix, bladder, and vagina) the external iliac lymph nodes should be added. 
o In participants with disease within 2 cm of the anal verge the inguinal lymph nodes and 
external iliac lymph nodes should be added. 
!
The planning target volume (PTV) 50 or 50.4 and PTV45 will consist of a 5 mm expansion 
around the CTV: 50.4 or CTV50 and CTV45, respectively, to compensate for inter and 
intrafraction uncertainly. 
!
Organs at risk (OAR) should include: cauda equina, anus, rectum, large intestinal, small 
intestine, vagina, external genitalia, bladder, and femoral heads. 
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!
Involved OARs should be delineated for treatment planning and dose volume histograms 
documentation.
!
The International consensus guidelines on Clinical Target Volume for delineation in rectal 
cancer (Valentini 2016) provides detailed consensus contouring descriptions that can serve as 
a guide.  
Treatment planning techniques
All treatment planning will be performed with computerized dosimetry and the dose should be 
prescribed to the isodose line that covers the treatment volume at risk.
!
A single intensity modulated RT or a volumetric modulated arc therapy plan may involve 
1.8 Gy to PTV45 and 2.0 Gy (111% isodose line) to PTV50 for a total of 25 fractions, if 
applicable.
!
No hot spot of dose above 110% should be accepted beyond PTV.
!
Alternatively, the PTV45 and PTV50.4 will initially be treated in 25 daily fractions of 1.8 Gy 
per fraction with a cone down for an additional 3 fractions for the PTV50.4 in a 3D plan.
Dose constraints for target volumes and organs at risk 
Table 14
Dose Constraints for Target Volumes and Organs at Risk
Listed above OARs must be delineated if involved in the treated area.
Radiation therapy review/quality control
Within 1 week of starting radiotherapy, simulation and treatment planning data must be submitted 
to a local Quality Assurance body in line with institutional guidelines including:
!
Pretreatment CT and MRI reports and images identifying the location of the primary rectal 
tumor
!
Isodose distributions for the composite treatment plan in the axial, sagittal, and coronal planes.
o The PTV, isocenter, and normalization method must be clearly indicated.
Organs
PTV
Small Intestine
Large Intestine (Outside 
of Rectum)
Femur Head
Dmax < 110%
Dmax < 50 Gy
Dmax < 50 
Dmax < 45 Gy
D95 > 95%
V45 < 30 cc
V45 < 30cc
V45 < 5 cc
Bladder
External genitalia
Cauda
V40 < 35%
V20 < 50%
Dmax < 50 Gy
V30 < 50%
V30 < 20%
Dmax=maximum diameter, PTV=planning target volume.
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!
Dose volume histograms for the composite treatment plan for all target volumes and required 
OAR. 
During RT, daily image guidance with orthogonal kilovoltage imaging is recommended, but is not 
required, to ensure patient position alignment during treatment and accurate targeting of the tumor 
and draining lymph node regions. 
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Appendix 5
Tumor Response Criteria
Table 15
Response Criteria After Induction Chemotherapy and Restaging Before 
Chemoradiation - Screening Period 
Participants who present with stable disease, partial response, or near-complete response may enter 
the study. Participants who present with tumor progression or cCR should be treated according to 
standard practice per institutional guidelines.
Method
Progressive 
Disease
Stable Disease or Partial 
Response
Nearly Complete 
Response
Complete Response
Endoscopy
Increase in 
tumor size
Partial response or no 
change in size
!
Irregular mucosa
!
Small mucosal nodules 
or minor mucosal 
abnormality
!
Superficial ulceration
!
Mild persisting 
erythema of the scar
!
Flat, white scar
!
Telangiectasia
!
No ulcer
!
No nodularity
Digital rectal 
exam
Palpable 
tumor
Palpable tumor
Smooth induration or minor 
mucosal abnormalities
Normal
MRI-T2W
Increase in 
tumor size
!
No change in extent of 
T2 scar if present or 
further regression in 
thickness of T2 scar or 
intermediate tumor.
!
No new immediate 
signal not thought to be 
mural edema.
!
Stable or further 
decrease in nodal size 
(no new nodes) 
!
Mostly dark T2 signal
!
Some remaining 
intermediate signal 
AND/OR 
!
Partial regression of 
lymph nodes
!
Normal appearing 
bowel wall without 
any fibrosis in the 
tumor bed  
!
Only dark T2 signal, 
no intermediate T2 
signal
!
No visible lymph 
nodes or very few, 
small (< 5 mm 
nodes)
MRI=magnetic resonance imaging.
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Table 16
Response Criteria After Chemoradiation and Restaging Before Surgery
Method
Progressive 
Disease
Incomplete response
Nearly Complete 
Response
Complete Response
Endoscopy
Increase in 
tumor size
Visible tumor
! Irregular mucosa
! Small mucosal nodules
! Superficial ulceration
! Mild persisting 
erythema of the scar
! Flat whitish scar
! Telangiectasia
! No ulcer
! No nodularity
Digital rectal 
exam
Palpable 
tumor
Palpable tumor nodules
Smooth induration or 
minor mucosal 
abnormalities 
Normal 
MRI-T2W
Increase in 
tumor size
! More intermediate 
than dark T2 signal,
! no T2 scar 
AND/OR
! No regression of 
lymph nodes
! Mostly dark T2 signal, 
! Some remaining 
intermediate signal
AND/OR
! Partial regression of 
lymph nodes
! Normal appearing 
bowel wall without 
any fibrosis in the 
tumor bed.
! Only dark T2 signal, 
no intermediate T2 
signal.
! No visible lymph 
nodes or very few, 
small (< 5 mm nodes)
MRI=magnetic resonance imaging.
All participants, including those not undertaking surgery after chemoradiation are expected to 
continue loco-regional status evaluation (Table 17, MRI and optional Endoscopy/Digital), until 
progressive disease, at the frequency described in Section 8.1.2 and the SoA (Table 2) for 
Long-term Follow-up evaluations (Week 27, thereafter every 3 months in Year 1: Weeks 39 and 
52).
Table 17
Response Criteria During Long-Term Safety Evaluation
Method
Progression
Complete Response
MRI-T2W or CT
! Local recurrence
AND/ OR
! distant recurrence
! No evidence of disease
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Appendix 6
Pathology Assessments
!
Grading of quality and completeness of the mesorectum in a TME
Mesorectum
Defects
Coning
CRM
Complete
Intact, smooth
Not deeper than 
5 mm
None
Smooth, regular
Nearly complete
Moderate bulk, 
irregular
No visible 
muscularis propria
Moderate
Irregular
Incomplete
Little bulk
Down to the 
muscularis propria
Moderate/ marked
Irregular
!
Definition of surgical margin status
o Margin Type
Proximal margins
The proximal surgical margin refers to the most cephalad portion of the specimen (i.e.
closest to participants’s head)
Distal margins
The distal margin refers to the most caudad portion (i.e. closest to participant’s anus)
Radial margins
The radial margin, synonymously termed circumferential margin refers to the outer 
circumference of the rectal specimen
o Margin positivity
Positive
A surgical margin is positive if the pathologist notes tumor within ≤1 mm of any edge of 
the primary tumor specimen
Close
A surgical margin is close if the pathologist notes tumor > 1 but ≤3 mm of any edge of 
the primary tumor specimen
Negative
A surgical margin is negative if the pathologist notes there is no tumor within 3 mm of 
any edge of the primary tumor specimen
!
Overall completeness of TME resection
o The AJCC 8th edition will be used to categorize the completeness of the TME resection. 
R0 resection
All gross disease has been removed and microscopic examination reveals all surgical 
margins free of tumor. This must include the proximal, distal, and radial margin. Tumor 
> 1 mm from the tumor resection margins is considered R0.
R1 resection
There is evidence of tumor cells at 1 or more surgical resection margin based on 
microscopic pathologic assessment of the tumor specimen but there is no macroscopic 
evidence of tumor at any resection margin nor is there macroscopic evidence of 
residual tumor based on the surgeon’s operative report
R2 resection
The surgical pathologist identifies any macroscopic evidence of tumor at any of the 
surgical resection margins or there is macroscopic evidence of residual tumor based on 
the surgeon’s operative report
No resection
Removal of the primary tumor was not performed
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o Pathology TNM staging: After TME resection, participants will be staged according to AJCC 
8th edition.
 T describes how far the main (primary) tumor has grown into the wall of the intestine and 
whether it has grown into nearby organs. Because this information will be ascertained 
from the surgical pathology report it is denoted with a prefix “p”. Because it is ascertained 
after neoadjuvant treatment, the prefix “y” is also added (i.e. ypTx).
Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ, intramucosal carcinoma (involvement of lamina propia with no extension 
through muscularis mucosae)
T1
Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis 
propria)
T2
Tumor invades the muscularis propria
T3
Tumor invades through the muscularis propria into pericolorectal tissues
T4a
Tumor invades the visceral peritoneum (including gross perforation of the bowel through tumor 
and continuous invasion of tumor through area of inflammation to the surface of the visceral 
peritoneum)
T4b
Tumor directly invades or adheres to adjacent organ or structures
 N describes the extent of spread to nearby (regional) lymph nodes based on rectal 
resection specimen. The prefix “yp” is added as described above.
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis 
N1a
1 regional lymph node is positive
N1b
2 or 3 regional lymph nodes are positive.
N1c
No regional lymph nodes are positive, but there are tumor deposits in the:
!
Subserosa
!
Mesentary
!
Non-peritonealized pericolic, or perirectal/ mesorectal tissues
N2a
4 to 6 regional lymph nodes are positive.
N2b
7 or more regional lymph nodes are positive. 
 M describes the extent of spread to distant sites outside the pelvis
M0
No distant metastasis outside the pelvis
M1a
Metastasis to 1 site or organ is identified without peritoneal metastasis
M1b
Metastasis to 2 or more sites or organs is identified without peritoneal metastasis
M1c
Metastasis to the peritoneal surface is identified alone or with other site or organ metastasis
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 Pathologic AJCC 8th Edition staging summary
When T is…
and N is…
and M is…
Stage group is
Tis
N0
M0
0
T1, T2
N0
M0
I
T3
N0
M0
IIA
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T1-T2
N1/N1c
M0
IIIA
T1
N2a
M0
IIIA
T3-T4a
N1/N1c
M0
IIIB
T2-T3
N2a
M0
IIIB
T1-T2b
N2b
M0
IIIB
T4a
N2a
M0
IIIC
T3-T4a
N2b
M0
IIIC
T4b
N1-N2
M0
IIIC
Any T
Any N
M1a
IVa
Any T
Any N
M1b
IVb
Any T
Any N
M1c
IVc
!
Degree of pathological treatment response
o Pathologic treatment response will be based on the assessment of the surgical specimen at 
the primary treatment site. 
o Modified Ryan scheme for tumor regression score.
Description
Tumor regression score
No viable cancer cells (complete response)
0
Single cells or rare small groups of cancer cells (near-complete response)
1
Residual cancer with evident tumor regression, but more than single cells or 
rare small groups of cancer cells (partial response)
2
Extensive residual cancer with no evident tumor regression (poor or no 
response)
3
!
Pathological complete response (pCR)
o A pCR must include no gross or microscopic tumor identified anywhere within the surgical 
specimen. This must include both:
 No evidence of malignant cells in the primary tumor specimen
AND
 No evidence of malignant cells in the lymph nodes
!
Pathological response other than a pathological complete response
o The definition of non-pCR will include any surgical specimen that has any evidence of 
residual tumor manifest in the primary or regional lymph nodes
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Appendix 7
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a participant administered a 
pharmaceutical product, regardless of causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, regardless if it is considered 
related to the medicinal product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the NCI-CTCAE, version 5.0 (publication date: 27 November 2017), 
a descriptive terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment.
The 5 general grades are:
!
Grade 1 or Mild
!
Grade 2 or Moderate
!
Grade 3 or Severe
!
Grade 4 or Life-threatening
!
Grade 5 or Death.
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (e.g. sudden death, 
unexplained death), the death per se might then be reported as an SAE.
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Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other nonstudy interventions, radiation therapy) 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 study intervention, medical history, concomitant medication, 
course of the underlying disease, and study procedures.
Unrelated:
Not reasonably related to the study intervention. 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. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under study 
in this clinical study protocol.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition (e.g.
anemia or increased 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
!
Is otherwise considered to be medically important. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered as SAEs when, based 
upon appropriate medical judgment, they may jeopardize the participant or may require medical 
or surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
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For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs, AEs of special 
interest and DLTs.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g. an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (i.e.
undesirable effects of any administered treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the participant’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the AE reporting period, as defined in Section 8.3.2 (Method of Detecting Adverse 
Events and Serious Adverse Events).
Adverse Events of Special Interest
For peposertib no AEs of special interest have been defined so far. Specific toxicities identified 
during the conduct of the study will be closely monitored and specific instructions for monitoring 
and management of expected toxicities will be incorporated into the protocol and the Investigator’s 
Brochure. When further safety data for this study intervention combination will become available, 
risk assessment and mitigation activities will be reviewed to assess the continued appropriateness.
Recording and Follow-up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented. If an AE constitutes a DLT this is documented accordingly.
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the Sponsor.
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Reporting Serious Adverse Events and Dose Limiting Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form in the eCRF following specific completion 
instructions.
Reporting of SAEs via paper Report Form is required as a back-up method only in case of 
electronic data capture failure. Names, addresses, and telephone and fax numbers will be included 
on the paper Report Form. All information reported via paper form must be transcribed into the 
eCRF as soon as the system becomes available.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be completed immediately thereafter in the eCRF.
Relevant pages from the CRF may be provided in parallel (e.g. medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g. laboratory 
results, hospital report, autopsy report).
The Investigator must respond to any request for follow-up information (e.g. additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via Study Monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
Dose Limiting Toxicities
Each event meeting the criteria of a DLT, as specified in Section 6.6.1, must be recorded in the 
CRF within 24 HOURS after becoming aware of the event. Serious DLTs must be reported in an 
expedited manner as SAEs, as outlined above.
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Appendix 8
Clinical Laboratory Tests
Clinical Laboratory assessments are summarized in Table 18.
Table 18
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelets
Mean Corpuscular Volume:
!
MCH
WBC Count with 
Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Hemoglobin
Hematocrit
Biochemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate aminotransferase 
(AST)
Bilirubin
Creatinine
Sodium
Alanine aminotransferase (ALT)
Total Protein
Chloride
Glucose 
Calcium
Alkaline phosphatase
Albumin
Creatinine 
clearance
Creatine 
phosphokinase
Lactate dehydrogenase
International 
normalized ratio
Magnesium
Phosphorous
Activated partial thromboplastin 
time
Uric acid
Routine 
Urinalysis
!
pH, glucose, protein, blood, and ketones
!
Microscopic examination (if blood or protein is abnormal).
Other Screening 
Tests
!
FSH and estradiol (as needed if not a woman of childbearing potential only)
!
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential).
ALT=alanine aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, FSH=follicle-stimulating 
hormone, hCG=human chorionic gonadotropin, MCH=mean corpuscular hemoglobin, WBC=white blood cell.
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Appendix 10
Model for Bayesian Dose Escalation
The Bayesian model will focus on the number of participants experiencing a DLT. The SMC will 
receive results of a Bayesian 2-parameter logistic regression model with overdose control updated 
with the observed DLT data (Neuenschwander 2008).
The target toxicity is 30%. Toxicity regions are defined in Table 19.
Table 19
Toxicity Region Definitions
Probability of DLT
Loss Term (Weight in Loss Function)
Under-dosing
(0.0, 0.20]
1
Targeted toxicity
(0.20, 0.33]
0
Excessive toxicity
(0.33, 0.60]
1
Unacceptable toxicity
(0.60, 1.00]
2
DLT=dose limiting toxicity.
Recommendation on the next dose level by the model is determined as follows:
!
Among dose levels that limit the risk of overdose (excessive or unacceptable toxicity) to a 
maximum of 25% (i.e. the 75% quantile of the estimated DLT risk at the dose level is equal to 
or below the lower threshold for excessive toxicity of 33%),
!
Select the dose level that minimizes the loss function. The loss function is defined as the sum 
of products of the probability to lie within each of the toxicity regions, and the associated loss 
term:
( !"-!$) × 1 + (&"! $'() × 0 + (') $'() × 1
+ ( &*& $'() × 2
Furthermore, dose increases must not exceed 100% of the highest dose level considered safe at the 
time of the escalation decision.
The set of potential dose levels is (30 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg); 
however, it may be changed at any time by the SMC. The starting dose is 50 mg.
The SMC will be notified once the estimate for DLT probability of the MTD reaches sufficient 
precision, i.e.:
!
The probability that the MTD is above highest planned dose level is > 90%,
!
the probability (target toxicity) > 90%,
!
or the upper bound of the 95% credible interval is lower than 40%.
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The 2-parameter logistic regression model will be set up as follows:
For a dose level dj, the relationship between dose and probability of toxicity P(DLT) is defined by:
,-./|!1, 3, 45 =
exp 93 + exp(4) × log 9 !1
!=>?@@
1 + exp 93 + exp(4) × log 9 !1
!=>?@@
with potential dose level dj, reference dose dref and bivariate normally distributed parameters (α, β). 
The parameters are set as follows: 
!
dj ε {30 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg}; however, can be changed any 
time by the SMC
!
dref = 600 mg
!
E(α) = -0.847, E(β) = 0.056
!
Var(α) = 3.24, Var(β) = 0.64, Cov(α, β) = 0.
The so determined prior distribution is presented in Figure 4.
Figure 4
Prior Distribution
CI=credible interval, DLT=dose limiting toxicity.
In case information arises from other studies that changes current knowledge on the dose-toxicity 
relationship, the prior distribution will be updated prior to the first participant being treated in this 
study. This change of prior distribution will be documented in the SMC charter.
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Posterior distribution and the next dose level recommended by the model will be calculated using 
EAST version 6.4 or higher (EAST version 6.4, Cytel Inc. Copyright 2016), or R version 3.1.2 or 
higher with library package Bayesian continual reassessment method (Sweeting 2013).
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Appendix 11
Protocol Amendment History
The information for the current amendment is on the title page.
Protocol Version 3.0 (11 May 2020): Overall Rationale for the Amendment
The main purpose of this protocol amendment is to provide clearer and more detailed guidance 
with regards to key therapeutic interventions, such as induction or adjuvant chemotherapy 
regimens, study treatment specifications (e.g. radiotherapy techniques), and surgical pathology 
assessment for pathological complete response. By incorporating these changes, the amended 
protocol aims at bringing more consistency in the above-mentioned procedures and is therefore 
expected that the variability inherent to a multi-site global study will be minimized, therefore 
helping with the interpretation of the results. The key changes are as follows: 
-
Guidance for induction and adjuvant chemotherapy: in line with international guidelines 
for the treatment of rectal cancer (e.g. NCCN, ESMO), only 5-fluorouracil (5-FU) and 
oxaliplatin-based combination regimens (i.e. FOLFOX, or CAPEOX) will be allowed to 
be used for the study participants. Since the chemotherapy regimen utilized may influence 
outcomes, by having these 2 regimens it is expected that the interpretation of the treatment 
outcomes within this study (e.g. pathological response, or disease-free survival) will be 
subject to less variability. 
-
New radiotherapy techniques such as intensity modulated radiotherapy (IMRT) or 
volumetric-modulated arc therapy (VMAT) have been established in the clinical practice 
in recent years. Therefore, details about these allowed radiotherapy techniques (IMRT, 
VMAT and 3D) have now been included in the protocol, as well as the dose constraints for 
target volumes and organs at risk; as these factors play a role in the radiation tolerability, 
and hence may impact the study treatment safety assessment.
-
The modified Ryan criteria for pathological assessment will be utilized to harmonize the 
pathological evaluation.
In addition to these changes, other relevant changes are:
-
A thorax-abdomen CT scan at diagnosis for correct staging will now be mandatory and 
included at screening. Additional imaging parameters from MRI at Baseline will be 
described, in order to better characterize the post neoadjuvant (yTNM) tumor staging.  The 
presence (or absence) of extramural venous invasion (EMVI) and the circumferential 
margin (CRM) parameters will now be collected.
-
As a result of the acquired knowledge about the PK properties of peposertib throughout the 
ongoing clinical studies, the extent of PK sampling has been minimized to reduce patient 
burden.
-
The benefit/risk section has been updated in line with the latest update of the Investigator’s 
Brochure, resulting in the addition of new risks (rash, vomiting, diarrhea) based on 
nonclinical studies. It should be noted, however, that the benefit/risk assessment for the 
current study has not changed and remains positive. 
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Section # and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
Activities (Table 5)
Deleted 4-h postdose PK sample 
on FD1 and FD 9 from Phase II.
As this analysis will be done by population PK, 
this sample can be skipped to reduce the 
burden of the participants.
Section 2.3 Benefit/Risk 
Assessment
Updated to include additional 
potential risks.
For consistency with the Investigator’s 
Brochure.
Section 3 Objectives and 
Endpoints
Changed “Genetic polymorphisms 
of genes involved in the ADME of 
peposertib” to genes involved in 
PK.
For greater specificity as to what is being 
done.
Section 4.1.2 Treatment 
Period
Section 4.3 Justification for 
Dose
Section 6.6.2.3 
Radiotherapy
Updated text to clarify RT dose of 
50 to 50.4 Gy to the tumor area.
To provide more clarity on the radiotherapy 
dosage used according to NCCN guidelines.
Section 5.1 Inclusion 
Criteria
Specified that FOLFOX and 
CAPEOX are allowed as induction
chemotherapies.
To align with the current NCCN guidelines.
Section 6.5 Concomitant 
Therapy
Specified that FOLFOX and 
CAPEOX or capecitabine are 
allowed as adjuvant
chemotherapies.
To align with the current NCCN guidelines.
Section 6.6 Dose Selection 
and Modification
Added statement that the selected 
RP2D and preliminary safety data 
from Phase Ib will be 
communicated to Investigators, 
Health Authorities and IEC/IRBs 
prior to initiating the Phase II part 
of the study, as per Sponsor’s 
internal communication plan.
For consistency with the communication plan.
Section 8
Updated to include a maximum 
blood volume to be collected in any 
one-month period from each 
participant in the study (255 mL).
To comply with new protocol template and EU 
directives.
Section 9.2 Sample Size 
Determination – Phase II
Lowered “go-criterion” for interim 
analysis.
Adjustment of statistical assumptions in line 
with current results in literature.
ADME=absorption, distribution, metabolism, and excretion, CAPEOX=capecitabine and oxaliplatin, DRE=digital rectal 
examination, ECG=electrocardiogram, EUS=endoscopic ultrasound, FD=Fraction day, FOLFOX=Folic acid, 
5-fluorouracil, and oxaliplatin, IEC=Independent Ethics Committee, IRB=Institutional Review Board, NCCN=National 
Comprehensive Cancer Network, QTc=corrected Q-T interval, PK=pharmacokinetics, RP2D=recommended Phase II 
dose, RT=radiotherapy.
Administrative and editorial changes throughout for better clarity:
Section # and Name
Description of Change
Section 1.3 Schedule of Activities (Table 1 
and 2)
For the visit of Wk 7 to 14 added a clarification that in case of a 
pandemic, it is per Investigator’s discretion if these visits can be 
done via a phone call.
Section 1.3 Schedule of Activities (Table 2)
For QoL assessments modified the assessment schedule to assure 
collection of responses to questionnaires during the treatment and 
Short-term Safety FU period.  
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Section # and Name
Description of Change
Brief Rationale
Time Period and Frequency 
for Collecting Adverse 
Event and Serious Adverse 
Event Information
Schedule of Activities,
Figure 1,
Figure 3 footnote
and
throughout document
To allow a 25 FD radiation 
schedule.
To align with local standard of care.
Schedule of Activities
Table 1
Table 2 
and 
throughout document
Physical examination, vital sign, 
laboratory assessments during 
treatment are to be done on a 
weekly basis, not necessarily on 
the specified FD.
To align the protocol with local practices.
Section 1.3, 
Schedule of Activities Table 
1, Table 2
Follow-up pregnancy test only on 
Week 14.
To synchronize this evaluation with planned 
follow-up visit schedule. 
Section 4.1.1
Screening Period
and 
Section 8
Study Assessment and 
Procedure
A DRE (and EUS if indicated) and 
endoscopy will be needed at 
screening for participants with prior 
chemotherapy.
To determine current stage before starting 
CRT, in compliance with the inclusion 
criteria.
Section 5.1
Inclusion Criteria
!
To allow for inclusion of 
participants with Stage II rectal 
cancer.
!
To include participants who may often 
benefit from concurrent chemoradiation 
according to clinical practice.
!
Removed leucocyte counts in 
inclusion criterion 6.
!
To focus on neutrophil count as it better 
represents the WBC ability to tolerate 
chemoradiotherapy.
!
Participants must have 
evaluable disease in both 
phases of the study.
!
Since RECIST was removed as tumor 
evaluation criteria, participants with only 
evaluable disease can be included.  
Section 6.5.1
Prohibited Medicines
!
To allow induction 
chemotherapy. 
!
To allow H2 blockers under 
certain circumstances
!
To reflect evolving clinical practice for 
locally advanced rectal cancer.
!
To improve participant’s ability to 
efficiently control adverse events.
Section 6.6
Added the option that the SMC can 
decide to decrease the dosing 
intensity, if needed.
If M3814 dosing interruptions are necessary
due to tolerability issues, the dosing schedule 
can be adapted. 
Section 6.6.2.3
Radiotherapy
Removed the sentence: 
“Generally, a 3 or 4 field technique 
should be used”.
To avoid RT technique suggestion as the 
focus should be on optimal dose distribution to 
both tumor and to organs at risk. 
Section 8.8
Added optional tumor biopsies and 
a mandatory post-surgical 
specimen collection.
Additional tumor tissue samples to support 
identification of mechanisms of sensitivity 
and resistance to the study intervention 
during and after treatment.
Section 8.1.2
Tumor Response 
Assessment
Figure 2
Removed RECIST 1.1. Updated 
text of tumor evaluation criteria to 
clarify that assessments will be 
based on MRI, endoscopic and 
To update in line with current standards for 
rectal cancer evaluation in the neoadjuvant 
setting.
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and 
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Section # and Name
Description of Change
Brief Rationale
and
throughout document
digital evaluation, per NCCN 
guideline.
Section 9.4.1 Efficacy 
Analysis
and
Table14
Statistical Analysis Methods 
for Efficacy Endpoints
Updated statistical analysis 
method for “best overall response” 
and added statistical analysis 
method R0 resection.
To update in line with current standards for 
rectal cancer evaluation. 
Section 9.4.1 Efficacy 
Analysis
Added subgroup analyses for 
baseline characteristics, such as 
tumor stage.
To increase clarity on planned analyses.
Schedule of Activities, 
and
Section 3.1, 
Section 4.1.1
Section 8
Addition of endoscopic 
ultrasonography, if indicated or if 
performed, to the DRE assessment 
An endoscopic ultrasonography if indicated or 
if performed per local practice, is added to the 
assessment of palpitations 
ctDNA= circulating tumor DNA; DRE=digital rectal examination; FD=Fraction day; FFPE= Formalin-fixed paraffin 
embedded; FU=Follow up; RECIST=Response evaluation criteria in solid tumors; RT=Radiotherapy; SoA=Schedule 
of activities.
Administrative and editorial changes:
Section # and Name
Description of Change
Brief Rationale
Section 1.3
Schedule of Activities
Table 5
Predose sampling window updated 
to 60 min.
To facilitate PK sampling schedule.
Section 2.2
Background
Clinical study information from the 
ongoing Study EMR100036-002 
and completed Study MS100036-
0022 were updated.
Text updated to refer to the current IB.
Section 5.1
Inclusion Criteria
and
Appendix 3
Inclusion criterion #9 (male and 
female contraception) updated.
To align with the current Merck KGaA/EMD 
Serono contraception content standards. that 
are based upon CHMP guidelines, as 
specified in the Clinical Study Facilitation 
Group (CTFG) Guidance.
Section 6.6.1
!
Removed the separate 
criterion #2 and 7 from DLT 
definition
!
These criteria were redundant.
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and 
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Section # and Name
Description of Change
Brief Rationale
!
Added text for drug-induced 
liver injury with Hy’s law.
!
To align the text language with FDA’s 
preference.
Section 6.6.3 
Management of Toxicities
Added a section for management 
of toxicities.
To update in line with local practices.
Section 6.6.3, 
Section 6.6.3.1
Diarrhea
and
Section 6.6.3.2 
Capecitabine Management 
for Toxicities Other Than 
Diarrhea
and Table 9
!
Added a section to mention 
the charter for diarrhea 
management. Removed the 
previous text for capecitabine 
dose adjustment and CTCAE 
grading for diarrhea from the 
protocol.
!
Replaced thrombocytes with 
platelets in the capecitabine 
dose adjustment table.
To update in line with local practices.
Section 6.6.3.3
M3814 and Radiotherapy
and 
Table 11
Table text updated.
To clarify dose modifications of M3814 and 
radiotherapy during the study for toxicities 
other than diarrhea.
Section 7.1
Discontinuation of Study 
Intervention
and
Section 7.2
Participant 
Discontinuation/Withdrawal 
from the Study
Sections updated
To be in line with the current Merck 
KGaA/EMD Serono content standard 
intended for clarity and better readability.
Appendix 2
Study Governance
!
Text added regarding 
monitoring plan.
!
To update the information to align with 
the current Merck KGaA/EMD Serono 
content standards.
!
Updated country list, and 
number of sites for both Phase 
Ib and Phase II. 
!
To update in line with current country 
plan.
Appendix 5
Updated the laboratory evaluation 
requirements.
To address standard laboratory evaluation 
requirement.
Throughout document
Administrative, grammatical, 
typographical and punctuation 
changes.
For clarity and better readability.
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Peposertib
Phase Ib/II study of peposertib in combination with capecitabine and 
MS100036-0020
radiotherapy in rectal cancer
C O N F I D E N T I A L
I N F O R M A T I O N
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Appendix 14
Principal Investigator Signature Page
Study Title:
A multicenter study with an open-label Phase Ib part 
followed 
by 
a 
randomized, 
placebo-controlled, 
double-blind, Phase II part to evaluate efficacy, safety, 
tolerability,
and pharmacokinetics of the DNA-PK
inhibitor peposertib
(M3814)
in combination with 
capecitabine and radiotherapy in participants with locally 
advanced rectal cancer
Regulatory Agency Identifying 
Numbers:
US FDA IND 
EudraCT: 2018-002275-18
Clinical Study Protocol Version:
06 May 2021/Version 4.0
Site Number:
I am responsible for the conduct of the study at this site, and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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SAP_001.pdf: 


Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
2/66
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 © 2021 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
3/66
Approval Page
Integrated Analysis Plan: MS100036-0020
A multicenter study with an open-label Phase Ib part followed by a randomized, placebo-
controlled, double-blind, Phase II part to evaluate efficacy, safety, tolerability, and 
pharmacokinetics of the DNA-PK inhibitor peposertib (M3814) in combination with 
capecitabine and radiotherapy in participants with locally advanced rectal cancer
Approval of the IAP by all Merck Data Analysis Responsibles has to be documented within 
ELDORADO via eSignature. With the approval, the Merck responsible for each of the analysis 
also takes responsibility that all reviewers’ comments are addressed adequately.
By using eSignature, the signature will appear at the end of the document.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
4/66
1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Approval Page
3
1
Table of Contents..................................................................................4
2
List of Abbreviations and Definition of Terms ....................................7
3
Modification History ..........................................................................10
4
Purpose of the Integrated Analysis Plan.............................................10
5
Objectives and Endpoints ...................................................................11
6
Overview of Planned Analyses...........................................................13
6.1
Analyses for SMC meetings ...............................................................13
6.2
Interim Analysis..................................................................................13
6.3
Primary Analysis ................................................................................13
6.4
Further Analyses.................................................................................14
7
Changes to the Planned Analyses in the Clinical Study Protocol ......14
7.1
COVID-19 Impact ..............................................................................14
8
Protocol Deviations and Analysis Populations...................................14
8.1
Definition of Protocol Deviations and Analysis Populations.............14
8.2
Definition of Analysis Populations and Subgroups............................15
9
General Specifications for Data Analyses ..........................................16
10
Study Participants ...............................................................................23
10.1
Disposition of Participants and Discontinuations...............................23
10.2
Protocol Deviations ............................................................................25
10.2.1
Important Protocol Deviations............................................................26
10.2.2
Reasons Leading to the Exclusion from an Analysis Population.......26
11
Demographics and Other Baseline Characteristics.............................26
11.1
Demographics.....................................................................................27
11.2
Medical History ..................................................................................27
11.3
Other Baseline Characteristics............................................................28
12
Previous or Concomitant Medications/Procedures.............................29
12.1
Prior Anti-Cancer Treatments and Procedures...................................29
12.2
Previous and Concomitant Medications.............................................30
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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12.3
Concomitant Procedures.....................................................................30
12.4
Subsequent Anti-cancer Treatment.....................................................30
13
Treatment Compliance and Exposure.................................................31
14
Efficacy Analyses ...............................................................................35
14.1
Secondary Endpoints: pCR, cCR, and pCR/cCR ...............................35
14.2
Secondary Endpoint: Disease-Free Survival ......................................39
14.2.1
Secondary Objective: Analysis of Disease-Free Survival..................40
14.3
Secondary Endpoint: Local Recurrence and/or Distant Metastasis....41
14.3.1
Secondary Objective: Analysis of Local Recurrence and/or Distant 
Metastasis ...........................................................................................42
14.4
Secondary Endpoint: Neoadjuvant Rectal Score................................43
14.4.1
Secondary Objective: Analysis of NAR score....................................43
15
Safety Analyses ..................................................................................44
15.1
DLT (Primary Endpoint) ....................................................................44
15.2
Adverse Events...................................................................................44
15.2.1
All Adverse Events.............................................................................45
15.2.2
Adverse Events Leading to Study Intervention Discontinuation .......49
15.2.3
Late Toxicities ....................................................................................50
15.3
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................50
15.3.1
Deaths .................................................................................................50
15.3.2
Serious Adverse Events......................................................................52
15.4
Clinical Laboratory Evaluation...........................................................52
15.5
Vital Signs ..........................................................................................58
15.6
Other Safety or Tolerability Evaluations............................................58
15.6.1
ECOG Performance Status .................................................................58
15.6.2
ECG and QT/QTc Evaluations...........................................................59
15.6.3
Pregnancy Test....................................................................................60
16
Analyses of Other Endpoints..............................................................60
16.1
Pharmacokinetics................................................................................60
64
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
6/66
65
16.4
Patient Reported Outcome..................................................................65
17
References...........................................................................................66
18
Appendices .........................................................................................66
18.1
SMC SAP............................................................................................66
18.2
Clavien-Dindo classification ..............................................................66
Table of tables
Table 1 Description of Analysis Sets.................................................................................15
Table 2 Summary of Analyses and associated Analysis Set..............................................16
Table 3 Stopping rules for medication/procedure end dates..............................................21
Table 4 Rules to define previous and/or concomitant medications...................................21
Table 5 Summary of analyses performed on the composite endpoint of pCR/cCR, pCR 
and cCR ..............................................................................................37
Table 8 Date of event / censoring for DFS analysis ..........................................................39
Table 9 Summary of analysis of the Disease-Free Survival..............................................40
Table 10 Date of event / censoring definition for Local/Distant recurrence Analysis ......41
Table 11 Summary of the analysis of the local recurrence and/or distant metastasis........42
Table 11 Summary of the analysis of the NAR score........................................................43
Table 12 Common Terminology Criteria (CTC) gradable parameters..............................53
Table 13 Non-CTC gradable parameters ...........................................................................55
Table 14 Vital signs categories..........................................................................................58
Table of figures
Figure 1 
Derivation of Composite Endpoint.....................................................36
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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2
List of Abbreviations and Definition of Terms
AE
Adverse event
ATC
Anatomical therapeutic chemical classification 
AUC
Area under the concentration-time curve 
AUCextra, %
The AUC from time tlast extrapolated to infinity
BSA
Body surface area
cCR
Clinical complete response
CI
Confidence interval
CL/f
Apparent total body clearance
Cmax
Maximum observed plasma concentration
COVID-19
Coronavirus disease 2019
CR
Complete response
CRM
Circumferential margin 
CRR
Complete response rate
CSP
Clinical study protocol
CSR
Clinical study report
CTC
Common terminology criteria
CTMS
Clinical trial management system
CV%
Coefficient of variation
DCR
Disease control rate
DE
Dose escalation 
DFS
Disease-free survival
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid 
DNA-PK
DNA protein kinase
DRE
Digital rectal exam
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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EMVI
Extramural venous invasion
ENR
Enrolled population
EudraCT
European Clinical Trials Database
EUS
Endoscopic ultrasonography
FAS
Full analysis population
FD
Fraction day
FU
Follow up
IAP
Integrated analysis plan
ICH
International Conference on Harmonization
IR
Incomplete response
KM
Kaplan-Meier
LCL
Lower confidence limit
LLOQ
Lower limit of quantification
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MR
Metabolite to parent ratio
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
n
Sample size
nd
Not done
n/a
Not applicable
NE
Not evaluable
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
pCR
Pathological complete response
PD
Progressive disease 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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PR
Partial response
PT
Preferred term
PTV
Planning target volume
PK
Pharmacokinetics
Q1
First quartile
Q3
Third quartile
QTc
Corrected QT interval
QTcF
Fridericia-corrected QT interval
Racc
Accumulation factor
RP2D
Recommended phase 2 dose
RT
Radiotherapy
SAE
Serious adverse event
SAF
Safety analysis population
SD
Stable disease
Sd
Standard deviation
SDTM
Study data tabulation model
SMC
Safety monitoring committee
SOC
System organ class
TEAE
Treatment-emergent adverse event
t1/2
Apparent terminal half-life
tmax
Time to reach maximum observed concentration
UCL
Upper confidence limit
ULN
Upper limit of normal
UNK
Unknown
Vz/f
Apparent volume of distribution at steady state
WHO-DD
World Health Organization Drug Dictionary
!z
Terminal elimination rate constant
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
10/66
3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
1.0
11 February 2020
NA
2.0
22 March 2021
- Updated author/reviewer list
- Update protocol version with V3.0: 
∀
addition TNM classification, MRI-EMVI 
score and MRI-CRM score on Disease 
History description
∀
addition TNM classification, MRI-EMVI 
score and MRI-CRM score on tumor 
evaluation
∀
addition of prior induction therapies 
description)
- Addition of Actual daily Dose PTV1 and PTV2 in 
radiotherapy cumulative dose calculation
- Add analysis to assess COVID-19 impact on the 
study.
- Removed objective “To characterize exposure 
response (exposure/safety and 
exposure/efficacy) for M3814 with respect to 
selected safety and efficacy endpoints” as it is 
planned only for Phase I and II combined
- TEAE leading to a delay in dose time of RT 
(corresponding to AEs with action taken = “Dose 
time delayed”) removed from the Adverse Events 
Leading to Study Intervention Discontinuation 
description
3.0
- Update protocol version to V4.0
- Long-term Safety Follow-up period shortened to 
1 year (previously 2 years) and removed Survival 
Follow-up.
- Removed the endpoints of “overall survival” and 
“best overall response”.- Added endpoint of 
“neoadjuvant rectal score”.
- Change date added on AE listing
4
Purpose of the Integrated Analysis Plan
The purpose of this integrated analysis plan (IAP) is to document technical and detailed 
specifications for all analyses of data collected for the Phase Ib (dose escalation) protocol 
MS100036-0020. Results of the analyses described in this IAP will be included in the clinical 
study report (CSR). Additionally, the planned analyses identified in this IAP may be included in 
regulatory submissions or future manuscripts. Any post hoc, or unplanned analyses performed to 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
13/66
AUC = area under the concentration time-curve ; cCR = clinical complete response; CL/f = apparent total body 
clearance; Cmax = maximum observed plasma concentration;
; DLT = dose limiting 
toxicity; ECG = electrocardiogram; FD = fraction day; MTD = maximum tolerated dose; NCI-CTCAE = National 
Cancer Institute – Common Terminology Criteria for Adverse Events; pCR = pathological complete response; 
 
 PK = pharmacokinetics; QTcF = fridericia-corrected QT interval; RP2D = recommended phase 
2 dose; RT = radiotherapy; TEAE = treatment emergent adverse event; t1/2 = apparent terminal half-life; tmax = time 
to reach maximum observed concentration; Vz/f = apparent volume of distribution at steady state.
6
Overview of Planned Analyses
6.1
Analyses for SMC meetings
During Phase Ib, to decide on dose escalation, safety and PK analyses will be provided for the 
purpose of SMC meetings. The cut-off for dose escalation assessments by the SMC will usually 
be triggered by the completion of the DLT period (or dropout) of the last participant in the 
respective dose escalation cohort of usually 3 participants. In addition, once a participant 
completed the Short-term safety follow-up period at approximately 19 weeks after starting 
treatment, data of the participant will be reviewed. In the event of severe toxicity, an ad-hoc SMC 
meeting will be scheduled to decide on potential dose adjustment.
Details of analyses for SMC meetings will be specified in the appendix of this IAP.
6.2
Interim Analysis
After the last subject has finished the DLT period and after last subject has finished short term 
follow-up, an analysis on key safety and efficacy endpoints will be provided to decide on further 
development and potentially answer HA requests.
6.3
Primary Analysis
This analysis will be the main analysis of the safety and preliminary antitumor activity data from 
the dose escalation phase. The cut-off will be triggered by when the last participant enrolled in 
dose escalation reaches the end of the Short-term safety follow-up period or dies or prematurely 
discontinues the study for any reason, whichever occurs first.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
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I N F O R M A T I O N
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6.4
Further Analyses
Follow-up analyses to report further efficacy and safety data will be done once all participants 
have completed the 1-year follow-up period and at the end of study.
Additional analyses of safety and preliminary antitumor activity might be performed for the 
purpose of publication at scientific congresses.
7
Changes to the Planned Analyses in the Clinical Study 
Protocol
Outcome of the tumor assessment prior to surgery is reflected in the analysis of cCR. As the 
number of subjects in the dose escalation cohorts is low, PK exposure of peposertib versus safety 
and exposure will not be performed.
7.1
COVID-19 Impact
Additional listings will be generated to assess potential impacts of COVID-19 to this study 
including: 
∀listing of participants potentially affected by pandemic and with any AEs or PDs related to 
COVID-19
∀listing of PDs related to COVID-19
∀listing of AEs related to COVID-19.
8
Protocol Deviations and Analysis Populations
8.1
Definition of Protocol Deviations and Analysis Populations
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being.
The following deviations will be identified and confirmed prior to or at the data review meeting, 
at the latest.
Important protocol deviations will be categorized into one of the following:
∀Subject enrolled and dosed on the study who did not satisfy enrolment criteria
∀Subject fulfills withdrawal criteria whilst on the study but is not withdrawn
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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∀Subject is administered the wrong study intervention or an incorrect dose
∀Subject is administered or takes concomitant medication excluded by the clinical study 
protocol (CSP)
∀Failure to collect data necessary to interpret primary endpoints
∀Failure to collect necessary key safety data
∀Deviations from good clinical practice (e.g. deviations related to informed consent of study 
participants)
∀Any other protocol deviation that might significantly affect the completeness, accuracy, 
and/or reliability of the study data or that might significantly affect a participant's rights, 
safety, or well-being
All important protocol deviations are listed in a separate document. In addition, all important 
protocol deviations are documented in study data tabulation model (SDTM) datasets whether 
identified through site monitoring, medical review or programming.
8.2
Definition of Analysis Populations and Subgroups
The analysis populations are specified below: 
Table 1 Description of Analysis Sets
Population
Description
Enrolled
All participants who sign informed consent
Dose escalation (DE)
The DE Analysis Set will include all participants treated in dose escalation cohorts, 
who receive at least 80% of peposertib, 50% of capecitabine, and 80% of RT planned 
dose and complete the DLT period (5 or 5.5 weeks after start of treatment or for the 
entire duration of the treatment). The DE set will also include participants treated in 
dose escalation cohorts who experience a DLT during the DLT period regardless of 
the amount of each study intervention received/completion of the DLT period.
Full analysis set (FAS)
The FAS will include all participants who are enrolled in the study and received at least 
1 dose of study intervention.
Safety (SAF)
The SAF analysis set will include all participants who receive at least 1 dose of study 
intervention. Participants will be analyzed according to the actual treatment they receive.
In case of differenct doses received the dose whith high number of administrations will 
be used as actual treatment.
Pharmacokinetics (PK)
The PK analysis set is defined as all participants who receive at least 1 dose of 
peposertib and have sufficient peposertib plasma concentration data to enable the 
calculation of at least 1 PK parameter. Sufficient concentration data is defined as at 
least 3 valid, post dose, concentration points in the PK profile to obtain any PK 
parameter.
DE=dose escalation, DLT=dose limiting toxicity, FAS=full analysis set, PK=pharmacokinetic, RT=radiotherapy, 
SAF=safety
.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
16/66
Table 2 Summary of Analyses and associated Analysis Set
Analyses
ENR 
SAF 
FAS
DE
PK
Disposition 

Baseline assessments

Past and concomitant therapies

Compliance and exposure

Primary endpoint: DLTs

Efficacy

Safety and tolerability

Pharmacokinetics

DE=dose escalation, ENR=enrolled, FAS=full analysis set, PK=pharmacokinetic, SAF=safety
9
General Specifications for Data Analyses
Study intervention groups
Unless otherwise indicated all analyses will be presented separately for each dose level, and 
overall.
Data handling after cut-off date
Data after cut-off do not undergo the cleaning process, will not be included in SDTMs, and will 
not be displayed in any listings or used for statistical analyses or imputation.
Stop dates are not affected by this rule, e.g. a stop date of AEs, which starts prior to the cut-off, 
but stops after date of cut-off, will not be changed.
Significance level
All statistical tests mentioned in this IAP are to be regarded as exploratory. All statistical tests 
comparing study intervention groups will be performed two-sided. If confidence intervals are to 
be calculated, these will be two-sided with a confidence probability of 95%, unless otherwise 
specified in the corresponding section of this IAP.
Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics, i.e.
∀number of participants, number of participants with non-missing values,
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
17/66
∀mean, standard deviation,
∀median, 25th Percentile - 75th Percentile (Q1-Q3),
∀minimum, and maximum.
Qualitative variables will be summarized by counts and percentages.
Unless otherwise stated the calculation of proportions will be based on the number of participants 
in the analysis population of interest. Therefore, counts of missing observations will be included 
in the denominator and presented as a separate category.
For summaries by visits, only visits where all subsequent visits have 3 or more participants will be 
displayed. In case the analysis refers only to certain visits, percentages will be based on the number 
of participants in the corresponding analysis set.
Presentation of PK concentration data
Peposertib, its metabolite (if available), capecitabine, and its metabolite (if available) 
concentration data will be descriptively summarized using: number of non-missing observations 
(n), arithmetic mean (Mean), standard deviation (Sd), coefficient of variation (CV%), minimum 
(Min), median (Median), and maximum (Max). If n ≤ 2, only n, Min, and Max will be reported.
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data:
Mean, Min, Median, Max: 
3 significant digits
Sd:
4 significant digits
CV%:
1 decimal place 
Presentation of PK parameter data
Pharmacokinetic parameter data will be descriptively summarized using: n, Mean, Sd, CV%, Min, 
Median, Max, geometric mean (GeoMean), and the geometric coefficient of variation (GeoCV)
and the 95% confidence interval for the GeoMean (LCL 95% GM, UCL 95% GM). For time to 
reach maximum observed concentration (tmax), only n, Min, Median, and Max will be reported.
If n ≤ 2, only n, Min, and Max will be reported.
The PK parameter maximum observed plasma concentration (Cmax) will be reported with the same 
precision as the source data. All other PK parameters will be reported to 3 significant figures. In 
export datasets, as well as in the SDTM and ADaM PP domain, PK parameters will be provided 
with full precision, and will not be rounded. Descriptive statistics of PK parameter data will be 
calculated using full precision values and rounded for reporting purposes only. 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
18/66
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits
Sd:
4 significant digits
CV%, GeoCV%:
1 decimal place
Study day
Study day (also called treatment day) is defined relative to the date of start of treatment (first 
administration of peposertib, RT, or capecitabine, whatever is earliest). Study day 1 defines the 
day of first treatment, the day before is defined as study day –1 (no study day 0 is defined).
Definition of baseline
The last measurement prior to first administration of trial treatment (either peposertib, RT or 
capecitabine) will be used as the baseline measurement. If an assessment is planned to be 
performed prior to the first dose of study treatment in the protocol and the assessment is performed 
on the same day as the first dose of study treatment, it will be assumed that it was performed prior 
to study treatment administration, if assessment time point is not collected or is missing. If 
assessment time points are collected, the observed time point will be used to determine pre dose 
on study day 1 for baseline calculation. Unscheduled assessments will be used in the determination 
of baseline. However, if time is missing, an unscheduled assessment on study day 1 will be 
considered to have been obtained after study treatment administration.
Definition of change from baseline (per visit)
Change from baseline: visit value – baseline value
Percent change from baseline: 100 * (visit value – baseline value) / baseline value
Definition of on treatment period:
On treatment period is defined as the time from the first administration of study intervention to the 
last administration of study treatment + 30 days,  or the clinical cut-off date (if the treatment is 
still ongoing), or death, whichever occurs first.
Date of last known to be alive
The date of last known to be alive will be derived for participants not known to be dead at the 
analysis cut-off using the latest complete date among the following:
∀All subject assessment dates:
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
19/66
∀Laboratory assessments using information from “Hematology”, “Biochemistry”, 
“Coagulation”, “Urinalysis”, “Pregnancy test” and “Creatinine Clearance” eCRF pages 
(LBDTC variable from LB SDTM domain to be used) 
∀Vital signs using information from “Vital signs” eCRF page (VSDTC variable from VS 
SDTM domain to be used)
∀Performance status using “ECOG Performance status” eCRF page (QSDTC variable from 
QS SDTM domain to be used)
∀ECG, using information from both local and central ECGS (EGDTC variable from EG 
SDTM domain to be used)
∀Tumor assessments using “Tumor assessments” eCRF pages (TRDTC/TUDTC variable 
from TR/TU SDTM domain to be used)
∀Surgery information using “Rectal Surgery at week 15”, “Rectal Surgery after Week 15”, 
“Surgery after discontinuation” eCRF pages
∀Anti-cancer treatment after discontinuation start and end date from “Anti-Cancer treatment 
after discontinuation” eCRF page.
∀Start dates of concomitant medications or anti-cancer therapies administered after study 
treatment termination using “Concomitant medications”, “Anti-cancer treatment after 
discontinuation details” eCRF pages (CMSTDTC variable from CM SDTM domain to be 
used)
∀AE start dates from “Adverse events details” eCRF page (AESTDTC variable from AE 
SDTM domain to be used)
∀Study treatment administration dates using “M3814 (PEPOSERTIB)/PLACEBO
Administration Details”, “RT Administration” and “Capecitabine Administration” eCRF 
pages (EXSTDTC variable from EX SDTM domain to be used)
∀Last known to be alive date using “Survival Follow-up page” (SSDTC variable from SS 
SDTM domain where SSCAT=”SURVIVAL FOLLOW-UP”), where status is “Alive”.
Only dates associated with actual examinations of the participant reported in the eCRF will be 
used in the derivation. Dates associated with a technical operation unrelated to participant status 
(such as the date a blood sample was processed) will not be used. Assessment dates after the cut-
off date will not be considered for derivation of last date known to be alive.
Definition of duration/ time since an event
Duration will be calculated by the difference of start and stop date + 1 (e.g., survival time [days] 
= date of death – date of Study day 1 + 1), if not otherwise specified.
The time since an event (e.g. time since first diagnosis) will be calculated as date of event – Study 
day 1 +1.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
20/66
Conversion factors
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days.
Handling of missing data
Unless otherwise specified, missing data will not be replaced.
In all participant data listings imputed values will be presented, and the imputed information will 
be flagged (if not specified otherwise). 
Missing statistics, e.g., when they cannot be calculated, should be presented as “nd” (not done). 
For example, if n=1, the measure of variability (Sd) cannot be computed and should be presented 
as “nd”.
Adverse events
For identification of AE treatment emergence, incomplete dates will be handled as follows:
∀In case the onset date is completely missing, or the onset is in the same year (if the onset 
year is available only) or the onset is in the same month and year (if the day is missing) as 
start of trial treatment then the onset date will be replaced either by the start of trial treatment 
date or the AE resolution date, whichever is the earliest.
∀In all other cases, the missing onset day or onset month will be replaced by 1.
∀Incomplete stop dates will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of subject’s death. In the latter case, the date of 
death will be used to impute the incomplete stop date.
∀In all other cases, the incomplete stop date will not be imputed.
Previous/Concomitant medication
For identification of previous or concomitant medications/procedures, no formal imputation will 
be performed on missing or incomplete dates. Table 3 indicates whether a treatment is considered 
to be stopped before or after start of treatment. Rules presented in Table 4 will be used to define if 
a medication/procedure is considered as a previous, concomitant or both previous and concomitant 
medication/procedure. 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
22/66
Tumor assessments
Tumor response assessments will be based on MRI, endoscopic and digital rectal evaluation.
(DRE). All investigation dates (e.g. MRI, endoscopy, DRE) must be completed with day, month 
and year.
If there are multiple dates associated with an evaluation, i.e., radiological assessments occur over 
a series of days rather than the same day, the choice of date of assessment could impact the date 
of progression and/or date of response. If there are multiple dates associated with an evaluation, 
the earliest of the dates associated with the evaluation will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation dates 
are available, the incomplete date(s) are not considered for calculation of the assessment date, and 
assessment date is calculated as the earliest of all investigation dates (e.g. MRI, endoscopy, DRE).  
If all measurement dates for an evaluation have no day recorded, the first of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If the previous or the following assessment is not available, the assessment 
in between will not be used for any calculations. 
Death date
For imputing missing day of death date, if month and year is available, the day will be imputed by 
15, unless this results in a date not later as a date the participant is known to be alive. In that case 
the date of death will be imputed by the last date known to be alive + 1.
Start/stop date of subsequent anti-cancer therapy
Incomplete dates for start date of subsequent anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows:
∀If only day is missing, it will be imputed as the last day of the month unless the end date of 
subsequent anti-cancer therapy is before that date. In that case, the incomplete anti-cancer 
therapy start date will be imputed as the end date of the anti-cancer therapy.
∀If both day and month are missing, no imputation will be performed. 
Incomplete subsequent anti-cancer therapy stop dates will not be imputed.
Categorization of participants for COVID-19 impact assessment
For the assessment of COVID-19 impact on this study, participants will be categorized as being 
potentially affected by COVID-19 based on the COVID-19 pandemic start date. 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
23/66
This date is defined as the minimum of the first COVID-19 death date per country and 11 March 
2020 (WHO-start of world-wide pandemic). First death from COVID-19 per country is determined 
according to the published data by European Centre for Disease Prevention and Control (Status of 
26 June 2020). 
If the pandemic start is before the end of DLT period, both DLT and FUP periods for the subject 
will be considered as potentially affected. If it starts during the FUP period, only this period will 
be considered as potentially affected.
Software
All statistical analyses will be performed using SAS® Software version 9.4 or higher. 
Non-compartmental computation of PK parameters will be performed using the computer program 
Phoenix® WinNonlin® Version 8.0 or higher (Pharsight Corporation, a Certara Company, 
Princeton, New Jersey).
10
Study Participants
The subsections in this section include specifications for reporting participant disposition and 
study intervention/study discontinuations. Additionally, procedures for reporting protocol 
deviations are provided.
10.1
Disposition of Participants and Discontinuations
All tables and listings related to disposition of participants and discontinuations will be generated 
using Enrolled analysis set.
A primary table of subject disposition will provide the overall summary of the analysis sets by 
dose level and overall:
∀
Number of screened participants (will be reported in the overall column only)
∀
Number of participants discontinued prior to treatment start (overall and by reason) (will 
be reported in the overall column only)
∀
Number of participants who continued beyond screening
∀
End of treatment status for peposertib with: 
o
Number of participants who did not receive peposertib (“M3814/PLACEBO 
ADMINISTRATION DETAILS” eCRF Page)
o
Number 
of 
participants 
with 
ongoing 
peposertib 
administration 
(“M3814/PLACEBO ADMINISTRATION DETAILS” and “M3814/PLACEBO 
TERMINATION” eCRF Page)
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
24/66
o
Number 
of 
participants 
who 
completed 
treatment 
with 
peposertib 
(“M3814/PLACEBO TERMINATION” eCRF Page)
o
Number of participants who discontinued from peposertib overall and by reason 
(“M3814/PLACEBO TERMINATION” eCRF Page)
∀
End of treatment status for RT with: 
o
Number of participants who did not receive RT (“RADIOTHERAPY 
ADMINISTRATION” eCRF Page)
o
Number of participants with ongoing RT administration (“RADIOTHERAPY 
ADMINISTRATION” and “RADIOTHERAPY TERMINATION” eCRF Page)
o
Number of participants who completed treatment with RT overall and by reason 
(“RADIOTHERAPY TERMINATION” eCRF Page)
o
Number of participants who discontinued from RT overall and by reason 
(“RADIOTHERAPY TERMINATION” eCRF Page)
∀
End of treatment status for capecitabine with: 
o
Number of participants who did not receive capecitabine (“CAPECITABINE 
ADMINISTRATION” eCRF Page)
o
Number 
of 
participants 
with 
ongoing 
capecitabine 
administration 
(“CAPECITABINE 
ADMINISTRATION” 
and 
“CAPECITABINE 
TERMINATION” eCRF Page)
o
Number of participants who completed treatment with capecitabine overall and by 
reason (“CAPECITABINE TERMINATION” eCRF Page)
o
Number of participants who discontinued from capecitabine overall and by reason 
(“CAPECITABINE TERMINATION” eCRF Page)
∀
Number of participants who underwent rectal surgery at week 15 (“RECTAL SURGERY 
AT WEEK 15” eCRF page) 
∀
End of study status with:
o
Number of participants with peposertib, RT and/or capecitabine administration 
ongoing
o
Number of participants off all treatments and in follow-up, and for those, the 
number of participants last known to be alive within 3 months before the cut-off 
date and the number of participants last known to be alive more than 3 month prior 
to the cut-off date (all ADMINISTRATION and TERMINATION related eCRF 
pages and “STUDY TERMINATION” eCRF pages)
o
Number of participants who discontinued or completed trial overall and by reason 
(“STUDY TERMINATION” eCRF page)
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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A second summary table on analysis sets will be generated:
∀Number of participants in Enrolled population (overall only)
∀Number of participants in FAS analysis set  
∀Number of participants in SAF analysis set 
∀Number of participants in DE analysis set 
∀Number of participants in PK analysis set 
A third summary table will display the number of participants overall, in each country and in each 
site (per analysis set).
A listing of subject disposition will include the following information (as applicable): Dose level, 
subject identification number, date of informed consent form (ICF), rectal surgery at 15 weeks flag 
and date, reason for screen failure, date of first and last dose, FAS/SAF analysis set, DE analysis 
set and PK analysis set.
A second listing will include the following study termination information: Dose level, subject 
identification number, end of trial status (completed, ongoing, discontinued), the reason for 
termination of the trial, the date of trial termination, time on trial (time from ICF signature to end 
of trial), and the date of first and last dose of peposertib, RT and capecitabine.
A third listing will include the following peposertib termination information: Dose level, subject 
identification number, end of treatment status (completed, ongoing, discontinued), the reason for 
peposertib termination, and the date of first and last dose.
A fourth listing will include the following RT termination information: Dose level, subject 
identification number, end of treatment status (completed, ongoing, discontinued), the reason for 
RT termination and the date of first and last dose.
A fifth listing will include the following capecitabine termination information: Dose level, subject 
identification number, end of treatment status (completed, ongoing, discontinued), the reason for 
capecitabine termination, and the date of first and last dose.
In addition, for the assessment of COVID-19 impact on this study, a listing will include the 
following information (as applicable): Formulation, dose level, subject identification number, date 
of first and last dose, pandemic start date in the country, if DLT or any FUP periods were 
potentially affected by pandemic, if any COVID-19 related AE or PD occurred during the 
pandemic period.
10.2
Protocol Deviations
Population: SAF analysis set
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
26/66
10.2.1
Important Protocol Deviations
Important protocol deviations will be summarized in a table on the safety population, by dose level 
and overall:
∀The number of participants with at least one important protocol deviation
∀The number of participants with deviation of inclusion/exclusion criteria, overall and by 
criteria using the information provided in “Study Entry” eCRF page
∀The number of participants with deviation of post inclusion criteria, overall and by criteria.
The following listings of important protocol deviations will be provided on the safety population, 
including:
∀Deviations from inclusion or exclusion criteria, using information provided in “Study Entry” 
eCRF page. This listing will include: dose level, subject identification number, 
inclusion/exclusion criteria not met and date of deviation.
∀Important protocol deviations. This listing will include: dose level, subject identification 
number, date of protocol deviation, deviation category, deviation description and if the PD 
occurred after pandemic start.
∀A subject listing of any COVID-19 related PD will also be provided.
10.2.2
Reasons Leading to the Exclusion from an Analysis 
Population
Participants excluded from the DE analysis set will be displayed in a listing. This listing will 
include: dose level, subject identification number, reason for exclusion from the DE Analysis Set. 
Reason for exclusion could be:
∀Insufficient exposure to peposertib
∀Insufficient exposure to RT
∀Insufficient exposure to capecitabine
∀DLT period not completed.
11
Demographics and Other Baseline Characteristics
Population: SAF analysis set
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
27/66
11.1
Demographics
The following demographic characteristics will be summarized using the information from the 
“Demographics” eCRF pages.
∀
Sex: male, female
∀
Race: White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, Not collected at this site, Other
∀
Ethnicity: Hispanic or Latino, Not Hispanic or Latino
∀
Age (years)
∀
Age categories:
o
< 65 years

< 50

50-64
o
≥ 65 years

65-74

75-84

≥ 85
Specifications for computation:
Age [years]: (date of given informed consent - date of birth + 1) / 365.25
∀
In case of missing day for at least one date, but month and year available for both dates: 
For the derivation of age, the day of informed consent and the day of birth will be set to 1 
and the formula above will be used
∀
In case of missing month for at least one date, but year available for both dates:
For the derivation of age, the day and the month of informed consent and the day and month 
of birth will be set to 1 and the formula above will be used.
The integer part of the calculated age will be presented.
Data will also be provided in listings (see Section 11.3).
11.2
Medical History
Population: SAF analysis set
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
28/66
The medical history will be summarized from the “Medical History” eCRF page, using the most 
recent available version of MedDRA (version 21.0 or later) preferred term (PT) as event category 
and MedDRA system organ class (SOC) body term as Body System category. Each participant 
will be counted only once within each PT or SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetic order.
A supportive listing of medical history data by subject will include all the relevant data fields as 
collected on the “Medical History” eCRF pages.
11.3
Other Baseline Characteristics
Population: SAF Analysis Set
The following baseline characteristics will be summarized using the information from the “Vital 
Signs” and “ECOG performance status” eCRF pages.
∀
Height (cm)
∀
Weight (kg)
∀
BSA (m²) = ([Height(cm) × Weight(kg)]/3600)½ (Mosteller,1987)
∀
ECOG Performance status
A listing of baseline characteristics will include the following information (as applicable): Dose 
level, subject identification number, date of birth, age (years), sex, race, height (cm), weight (kg), 
BSA (m2), ECOG performance status and result from pregnancy test (serum β-HCG). 
Disease history will be summarized by dose level and overall, in a frequency table including the 
following information from the ‘DISEASE HISTORY’ eCRF page: 
∀
Disease stage at diagnosis, by stage
∀
Disease stage at study entry, by stage
∀
Histopathological classification, by classification.
∀
TNM classification: each T, N, M category and the TNM classification will be described 
(TX, T0, N1, etc.)
∀
MRI-EMVI score
∀
MRI-CRM score
In addition, a supportive listing of disease history will be provided including the following 
information from the ‘DISEASE HISTORY’ eCRF page: Dose level, subject identification 
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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number, site of primary tumor, sub site of primary tumor, date of initial cancer diagnosis, 
histopathological classification, stage at initial diagnosis, stage at study entry, TNM at initial 
diagnosis and at study entry, MRI-EMVI socre at initial diagnosis and at study entry and MRI-
CRM score at initial diagnosis and at study entry.
Prior induction therapy details will be displayed in a listing including the following information 
from the ‘PRIOR INDUCTION THERAPIES’ and ‘PRIOR INDUCTION THERAPY DETAILS’ 
eCRF pages: Dose level, subject identification number, prior induction therapy (Yes/No), regimen 
name, overall response, documented progression disease date, Drug(s) given as part of the therapy, 
start and end dates.
Finally, a listing of the pharmacogenomics findings will include the following information 
regarding the molecular diagnosis for each participant: Dose level, subject identification number 
and all relevant information from the “Molecular Diagnosis” section of the “Disease History” 
eCRF page.
12
Previous or Concomitant Medications/Procedures
Population: SAF analysis set
12.1
Prior Anti-Cancer Treatments and Procedures
The prior anti-cancer treatments and procedures are collected under the “Prior anti-cancer drug 
therapies”, “Prior anti-cancer surgeries”, and “Prior anti-cancer radiotherapy” eCRF pages.
The listings of prior anti-cancer treatments and procedures will be provided: 
∀
Listing of prior anticancer drug therapies, 
∀
Listing of prior anticancer surgeries, 
∀
Listing of prior anticancer RT. 
These will include the subject identification number, dose level and all the relevant collected data-
fields on the corresponding eCRF pages.
In addition, a summary table will be provided by dose level and overall, with; 
∀
The number of participants having received prior anti-cancer drug therapies, overall and 
by type of therapy
∀
The number of participants having received prior anti-cancer surgeries, overall and by
intent (curative intent or not)
∀
The number of participants having received prior anti-cancer RT.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
30/66
12.2
Previous and Concomitant Medications
Concomitant medications are medications other than study medications and premedications for 
study drug, which started prior to first dose date of study treatment and continued during the on 
treatment period as well as those started during the on treatment period. Previous medications are 
medications, other than study medications and pre medications for study drug, which started before 
first dose date of study treatment. A medication may be classified as both concomitant and 
previous.
In case the date values will not allow unequivocal allocation of a medication to 
previous/concomitant medication, the medication will be considered as both, previous and 
concomitant medication (see Section 0 for incomplete or missing dates). 
Previous and concomitant medications will be summarized separately based on the “Relevant 
previous medications” and “Concomitant medications” eCRF pages. The anatomical therapeutic 
chemical (ATC)-second level and PT will be tabulated as given from the World Health 
Organization Drug Dictionary (most recent available version of WHO-DD). If multiple ATC can 
be assigned to a drug, all ATCs will be reported.
Previous and concomitant medications will also be listed. The listings will include: dose level, 
subject identification number and all corresponding collected data-fields on the corresponding 
eCRF page.
12.3
Concomitant Procedures
Concomitant procedures are procedures other than study medications and pre medications for 
study drug, which started prior to first dose date of study treatment and continued during the on 
treatment period as well as those started during the on treatment period. These will be listed 
according to the CRF page “Concomitant Procedures”. Procedures started after the on treatment 
period will be presented and flagged in listing.
In case the date values will not allow unequivocal allocation of a procedure to concomitant 
procedure, the procedure will be considered as concomitant procedure (see Section 0 for 
incomplete or missing dates).
The listing will include: dose level, subject identification number and all collected data-fields on 
the corresponding eCRF page. 
12.4
Subsequent Anti-cancer Treatment
Subsequent anti-cancer treatments will be listed according to eCRF pages “Anti-cancer treatment 
after discontinuation”, “Surgery after discontinuation” and “Anti-cancer radiotherapies after 
discontinuation”. The listings will include: dose level, subject identification number and all 
collected data-fields on the corresponding eCRF pages. Name of the anti-cancer RT will be 
tabulated as given from the most recent available version of WHO-DD .
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In addition, participants who underwent rectal surgery after Week 15 will be listed according to 
eCRF page “Rectal surgery after Week 15 details”. This listing will include: dose level, subject 
identification number and all collected data fields on the corresponding eCRF page.
13
Treatment Compliance and Exposure
Population: SAF analysis set
Treatment compliance and exposure will be listed and summarized by dose level and overall using 
the SAF analysis set.
All dosing calculations and summaries will be based on “M3814 (PEPOSERTIB)/PLACEBO
Administration”, “Radiotherapy Administration” and “Capecitabine Administration” eCRF pages.
In the Phase Ib part, participants will be assigned peposertib given in combination with 
capecitabine 825 mg/m2 twice daily 5 days/week. The starting dose of peposertib for the first 
cohort will be 50 mg once daily 5 days/week. The planned dose of RT to the tumor area is
∀
50 Gy with a schedule of 25 days and
∀
50.4 Gy with a schedule of 28 days
For the calculations, only doses > 0 will be taken into account if not otherwise specified.
Treatment duration
The duration of peposertib treatment (in weeks) during the study is defined as :
duration= date of last dose of peposertib -date of first dose of peposertib +1
7
.
The durations of RT and capecitabine treatments (in weeks) are derived correspondingly.
Cumulative dose 
Cumulative doses will be calculated based on the actual doses received by the participants as filled 
in the relevant administration eCRF pages. 
The cumulative dose (mg) of peposertib will be calculated as the sum of all actual doses that the 
subject received.
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Peposertib (M3814) 
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The cumulative dose (Gy) of RT will be calculated as the sum of all actual doses that the subject 
received (Actual daily Dose PTV1).
The cumulative dose (mg/m2) of capecitabine will be calculated as the sum of the total daily doses 
that the subject received.
The total daily dose (mg/m²) of capecitabine per subject is the sum of the total dose that the subject 
received at each fraction day. At a given fraction day, the total daily dose (mg/m²) received is 
derived as:
Total daily dose = [Actual morning dose administered (mg) + Actual evening dose administered 
(mg)] / BSA (m²)
The BSA measured at baseline will be used for all visits, unless the measured weight for a 
participant varies more than 10% from baseline The recalculated BSA is derived based on formula 
described in Section Error! Reference source not found., using weight measured at the 
corresponding visit. In case the weight measurement is missing, the weight measurement closest 
to the administration date will be used. If there are two measurements that are equal distance away 
from the missing measurement, the earliest measurement will be used.
Dose intensity 
Dose intensity will be based on the planned dose as defined in the CTP and defined as:
∀
For peposertib:
Dose intensity (mg/weeks) = cumulative dose (mg)
duration (weeks)

∀
For RT:
Dose intensity (Gy/weeks) = cumulative dose (Gy)
duration (weeks)

∀
For capecitabine:
Dose intensity (mg/m²/weeks) = !cumulative dose (mg/m²)
duration (weeks)
"
Relative dose intensity
Relative dose intensity will be based on the planned dose as defined in the CSP. The relative dose 
intensity is defined as:
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Peposertib (M3814) 
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∀
For peposertib:
Relative dose intensity (%) = cumulative dose (mg)
x ∗dose level (mg)
∗100
∀
For RT:
Relative dose intensity (%) = 
cumulative dose (Gy)
x ∗planned daily dose (Gy) ∗100
∀
For capecitabine:
Relative dose intensity (%) = !
cumulative dose (mg/m²)
x ∗planned daily dose (mg/m²) ∗100"
Where planned daily dose (mg/m²) is the sum of planned doses per day . Each fraction day, the 
planned daily dose (mg/m²) is derived as:
Planned daily dose = Planned morning dose (mg/m²) + Planned evening dose (mg/m²) 
For all 3 relative intensity formula above, x = 25 or 28, depending on the number of fraction doses 
the participant received.
The relative dose intensity will be displayed using the following categories:
∀
> 110%
∀
[80% - 110%]
∀
[65% - 80%[
∀
[50% - 65%[
∀
< 50%
Statistical outputs
The treatment exposure and compliance will be summarized in 4 tables including informations for 
each study treatment (peposertib /RT/capecitabine).
The first table will summarize the duration in weeks of each treatment (peposertib 
/RT/Capecitabine), by displaying the number of participants by dose level in each of the following 
categories: 
∀
< 2 weeks
∀
[2 - 4 weeks[
∀
[4 - 6 weeks[
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
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∀
≥6 weeks
The table will also display summary statistics of the duration in weeks of each treatment. 
The second table will summarize the number of total administrations of each treatment (peposertib 
/RT/capecitabine), by displaying the number of participants by dose level in each of the following 
categories:
∀
< 10 administrations/fraction days (peposertib /RT)
∀
]10 -20 administrations/fraction days] (peposertib /RT)
∀
]20 - 25 administrations/fraction days] (peposertib /RT)
∀
]25 - 28 administrations/fraction days] (peposertib /RT)
∀
> 28 administrations/fraction days (peposertib /RT)
The categories to display for cisplatin are: 
∀
<=20 administrations
∀
]20 - 40 administrations]
∀
]40 - 56 administrations]
∀
> 56 administrations. 
The third table will summarize the cumulative dose, dose intensity and relative dose intensity for 
each treatment.
The fourth table will summarize dose reductions by dose level, with for each treatment (peposertib 
/RT/capecitabine):
∀
Number of participants without any dose reduction
∀
Number of participants with at least one dose reduction
∀
Number of participants who did not receive this study intervention
∀
Number of participants with a minimum of 90%, 70-90%, 50-70%, and < 50% level of the 
planned dose. 
The listing of exposure data (including e.g. start date and time of administration, planned and 
actual doses, frequency, change in dose and meal time before dose) will be provided by subject as 
recorded from the related eCRF pages and for each peposertib, RT and capecitabine
administration.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
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In addition, a summary listing will be provided with the treatment duration in weeks, the total 
number of treatment administrations/fraction days received, the cumulative dose, and the relative 
dose intensity for each subject and treatment.
In addition, a listing of all participants receiving peposertib will be displayed to address 
accountability for peposertib according to page “peposertib/Placebo accountability” of eCRF. This 
listing will include the subject identification number, and all collected fields of the corresponding 
eCRF Page. 
14
Efficacy Analyses
No primary efficacy endpoints are planned in Phase Ib of this study. Secondary efficacy endpoints 
include the composite endpoint of pathological complete response / clinical complete response 
(pCR/cCR), disease-free survival (DFS) time, pCR according to local review, cCR and time to 
local/distant recurrence.
In the context of efficacy analyses when using ‘surgery’, the rectal surgery at Week 15 is meant. 
Consequently, delayed rectal surgeries, or surgeries other than the one planned at Week 15 are not 
considered.
14.1
Secondary Endpoints: pCR, cCR, and pCR/cCR
Population: FAS analysis set
Pathological complete response
Only subjects who undergo surgery at Week 15 can be considered as pathological complete 
responders. Subjects with pCR will be identified based on the “Histological response” item on the 
“RECTAL SURGERY AT WEEK 15 DETAILS” eCRF page.
Clinical complete response
Clinical complete response will be assessed according to the tumor evaluation charter. Participants 
with cCR will be identified based on the “Overall response” item on the “Tumor Assessement 
(According to NCCN) after RT in ETT/ Week 14” eCRF page . 
Composite endpoint of pathological complete response/clinical complete response
Participants are considered as responders to the composite endpoint pCR/cCR if 1 of the following 
2 criteria is fulfilled (Figure 1):
∀
Participant had surgery and has pCR (Histological response on “Rectal surgery at week 15 
Details” eCRF page is ‘Pathological Complete response (pCR)’)
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
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∀
Participant did not undergo surgery but has cCR (defined above; Overall Status on “Tumor 
Assessement (According to NCCN) after RT in ETT/ Week 14” eCRF page is ‘Clinical
Response’).
Participants who are not operated and do not undergo the procedures to define cCR or have 
histological response and pathological response not ‘Complete response’ will be regarded as non-
responders for the composite endpoint.
Figure 1
Derivation of Composite Endpoint
cCR=Clinical complete response, MRI=Magnetic Resonance Imaging, pCR=Pathological complete response.
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
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Additionally all information available on the “TUMOR EVALUATION - WEEK 14” and 
“TUMOR EVALUATION - WEEK 15” eCRF pages will be described in a table with the 
following variables:
∀
MRI-EMVI score
∀
MRI-CRM score
∀
ypTNM score
∀
Surgical-CRM score
∀
Modified Ryan scheme
All tumor assessments will be displayed in two listings. Tumor assessments at Screening and at 
Week 14/ETT will be sorted by dose level and subject identification number and listed with the 
following variables: 
∀
Dose level
∀
Visit
∀
Subject identification number
∀
Method of tumor assessment
∀
Date of tumor assessment
∀
Outcome of the tumor assessment
Tumor assessments during the long-term safety and survival follow-up period will be sorted by 
dose level, subject identification number and assessment visit and listed with the following 
variables: 
∀
Dose level
∀
Subject identification number
∀
Assessment visit
∀
Date of imaging
∀
Assessment method
∀
Overall status.
Finally, all information available on the “RECTAL SURGERY AT WEEK 15” eCRF page will 
be listed. The listing will be sorted by dose level, subject identification number and date of surgery 
and will display the following variables: 
∀
Dose level
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
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∀
Subject identification number
∀
Date of surgery
∀
Surgery procedure
∀
Outcome of surgery
∀
Histological response.
14.2
Secondary Endpoint: Disease-Free Survival
Population: FAS analysis set
Disease-free survival (DFS) time is defined as the time from the first treatment day to the date of 
the first documentation of objective progression of disease (PD) or death due to any cause, 
whichever occurs first. DFS data will be censored on the date of the last adequate tumor assessment 
for participants who do not have an event (PD or death) or for participants with an event after two 
or more subsequent missing tumor assessments (i.e. 2 times the scheduled time interval between 
two subsequent response assessments). Participants who do not have a baseline tumor assessment 
or who do not have any post baseline tumor assessments will be censored at the start of first trial 
treatment unless death occurred on or before the time of the second planned tumor assessment, in 
which case the death will be considered an event.
The last adequate tumor assessment is defined as the last tumor assessment result that is not “NE” 
or “NA”.
Disease-free survival in months is calculated as follows:
DFS (months) = [date of event or censoring– treatment start date +1]/30.4375
Table 6 Date of event / censoring for DFS analysis
Status
Censoring
Date of event / censoring
Progressed or 
died
No consecutive missing tumor 
assessments
Event
Minimum (Date of PD, Date of death)
After two or more subsequent 
missing tumor assessments (i.e. 2 
times the scheduled time interval 
between two subsequent response 
assessments)
Censored
Date of last tumor assessment with 
outcome CR, Nearly-CR or IR or 
treatment day 1, whatever is later
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                     Phase Ib/II study of M3814 in combination with
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14.3
Secondary Endpoint: Local Recurrence and/or Distant 
Metastasis
Population: FAS analysis set (participants with surgery only)
Time from surgery to local recurrence will be defined as time from day of surgery to the date of 
the first documentation of progression of disease, flagged as ‘local recurrence’ or ‘local recurrence 
and distant metastasis’(‘TUMOR ASSESSMENT(ACCORDING TO NCCN) DURING LONG-
TERM SAFETY AND SURVIVAL FOLLOW-UP’ eCRF page).
Time from surgery to distant metastasis will be defined as time from day of surgery to the date of 
the first documentation of progression of disease, flagged as ‘distant metastasis’ or ‘local 
recurrence and distant metastasis’ (‘TUMOR ASSESSMENT(ACCORDING TO NCCN) 
DURING LONG-TERM SAFETY AND SURVIVAL FOLLOW-UP’ eCRF page). Only subjects 
who undergo rectal surgery (week 15) will be included in this analysis.
Table 8 Date of event / censoring definition for Local/Distant recurrence Analysis
Status
Censoring
Date of event / censoring
Time to local 
recurrence: PD 
flagged as ‘Local 
recurrence’ or 
‘Local recurrence 
and distant 
metastasis’
Time to distant 
metastasis: PD 
flagged as 
‘Distant 
metastasis’ or 
‘Local recurrence 
and distant 
metastasis’
No consecutive missing tumor 
assessments
Event
Date of progression
After two or more subsequent missing 
tumor assessments (i.e. 2 times the 
scheduled time interval between two 
subsequent response assessments)
Censored
Date of last tumor assessment 
with outcome CR or date of 
surgery, whatever is later
Time to local recurrence: No consecutive 
missing tumor assessments and PD 
flagged as ‚Distant metastasis‘
Time to distant metastasis: No 
consecutive missing tumor assessments 
and PD flagged as ‚Local recurrence‘
Censored
Date of progression
No PD flagged as ‘Local recurrence’, ‘Distant metastasis’ or 
‘Local Recurrence and Distant metastasis’ and no missed tumor 
assessment
Censored
Date of last tumor assessment 
with outcome CR or date of 
surgery, whatever is later
CR = Complete response; PD = Progressive disease 
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14.3.1
Secondary Objective: Analysis of Local Recurrence and/or 
Distant Metastasis
Table 9 Summary of the analysis of the local recurrence and/or distant metastasis
Analysis 
Population
Derivation
Statistical Analysis Methods
Missing 
data 
handling
FAS
The following analyses will 
be performed:
∀Time from surgery to local 
recurrence
∀Time from surgery to 
distant metastasis.
Kaplan-Meier estimates will be presented overall, 
together with a summary of associated statistics 
(median survival time and survival rate estimates) 
including the corresponding 2-sided 95% CIs. 
Confidence intervals for the median will be calculated 
according to Brookmeyer and Crowley (Brookmeyer 
& Crowley, 1982) and CIs for the survival function 
estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice
(Kalbfleisch & RL, 1980): conftype=loglog default 
option in SAS Proc LIFETEST. The estimate of the 
standard error will be computed using Greenwood's 
formula
Model 
based
CI = Confidence interval; FAS = Full analysis set
The listing of tumor assessments prior Surgery (including Screening tumor assessments) and all 
relevant informations as recorded on the ‘TUMOR ASSESSEMENT (ACCORDING TO NCCN) 
AFTER RADIOTHERAPY in ETT/WEEK14’   and  ‘TUMOR ASSESSEMENT (ACCORDING 
TO NCCN) DURING LONG-TERM SAFETY and SURVIVAL FOLLOW-UP’  eCRF pages,will 
be provided by subject.
A swimmer plot displaying some key radiological milestones as well as surgery will be produced, 
sorted by follow-up time. For the purpose of CSR, a version of the swimmer plot without subject 
id will be provided. For each subject, the time from treatment start until end of follow-up will be 
represented (from treatment start to last date known to be alive or date of death). In addition, the 
following information will be displayed: time of first occurrence of CR, Nearly-CR, IR, and PD , 
time of surgery, pCR achievement and status at the end of the follow-up (alive or dead). 
In addition, a listing will be provided summarizing all of the efficacy endpoints (as defined above)
for each participant. This listing will include dose level, subject identification number, date of first 
dose, date of last evaluable tumor assessment, efficacy endpoint, and event. In addition, for DFS, 
and local/distant recurrence, event/censor date, censor flag, and the time-to-event/censoring will 
be included.
Finally, all tumor assessments performed during the long-term safety and survival follow-up 
period will be listed. This listing will include dose level, subject identification number, assessment 
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                     Phase Ib/II study of M3814 in combination with
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visit, imaging date, assessment method and the overall status. This listing will be sorted by dose 
level, subject identification number and Imaging date.
14.4
Secondary Endpoint: Neoadjuvant Rectal Score
Population: FAS analysis set 
The neoadjuvant rectal score (NAR) was developed by George and colleagues to serve as a short 
term clinical study surrogate endpoint (George 2015). The Valentini nomograms (Valentini 2011) 
to predict overall survival in rectal cancer patients after neoadjuvant treatment are the basis of the 
NAR score. Its score ranges from 0 to 100, whereas a score close to 100 is indicative of a poorer 
prognosis.
14.4.1
Secondary Objective: Analysis of NAR score
Table 10 Summary of the analysis of the NAR score
Analysis 
Population
Derivation
Statistical Analysis Methods
Missing data 
handling
FAS
See NAR formula below.
The neoadjuvant rectal score will be presented in 
terms of summary statistics (such as mean, 
median, standard deviation, and quartiles) and 
graphically using a boxplot by dose level.
Participants with at 
least one item of the 
NAR score missing 
will be considered as 
having a missing 
NAR score.
FAS = Full analysis set
The Neoadjuvant Rectal Score (NAR) will  be calculated using a formula that includes the clinical 
tumor (cT) stage, pathologic tumor (pT), and node (pN) stage according to the tumor, node, 
metastasis classification system for colorectal cancers. The NAR score is calculated as follows:
*+, = [5/* −3(23 −/3) + 12]7
9.61
Where cT is an element of the set {1, 2, 3, 4}, pT is in {0, 1, 2, 3, 4}, and pN is in {0, 1, 2}. 
cT is collected on the “DISEASE HISTORY” eCRF page, from the “TNM classification at study 
entry” item, as follows:
∀
Numeric part of the T stage = cT
pN and pT are collected on the “TUMOR EVALUATION – WEEK 15” eCRF page, from the 
“ypTNM score”, as follows:
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∀
Numeric part of the N stage = pN
∀
Numeric part of the T stage = pT
The listing of NAR socre and all relevant informations for calculation pN and cT from ‘DISEASE 
HISTORY’ eCRF page and PT from ‘TUMOR EVALUATION – WEEK 15’ eCRF page,will be 
provided by subject.
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as AE, laboratory tests and vital signs.
The primary endpoint of the Phase Ib is the occurrence of DLTs during the DLT observation period 
(5.5 weeks after the start of treatment). Based on the data observed, a recommendation of the next 
dose level is based on a Bayesian dose escalation design using a two-parametric logistic regression 
model. More details about the analysis to be provided to SMC members are presented in a 
dedicated IAP.
15.1
DLT (Primary Endpoint)
Population: DE analysis set
The DLT information will be based on “Adverse Events” eCRF page with “Is the adverse event a 
dose limiting toxicity?” = Yes or with “Is the adverse event a dose limiting toxicity upon SMC 
review” = Yes.
A summary table of DLTs during the DLT period will be provided for each dose level and overall 
with:
∀
Number of participants with at least one DLT as per SMC decision
The listing of DLTs will also be provided.
15.2
Adverse Events
Definitions
Treatment-emergent adverse events: those events with onset dates occurring within the on 
treatment period.
Counting rules and observation periods for AEs during the on treatment period (TEAEs):
∀
If an AE is reported for a given subject more than once during treatment, the worst severity 
and the worst relationship to trial treatment will be tabulated.
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∀
Adverse events related to trial treatment are those events with relationship missing, 
unknown or related to at least one treatment (peposertib, RT or capecitabine).
∀
Adverse events related to peposertib are those events related to peposertib, regardless of 
relationship with RT and/or capecitabine
∀
Adverse events related to RT are those events related to RT, regardless of relationship with 
peposertib and/or capecitabine
∀
Adverse events related to capecitabine are those events related to capecitabine, regardless 
of relationship with peposertib and/or RT
∀
In case a subject has events with missing and non-missing grades, the maximum of the 
non-missing grades will be displayed.
For identification of AE treatment emergence, incomplete dates will be handled using the rules 
presented in Section 0.
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 5.0) per 
participant, using the latest version of MedDRA preferred term (PT) as event category and 
MedDRA primary system organ class (SOC) body term as Body System category. 
Missing data handling
Incomplete AE-related dates will be handled using the rules presented in Section 0. In case a 
participant has events with missing and non-missing grades, the maximum of the non-missing 
grades will be displayed. No imputation of missing grades will be performed.
15.2.1
All Adverse Events
Population: SAF Analysis Set
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 5.0) per 
subject, using the most recent available MedDRA version (21.1 or higher) PT as event category 
and primary SOC body term as Body System category. 
Frequency tables for AEs captured on the “Adverse Events” eCRF pages will be based on TEAEs 
as defined above.
A first overview table of adverse events will be provided by dose level and overall by summarizing 
the number and percentage of participants with any:
∀
TEAE
∀
TEAEs related to trial treatment, (i.e. peposertib, RT, or capecitabine)
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                     Phase Ib/II study of M3814 in combination with
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∀
TEAEs related to peposertib
∀
TEAEs related to RT
∀
TEAEs related to capecitabine
∀
Serious TEAE
∀
Serious TEAE related to trial treatment (i.e. peposertib, RT, or capecitabine)
∀
Serious TEAEs related to peposertib
∀
Serious TEAEs related to RT
∀
Serious TEAEs related to capecitabine
∀
TEAEs with grade # 3
∀
TEAEs with grade # 4
∀
TEAEs with grade # 3 related to trial treatment (i.e. peposertib, RT or capecitabine)
∀
TEAEs with grade # 4 related to trial treatment (i.e. peposertib, RT or capecitabine)
∀
TEAEs with grade # 3 related to peposertib
∀
TEAEs with grade # 4 related to peposertib
∀
TEAEs with grade # 3 related to RT 
∀
TEAEs with grade # 4 related to RT 
∀
TEAEs with grade # 3 related to capecitabine 
∀
TEAEs with grade # 4 related to capecitabine
∀
TEAEs leading to dose modification of any trial treatment (i.e. peposertib, RT or 
capecitabine)
∀
TEAEs leading to dose modification of peposertib
∀
TEAEs leading to dose modification of RT
∀
TEAEs leading to dose modification of capecitabine
∀
TEAE leading to death
∀
TEAE leading to death related to trial treatment, peposertib, RT or capecitabine 
∀
TEAE leading to death related to peposertib
∀
TEAE leading to death related to RT 
∀
TEAE leading to death related to capecitabine
∀
TEAE leading to trial discontinuation
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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∀
TEAE leading to temporary discontinuation of at least one trial treatment 
∀
TEAE leading to temporary discontinuation of all trial treatments
∀
TEAE leading to temporary discontinuation of M3814
∀
TEAE leading to temporary discontinuation of RT 
∀
TEAE leading to temporary discontinuation of Capecitabine
∀
TEAE leading to permanent discontinuation of at least one trial treatment 
∀
TEAE leading to permanent discontinuation of all trial treatments
∀
TEAE leading to permanent discontinuation of M3814 
∀
TEAE leading to permanent discontinuation of RT
∀
TEAE leading to permanent discontinuation of Capecitabine 
Frequency tables summarizing events in the following categories will be prepared by dose level 
and overall, sorted by alphabetical order of SOC and PT:
∀
TEAEs
∀
TEAEs related to trial treatment (i.e. peposertib, RT, or capecitabine)
∀
TEAEs related to peposertib
∀
TEAEs related to RT
∀
TEAEs related to capecitabine
∀
Serious TEAEs
∀
TEAEs excluding SAEs, with overall frequency ≥ 5% by SOC and PT (threshold will be 
applied on PT)
∀
Serious TEAEs related to trial treatment
∀
Serious TEAEs related to peposertib
∀
TEAEs by worst CTCAE grade: any grade (including AEs with missing grade), grades # 3, 
# 4 and 5
∀
TEAEs related to trial treatment by worst CTCAE grades: any grade (including AEs with 
missing grade), grades # 3, # 4 and 5
∀
TEAEs related to peposertib by worst CTCAE grades: any grade (including AEs with 
missing grade), grades # 3, # 4 and 5
∀
TEAEs related to RT by worst CTCAE grades: any grade (including AEs with missing 
grade), grades # 3, # 4 and 5
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
48/66
∀
TEAE related to capecitabine by worst CTCAE grades: any grade (including AEs with 
missing grade), grades # 3, # 4 and 5
∀
TEAEs leading to death
In addition, all TEAEs and TEAEs related to peposertib with at least 2 participants will be 
summarized in two tables sorted by frequency (descending order) and PT. 
The following listings will be produced based on the “Adverse Events” eCRF page:
∀
All AEs (whether treatment-emergent or not)
∀
Serious TEAEs related to any trial treatment
∀
TEAEs within 6 weeks after surgery and delayed surgery
These listings will include the following items: 
∀
Dose level
∀
Subject identification number 
∀
Age
∀
Sex
∀
Race
∀
First and last dose date for peposertib, RT and capecitabine
∀
Reported Term with SOC and PT
∀
Start, change and end date with their corresponding treatment day
∀
Treatment Emergent Adverse Events flag (N/Y; only for the listing of all AEs)
∀
Timing related to treatment (if same day of treatment administration)
∀
TEAE related to peposertib flag (N/Y)
∀
TEAE related to RT flag (N/Y)
∀
TEAE related to capecitabine flag (N/Y)
∀
Serious Adverse Events flag (N/Y; only for the listing of all AEs) 
∀
DLT flag (Y/N)
∀
CTCAE Grade
∀
Action taken with peposertib, with RT and with capecitabine
∀
Outcome of AE
∀
AE occurred after COVID-19 pandemic start (Y/N).
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
49/66
Evaluation of COVID-19 effects on AEs
The direct effect of COVID-19 for AEs will be assessed via listing of COVID-19 related AEs. The 
following listing will be generated using the ‘COVID-19 related terms MedDRA 23.0 update 
Spreadsheet’, considering all ‘search terms for COVID-19-related’ =’Y’. Same information as for 
the listing of all AEs will be provided.
15.2.2
Adverse 
Events 
Leading 
to 
Study 
Intervention 
Discontinuation
Population: SAF analysis set
An overview table of adverse events leading to discontinuation or dose reduction will be provided, 
by dose level and overall, summarizing the number and percentage of participants with any:
∀
TEAE leading to temporary discontinuation of at least one trial treatment, all trial 
treatments, peposertib (regardless of other trial treatments status), RT (regardless of other 
trial treatments status), capecitabine (regardless of other trial treatments status) 
(corresponding to AEs with action taken = “Drug interrupted” for peposertib, RT or 
capecitabine)
∀
TEAE leading to permanent discontinuation of at least one study intervention, all trial 
treatments, peposertib (regardless of other trial treatments status), RT (regardless of other 
trial treatments status) or capecitabine (regardless of other trial treatment) (corresponding 
to AEs with action taken = “Drug withdrawn” for peposertib, RT or capecitabine
respectively)
The following frequency tables will be produced for each dose level and overall, by SOC and PT 
in alphabetical order:
∀
TEAEs leading to temporary discontinuation of at least one trial treatment
∀
TEAEs leading to temporary discontinuation of peposertib (regardless of other trial 
treatments status)
∀
TEAEs leading to temporary discontinuation of RT (regardless of other trial treatments 
status)
∀
TEAEs leading to temporary discontinuation of capecitabine (regardless of other trial 
treatments status)
∀
TEAEs leading to permanent discontinuation of at least one trial treatment
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
50/66
∀
TEAEs leading to permanent discontinuation of peposertib (regardless of other trial 
treatments status)
∀
TEAEs leading to permanent discontinuation of RT (regardless of other trial treatments 
status)
∀
TEAEs leading to permanent discontinuation of capecitabine (regardless of other trial 
treatments status)
∀
TEAEs leading to a delay in dose time of RT
15.2.3
Late Toxicities
A number of outputs will be produced for late adverse events. An adverse event is defined as a late 
toxicity if it starts after the on-treatment period, and it meets one of the following criteria:
∀
It is the first occurrence of adverse event for this participant on MedDRA preferred term 
level
∀
It is a recurring adverse event but there is gap between the end date of the previous 
occurrence and the start date of the re-occurrence (start date of re-occurrence – end date of 
previous occurrence > 0) 
∀
It is a recurring adverse event and  there is no gap between the end date of the previous 
occurrence and the start date of the re-occurrence, and the grade has worsened.
The following outputs will be produced for late toxicities:
∀
Table of all late toxicities by worst CTCAE grades: any grade (including AEs with missing 
grade), grades # 3, # 4 and 5
∀
Listing of all late toxicities related to any trial treatment
∀
Listing of all late toxicities grade # 3   
15.3
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.3.1
Deaths
Population: SAF analysis set
All deaths, deaths within 60 days after first dose of trial treatment, and deaths within 30 days and 
within 90 days after last dose of trial treatment, as well as reasons for deaths (disease progression, 
adverse event related to study treatment, adverse event not related to study treatment, other, 
unknown), will be tabulated based on all relevant information available in the eCRF:
∀
Number of deaths
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
51/66
∀
Number of deaths within 60 days after first dose of trial treatment 
∀
Number of deaths within 30 days after last dose of trial treatment
∀
Number of deaths within 90 days after last dose of trial treatment
∀
Primary reason of death
In addition, the date (non-imputed) and cause of death will be provided in individual subject data 
listings together with selected dosing information (date of first/last administration of peposertib, 
RT and capecitabine, dose level and number of fraction days/duration). 
Subject listing of deaths includes columns for: 
∀
Subject identification 
∀
Age 
∀
Sex
∀
Race
∀
AEs with fatal outcome (list PTs of AEs with outcome=fatal), 
∀
Flag for death within 60 days after first dose of peposertib
∀
Flag for death within 60 days after first dose of RT
∀
Flag for death within 60 days after first dose of capecitabine
∀
Flags for death within 30, 90 days after last dose of peposertib
∀
Flags for death within 30, 90 days after last dose of RT
∀
Flags for death within 30, 90 days after last dose of capecitabine
Finally, all treatment related TEAEs (i.e. peposertib, RT or capecitabine) leading to death, will be 
listed in a separate listing, displaying:
∀
Dose level
∀
Subject identification number 
∀
Age
∀
Sex
∀
Race
∀
First and last dose date for peposertib, RT and capecitabine 
∀
Reported Term with SOC and PT
∀
Start and end date with their corresponding treatment day
∀
Treatment Emergent Adverse Events flag (N/Y)
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Peposertib (M3814) 
                     Phase Ib/II study of M3814 in combination with
capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
52/66
∀
Timing related to treatment (if same day of treatment administration)
∀
TEAE related to peposertib flag (N/Y)
∀
TEAE related to RT flag (N/Y)
∀
TEAE related to capecitabine flag (N/Y)
∀
Serious Adverse Events flag (N/Y) 
∀
DLT flag (Y/N)
∀
CTCAE Grade
∀
Action taken with peposertib, with RT and with capecitabine 
∀
Outcome of AE
∀
Date of death with the corresponding treatment day
15.3.2
Serious Adverse Events
Population: SAF analysis set
SAEs will be summarized for each dose level and overall, by SOC, and PT in alphabetical order 
(please refer to Section 15.2.1 for items to be listed).
In addition, subject listings of SAEs will be provided.
15.4
Clinical Laboratory Evaluation
Population: SAF analysis set
Listings and summaries by visit will include all assessments, whereas shift tables and summaries 
of worst on-treatment values will not consider assessments after the on-treatment period.
Local laboratory values (including corresponding normal ranges) will be presented in summary 
statistics, shift tables and boxplots. In addition, liver toxicity will be assessed with Hy’s Law 
analysis.
Laboratory results will be classified according to the NCI-CTCAE version 5.0. Additional 
laboratory results that are not part of NCI-CTCAE will be presented according to the categories: 
below normal limits, within normal limits and above normal limits (according to the laboratory 
normal ranges).
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
56/66
Boxplots will be produced for all quantitative hematology and biochemistry parameters, to display: 
∀
Values by time point  
∀
Difference from baseline to highest deviation on treatment by cohort
All CTC gradable and non-CTC gradable parameters will be listed for each measurement (pre 
treatment, on treatment and post treatment). Parameters will be grouped by category.
Listings will include at least the following items:
∀
Dose level
∀
Subject identification number
∀
First / last dosing date for peposertib, RT and capecitabine
∀
Parameters
∀
Visit
∀
Date (Treatment day)
∀
Analysis value
∀
SI unit
∀
Change from baseline
∀
Reference range status (Low, Normal, High)
∀
CTC grade (with associated CTC name)
∀
Baseline flag (Yes/No)
∀
Worst value on-treatment flag (Yes/No)
∀
On treatment flag (pre/on/post)
Gradable parameters with at least one value with Grade ≥ 3, will be considered clinically 
significant laboratory values. For hematology and biochemistry, a listing displaying clinically 
significant laboratory values will be provided. For each participant, only parameters where at least 
one value has Grade ≥ 3 will be displayed (all visits for the corresponding parameter will be 
displayed). The listing will be sorted by dose level, subject ID, parameter name, and datetime. 
Coagulation parameters
All coagulation parameters will be listed for each measurement (pre treatment, on treatment and 
post treatment).
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
57/66
Urinalysis
A listing of urinalysis and microscopic analysis will be provided.
Liver toxicity
On-treatment liver function tests will be summarized in a table presenting the number and 
percentage of participants, by dose level and overall: 
-
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN
-
AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN
-
Total Bilirubin ≥ 2×ULN
-
(ALT or AST) ≥ 3×ULN and Total Bilirubin ≥ 2×ULN (Hy’s Law case)
Categories will be cumulative, i.e., a participant with an elevation of AST ≥10×ULN will also 
appear in the categories ≥ 5×ULN and ≥ 3×ULN. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created by 
graphically displaying:
-
peak serum ALT(/ULN) vs simultaneous Total Bilirubin (/ULN) including reference 
lines at ALT > 3ULN and bilirubin > 2ULN.
-
peak serum AST(/ULN) vs simultaneous Total Bilirubin (/ULN) including reference 
lines at AST > 3ULN and bilirubin > 2ULN.
Participants under the Hy law’s case (right upper corner) will be flaged with their subject identifier.
In addition, a listing of all TBILI, ALT, AST and ALP values for subjects with an on-treatment
TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided.
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
58/66
15.5
Vital Signs
Population: SAF Analysis Set
Body temperature, SBP, DBP, respiratory rate and heart rate will be analyzed with shift tables of 
maximum CFB of on-treatment assessments using the categories defined below:
Table 13 Vital signs categories
Parameter
Unit
Shift
Baseline categories
On-treatment categories 
(absolute change)
Temperature
°C
Increase
< 37 / ≥ 37 - < 38 / ≥ 38 -
< 39 /≥ 39 - < 40 / ≥ 40
< 1ª / ≥ 1 - < 2 /≥ 2 - < 3 / ≥ 3
Heart rate
Bpm
Increase
and decrease
< 100 / ≥ 100
≤ 20ª / > 20 - ≤ 40 / > 40
SBP
mmHg
Increase
and decrease
< 140 / ≥ 140
≤ 20a / > 20 - ≤ 40 / > 40
DBP
mmHg
Increase
and decrease
< 90 / ≥ 9≥ 90
≤ 20ª / > 20 - ≤ 40 / > 40
Respiratory rate 
breaths/min Increase
and decrease
< 20 / ≥ 20
≤ 5ª / > 5 - ≤ 10 / > 10
a This category will include the subjects with no changes or decrease/increase in the increase/decrease part of the 
table, respectively.
Line plots per dose level and overall will be produced for systolic blood pressure, diastolic blood 
pressure, heart rate, temperature and weight. These will be presented by visit.
Maximum change from baseline will also be listed for each parameter and participant and will 
include: Dose level, subject ID, parameter, visit, date, unit, baseline value and maximum change 
from Baseline for each participant. This listing will be sorted by dose level, subject ID, parameter 
and visit. 
Finally, all vital signs data from “Vital Signs” eCRF pages will be listed.
15.6
Other Safety or Tolerability Evaluations
15.6.1
ECOG Performance Status
Population: SAF analysis set
The listing will include all the data from the “ECOG Performance Status” eCRF section.
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
59/66
Additionally, one spaghetti plot per dose level will be produced, using different colors/line types 
per participant.  
15.6.2
ECG and QT/QTc Evaluations
Population: SAF analysis set
Electrocardiogram values based on the “Electrocardiogram” eCRF section will be used for 
summary statistics and shift tables. 
ECG parameters (Heart Rate, R-R duration, PQ/PR duration, QT duration, QR duration, QTcF)
will be summarized by dose level and visit, using descriptive statistics (see Section 9) for absolute 
values and absolute change from baseline. 
The number of participants with normal ECGs at baseline and abnormal ECGs post baseline will 
be calculated by visit and summarized in a frequency table by dose level and overall. In addition, 
ECG parameters on treatment will be presented by the following frequency table (by dose level 
and overall):
∀
Shift from normal baseline result to the worst on-treatment value
∀
Worst mean absolute QTcF interval on treatment
o
<= 450 ms
o
> 450 ms and ≤ 480 ms
o
> 480 ms and ≤500 ms
o
> 500 ms
∀
Worst on treatment mean QTcF increase from baseline
o
<= 30 ms 
o
> 30 ms and ≤ 60 ms
o
> 60 ms
If duplicate/triplicate measurements are performed at any time point, the following will apply:
∀
For quantitative parameters, the mean of the triplicate measurement will be used as 
summary 
∀
For results interpretation, the worst Overall conclusion will be retained.
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
60/66
Visits and time points to be displayed in summary tables are all scheduled visits where ECG 
assessments are performed.
Two listings will display all the results as presented in “ECG” eCRF page, one on qualitative 
results and another one on quantitative results. All visits, time points, flag for pre /on /post
treatment, and, in case of triplicates, mean for quantitative results and worst overall conclusion for 
qualitative results, will be included in listings. 
15.6.3
Pregnancy Test
Pregnancy testing (serum β-HCG) will be performed at screening and 30 days post treatment. A 
listing will display all the results as presented in “Pregnancy Test” eCRF page. 
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
Population: PK Analysis Set
Pharmacokinetic parameters will be calculated by the Clinical PK/Pd  Group of QP, Merck, 
Darmstadt, Germany, or by a clinical research organization selected by the sponsor, using standard 
non-compartmental methods and the actual administered dose. Pharmacokinetic parameters will 
be calculated using the actual elapsed time since dosing, given with a precision of 15 significant 
digits or the SAS format Best12. In cases where the actual sampling time is missing, calculations 
will be performed using the scheduled time. Otherwise, there will be no further imputation of 
missing data.
Missing concentrations (e.g. no sample, insufficient sample volume for analysis, no result or result 
not valid) will be reported and used generally as “N.R.”.
PK concentrations which are erroneous due to a protocol violation (as defined in the CSP), 
sampling processing or analytical error (as documented in the bioanalytical report) may be
excluded from the PK analysis, if agreed by the sponsor. In this case the rationale for exclusion 
must be provided in the CSR. Any other PK concentrations that appear implausible to the clinical 
pharmacologist/clinical PK/Pd scientist will not be excluded from the analysis. Any implausible 
data will be documented in the CSR.
The following PK parameters will be calculated from peposertib and peposertib metabolite (
M467) plasma concentrations for fraction day (FD) FD1 and/or FD9 as indicated. Appropriate 
adjustments will be made for differences in molecular weight (MW) (peposertib MW = 481.92 
gmol-1; metabolite M467 MW = 467.12 gmol-1).
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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Cmax
Maximum observed concentration
Cmax/Dose
The dose-normalized Cmax. Normalized using the formula Cmax/Dose.
tmax
The time to reach Cmax during a dosing interval (unless otherwise defined, 
the first occurrence is taken if multiple/identical Cmax values)
AUC0-t
The area under the curve (AUC) from time 0 (dosing time) to the last 
sampling time at which the concentration is at or above the lower limit of 
quantification (LLOQ). Calculated using the mixed log linear trapezoidal 
rule (linear up, log down)
AUC0-24
The AUC from time 0 (dosing time) to 24 hours postdose. AUC0-24 will be 
based on the estimated concentration at 24 hours, and not the concentration 
at the actual observation time. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down)
AUC0-∞
The AUC from time 0 (dosing time) to infinity based on the predicted 
value for the concentration at tlast, as estimated using the linear regression 
from !z determination for FD1. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down). AUC0-∞=AUC0-t+Clast pred/!z
AUC0-t/Dose
The dose-normalized AUC0-t. Normalized using the formula AUC0-t/Dose.
AUC0-24/Dose
The 
dose-normalized 
AUC0-24. 
Normalized 
using 
the 
formula 
AUC0-24/Dose.
AUC0-∞/Dose
The 
dose-normalized 
AUC0-∞. 
Normalized 
using 
the 
formula 
AUC0-∞/Dose.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-∞, AUCextra% = (extrapolated area/AUC0-∞)*100 for FD1
t½
Apparent terminal half-life, t½ = ln 2/!z
CL/f
Apparent total body clearance of drug, calculated as Dose/AUC0-∞
(predicted) for FD1 for peposertib only
Vz/f
Apparent volume of distribution during the terminal phase following 
extravascular administration for peposertib only. 
Vz/f = Dose/(AUC0-∞*!z) for FD1 and Vz/f = Dose/(AUC0-24*!z) for FD9
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
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CLss/f
The apparent total body clearance at steady state following extravascular 
administration, taking into account the faction of dose absorbed. 
Calculated by Dose/AUC0-24 for FD9 for peposertib only
Racc(Cmax)
The accumulation factor to assess the increase in maximum concentration 
from FD1 to FD9 Racc(Cmax) = (Cmax FD9)/(Cmax FD1) for peposertib and 
M467
Racc(AUC0-24)
The accumulation factor to assess the increase in exposure from FD1 to 
FD9 
during 
time 
0 
to 
24 
hours. 
Racc(AUC0-24) 
= 
(AUC0-24 FD9)/(AUC0-24 FD1) for peposertib and M467
MRAUC0-t
Metabolic ratio of AUC0-t. AUC0-t for  M467 divided by the AUC0-t of 
peposertib corrected for MW: MRAUC0-t*481.92/467.12
MRAUC0-24
Metabolic ratio of AUC0-24. AUC0-24 for  M467 divided by the AUC0-24 of 
peposertib corrected for MW: 
MRAUC0-24*481.92/467.12
MRAUC0-∞
Metabolic ratio of AUC0-∞for FD1 only. AUC0-∞for  M467 divided by 
the AUC0-∞of peposertib corrected for MW: MRAUC0-∞*481.92/467.12
MRCmax
Metabolic ratio of Cmax. Cmax for  M467 divided by the Cmax of peposertib
corrected for MW:  MRCmax*481.92/467.12
The following PK parameters will be calculated from capecitabine and its metabolite 
(5-fluorouracil) plasma concentrations for FD1 and/or FD9 as indicated.
Cmax
Maximum observed concentration
tmax
The time to reach Cmax during a dosing interval (unless otherwise defined, 
the first occurrence is taken if multiple/identical Cmax values)
tlast
The time at which last quantifiable concentration occurs.
AUC0-t
The area under the curve (AUC) from time 0 (dosing time) to the last 
sampling time at which the concentration is at or above the LLOQ. 
Calculated using the mixed log linear trapezoidal rule (linear up, log down)
AUC0-∞
The AUC from time 0 (dosing time) to infinity based on the predicted 
value for the concentration at tlast, as estimated using the linear regression 
from !z determination for FD1. Calculated using the mixed log linear 
trapezoidal rule (linear up, log down). AUC0-∞=AUC0-t+Clast pred/!z
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
64/66
∀
Scatter plot of individual dose-normalized AUC0-24, AUC0-t, AUC0-∞, and Cmax versus dose 
on a linear scale. A linear regression may also be overlaid. 
The following listings, figures, and summary statistics of peposertib, its metabolite 
(0-
demethylated product M467), and capecitabine and its metabolite (5-fluorouracil) PK 
concentration and parameter data will be provided:
∀
Listing of individual PK concentration data by scheduled time point, dose level, and 
fraction day
∀
Listing of individual PK parameters by dose level and fraction day
∀
Descriptive summary table of PK concentration data by scheduled time point, dose level, 
and fraction day
∀
Descriptive summary table of PK parameter data by dose level and fraction day
∀
Individual peposertib , M467, and capecitabine and 5-fluorouracil concentration-time 
profiles (linear and semi-logarithmic scales) will be plotted by dose level for each fraction 
day as spaghetti plots, using actual time points (where available). 
∀
Arithmetic mean concentrations will be plotted on both linear (±Sd) and semi-logarithmic 
scales using scheduled time points – with all dose levels overlaid per fraction day, and with 
all fraction days overlaid per formulation dose level. Additional mean plots will be 
produced (on both linear [±(Sd]  and semi-log scale) to show the mean concentration-time 
data per dose level over the entire-time course. PK concentrations excluded form summary 
statistics will not be included in mean figures. Mean plots will only contain averages when 
n> 2.
All descriptive summaries of PK data will be performed using the PK analysis set.
Any PK concentrations or PK parameters excluded from PK evaluation or summary statistics will 
be included in subject listings and flagged; a reason for exclusion will detailed in a footnote. Any 
flags should be included in the study specific SDTM and ADaM data sets. The Phoenix WinNonlin 
NCA Core Output will be provided in a separate listing.
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
65/66
16.4
Patient Reported Outcome
Not applicable for Phase Ib. 
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Peposertib (M3814)
      Phase Ib/II study of M3814 in combination
    with capecitabine and radiotherapy in rectal cancer
MS100036-0020 
       Version 3.0
C O N F I D E N T I A L
I N F O R M A T I O N
66/66
17
References
Brookmeyer R and Crowley J. A confidence interval for the median survival time. Biometrics
1982;38:29-41.
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26:404-13.
Kalbfleisch JD and Prentice RL. The statistical analysis of failure time data, New York: John 
Wiley & Sons 1980.
Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological 
complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient 
data. Lancet Oncol 2010;11:835-44.
Mosteller RD. Simplified calculation of body-surface area. N Eng J Med 1987;317:1098.
18
Appendices
18.1
SMC SAP
Refer to : ctp-ms100036-0020-smc-iap-v1-26apr2019
18.2
Clavien-Dindo classification
Refer to : Peposertib-Clavien_Dindo-Terms-v23_1.xlsx
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