A Phase 1/2 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: Sierra Oncology LLC - a GSK company

Sierra Oncology, Inc. 
Clinical Study Protocol No. SRA737-02 
SRA737 
Page 1 of 157 
SRA737-02 Protocol Amendment Final Version 7.0 (03-Aug-2018) 
CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
 
A Phase 1/2 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in 
Combination with Gemcitabine plus Cisplatin or Gemcitabine Alone 
in Subjects with Advanced Cancer 
 
 
Sponsor Protocol Number: 
SRA737-02 
EudraCT Number: 
2015-004467-36 
Chief Investigator: 
Dr. Udai Banerji 
Section of Medicine 
Institute of Cancer Research 
Drug Development Unit 
Royal Marsden Hospital 
Sycamore House 
Downs Road 
Sutton 
SM2 5PT, UK. 
 
Tel: 
020 8661 3984 
 
Email: 
udai.banerji@icr.ac.uk 
 
 
 
Sponsor: 
Sierra Oncology, Inc. 
46701 Commerce Center Drive 
Plymouth, MI 48170, USA. 
 
Tel: 
734-233-3966 
 
 
Confidentiality Statement: 
This document contains information that is confidential and 
proprietary to Sierra Oncology, Inc. (hereafter referred to as 
Sierra Oncology) and is provided for the purpose of 
conducting a clinical trial for Sierra Oncology.  The contents 
of this document may be disclosed only to study personnel, 
the institutional review board/ independent ethics committee, 
or duly authorized representatives of regulatory agencies for 
this purpose under the condition that they maintain 
confidentiality.  The contents of this document may not be 
used in any other clinical trial, disclosed to any other person 
or entity, or published without prior written permission from 
Sierra Oncology. 
Compliance Statement: 
This study will be conducted in accordance with 
Protocol SRA737-02, the International Conference on 
Harmonization (ICH), Guideline for Good Clinical Practice 
(GCP), and the applicable country and regional (local) 
regulatory requirements. 
 

Sierra Oncology, Inc. 
Clinical Study Protocol No. SRA737-02 
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CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
VERSION HISTORY 
 
Version No. 
Date of Issue 
Reason for Update 
1.0 
25-January-2016 
Initial version submitted for MHRA/REC approval 
2.0 
03-March-2016 
Addition of hearing impairment and history of allergy 
to cisplatin or gemcitabine exclusion criteria and 
amendments to contraceptive advice (made at the 
request of the MHRA prior to approval) 
 
 
Note:  Superseding version 2.0 was withdrawn prior 
to review in order to retain the current 
Investigational Medicinal Product name 
(CCT245737). 
Superseding 
3.0 
11-October-2016 
Sponsor change – All sponsor specific details have 
been updated to reflect the new sponsor Sierra 
Oncology, Inc. (formerly known as ProNAi 
Therapeutics, Inc.), including sponsor name, 
responsibilities, address, emergency contact details, 
and the protocol title and number.   
4.0 
05-December-2016 
Protocol Amendment Version 4.0 of the protocol 
includes changes to the name of the sponsor and 
investigational product.  In addition, the study is 
being amended to focus on assessment safety and 
preliminary efficacy in subjects with tumors 
anticipated to be sensitive to inhibition of Chk1 
mainly in the SRA737+gemcitabine combination.  
Procedures are being revised to ensure appropriate 
subject selection, in accordance with the new and 
retained study objectives.   
5.0 
17-February-2017 
Protocol Amendment Version 5.0 updates the 
frequency of bone scans.  In addition, clarifications 
have been provided for IMP dosing, tumor biopsies, 
and laboratory assessments. 
6.0 
05-October-2017 
Protocol Amendment Version 6.0 changes the 
indications in the Cohort Expansion Phase (adding 
small cell lung cancer, cervical/anogenital cancer, 
and soft tissue sarcoma, and removing pancreatic 
cancer) and increases the size of each cohort from 
6-8 to approximately 20 subjects. The genetic 
selection strategy is modified so that the sponsor 
may choose to refine or select particular genomic 
profile requirements in expansion cohorts based on 
observations of tumor response and clinical benefit 
in the ongoing study and/or other emerging clinical 
and nonclinical data. 
In addition, clarifications and corrections were 
made.  

Sierra Oncology, Inc. 
Clinical Study Protocol No. SRA737-02 
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SRA737-02 Protocol Amendment Final Version 7.0 (03-Aug-2018) 
CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
ES-6.1 
27-April-2018 
Protocol Version ES-6.1 is specific to Spain and 
contains the changes submitted in response to 
questions from the Agencia Española de 
Medicamentos y Productos Sanitarios (AEMPS) 
dated 23-March-2018.   
An Introduction was added to clarify the trial design, 
stage of participation, and the number of patients 
enrolled to date. 
Exclusion criterion 2 was revised to clarify that prior 
gemcitabine therapy is permitted. 
Section 2.3.1.1 Dose Justification for Stage 2 
Expansion Phase was added to provide justification 
from previous studies of the dose in the expansion 
phase. 
Sections 2.4.1.1 and 2.4.1.2 were added to provide 
safety summaries of the two ongoing clinical trials of 
SRA737. 
7.0 
03-Aug-2018 
This amendment superseded versions 6.0 and 
6.1-ES and includes the following changes: 
Removal of urothelial carcinoma cohort and 
replacement with a cohort of 20 subjects with 
platinum resistant or refractory high-grade serous 
ovarian cancer (HGSOC). 
The inclusion criterion describing predictors of 
sensitivity to Chk1 inhibition (#10) was updated to 
include eligibility according to factors including: 
genetic profiling of tumor tissue or ctDNA, HPV 
status, and germline BRCA1 and BRCA2 gene 
status.  
Washout periods for prior therapy were updated 
(exclusion #1). 
Guidance was included on treatment in the event of 
rash (Section 5.5.1.8). 
The requirement for triplet biopsies was amended 
such that biopsies will be taken when subjects have 
accessible tumor and consent to a biopsy in up to 
1 subject, if available, per dose level in Dose 
Escalation, and subjects with accessible tumor and 
who consent to a biopsy in Cohort Expansion. 
The Trial Status (Section 2) and Clinical Experience 
(Sections 2.4.1.1 and 2.4.1.2) were updated with 
more current information. 
The background section was updated to include 
background on ovarian cancer. 
Clarification of the term "first dose" was made to 
specify whether this applies to SRA737 or 
gemcitabine in each instance. 

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CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ......................................................................................................................... 4 
1 
PROTOCOL SYNOPSIS ......................................................................................................... 15 
2 
INTRODUCTION ...................................................................................................................... 25 
TRIAL STATUS ....................................................................................................... 25 
2.1 
Background .................................................................................................. 26 
2.1.1 
DNA Damage/Chk1 Biology .......................................................... 26 
2.1.2 
Identifying Correlates of Chk1 Sensitivity (Replication Stress) ....... 29 
2.1.3 
Exogenous sources of replication stress and gemcitabine synergy 30 
2.1.4 
Low-Dose Gemcitabine ................................................................. 32 
2.2 
Background on Cohort Expansion Indications .............................................. 33 
2.2.1 
Ovarian Cancer ............................................................................. 34 
2.2.2 
Small Cell Lung Cancer ................................................................. 36 
2.2.3 
Soft Tisue Sarcoma ....................................................................... 37 
2.2.4 
Cervical/Anogenital Cancer (Human Papilloma Virus related 
Cancers) ........................................................................................ 38 
2.3 
Investigational Medicinal Product: SRA737 .................................................. 40 
2.3.1 
Starting Dose Rationale: SRA737 .................................................. 40 
2.3.1.1 
Dose Justification for Stage 2 Expansion Phase .......... 40 
2.3.2 
Non-Clinical Pharmacology ........................................................... 41 
2.3.2.1 
Efficacy/Primary pharmacology .................................... 41 
2.3.3 
In Vitro ADMET and Nonclinical Pharmacokinetics ........................ 47 
2.3.3.1 
In Vitro Metabolism ...................................................... 48 
2.3.3.2 
In Vitro Safety and Developability Assessments ........... 48 
2.3.4 
In Vivo Pharmacokinetics .............................................................. 49 
2.3.5 
Safety Pharmacology .................................................................... 50 
2.3.5.1 
In Vitro Cardiac Safety Assessments ........................... 50 
2.3.5.2 
In Vivo Cardiac Safety Assessments ............................ 50 
2.3.5.3 
Cardiovascular Safety Summary .................................. 51 
2.3.6 
Toxicology ..................................................................................... 51 
2.3.6.1 
28-Day Mouse Study .................................................... 51 
2.3.6.2 
Three-Cycle Mouse Triple Combination Study ............. 52 
2.3.6.3 
28-Day Minipig Study ................................................... 53 

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EudraCT Number:  2015-004467-36 
2.3.6.4 
28-Day Monkey Study .................................................. 54 
2.3.6.5 
Toxicology Summary .................................................... 54 
2.4 
Clinical experience ....................................................................................... 55 
2.4.1 
SRA737-01 (Monotherapy) ............................................................ 56 
2.4.2 
SRA737-02 (In Combination with Gemcitabine and Cisplatin or 
Gemcitabine Alone) ....................................................................... 57 
2.5 
Rationale for the proposed trial: ................................................................... 58 
2.6 
BENEFIT/RISK ASSESSMENT ................................................................... 58 
3 
TRIAL DESIGN ........................................................................................................................ 60 
3.1 
Clinial Trial Objectives and Endpoints .......................................................... 60 
3.1.1 
Primary Objectives and Endpoints ................................................. 60 
3.1.2 
Secondary Objectives and Endpoints ............................................ 60 
3.1.3 
Exploratory Objectives and Endpoints ........................................... 61 
3.2 
Design of Clinical Trial ................................................................................. 61 
3.3 
Dose Escalation Scheme ............................................................................. 64 
3.3.1 
Cohort Review Process ................................................................. 65 
3.3.2 
Dose Escalation Decision Rules .................................................... 65 
3.4 
Definition of Dose-Limiting Toxicity .............................................................. 67 
3.5 
Definition of Maximum Tolerated Dose and Recommened Phase 2 Dose ... 68 
3.6 
Cohort Expansion Scheme .......................................................................... 68 
3.7 
Intra-Subject Dose Escalation for Stage 2 .................................................... 69 
3.8 
Subject Evaluability ...................................................................................... 69 
3.8.1 
DLT Evaluable ............................................................................... 69 
3.8.2 
Replacement of Subjects ............................................................... 70 
4 
SUBJECT SELECTION AND ENROLLMENT ........................................................................ 70 
4.1 
Number of Subjects ..................................................................................... 70 
4.2 
Subject Selection Criteria ............................................................................. 70 
4.2.1 
Inclusion criteria ............................................................................ 70 
4.2.2 
Exclusion criteria ........................................................................... 73 
5 
DOSAGE AND TREATMENT ADMINISTRATION ................................................................. 75 
5.1 
Treatment Schedule ..................................................................................... 75 
5.2 
Dose Levels ................................................................................................. 77 
5.3 
Duration of Study Treatment ........................................................................ 78 
5.3.1 
SRA737 ......................................................................................... 78 
5.3.2 
Gemcitabine and Cisplatin ............................................................. 78 

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5.4 
Dose modifications ....................................................................................... 79 
5.4.1 
Dose Reductions of SRA737 ......................................................... 79 
5.4.2 
Dose modifications for gemcitabine and cisplatin........................... 79 
5.4.3 
Treatment Modifications on Day 1 ................................................. 80 
5.4.4 
Treatment Modifications on Day 8 (and Day 15 in Stage 2) ........... 81 
5.4.5 
Treatment Modifications due to Nonhematologic Adverse Events . 82 
5.4.5.1 
Renal Impairment ......................................................... 83 
5.4.5.2 
Neurotoxicity ................................................................ 84 
5.4.5.3 
Other Nonhematologic Toxicities .................................. 84 
5.5 
Supportive Care, Concomitant Medications, and Study Restrictions ............ 84 
5.5.1 
Optional and Allowed Concomitant Medications ............................ 84 
5.5.1.1 
Granulocyte-colony Stimulating Factor ......................... 84 
5.5.1.2 
Palliative Radiotherapy ................................................. 84 
5.5.1.3 
Acid-reducing Agents ................................................... 85 
5.5.1.4 
Contraception Usage.................................................... 85 
5.5.1.5 
QT Prolonging Drugs.................................................... 85 
5.5.1.6 
Drugs Metabolized by Cytochrome P450 (CYP) 
Isoforms ....................................................................... 85 
5.5.1.7 
Sun Protection.............................................................. 85 
5.5.1.8 
Treatment for Rash ...................................................... 86 
5.5.2 
Excluded Concomitant Medications ............................................... 86 
5.6 
Discontinuation from Treatment ................................................................... 86 
5.7 
Discontinuation from Study .......................................................................... 87 
6 
PHARMACEUTICAL INFORMATION ..................................................................................... 88 
6.1 
SRA737 ....................................................................................................... 88 
6.1.1 
Storage Conditions for SRA737 ..................................................... 88 
6.1.2 
Dispensing .................................................................................... 88 
6.1.3 
SRA737 Administration ................................................................. 89 
6.2 
SRA737 Accountability ................................................................................ 89 
6.3 
Gemcitabine and Cisplatin ........................................................................... 89 
6.3.1 
Gemcitabine Reconstitution, Stability and Adminstration ............... 90 
6.3.2 
Cisplatin Reconstitution, Stability and Adminstration ..................... 90 
6.4 
Gemcitabine and cisplatin accountability ...................................................... 90 
7 
INVESTIGATIONS SCHEDULE .............................................................................................. 90 
7.1 
Pre-Treatment Enrollment Evaluations ......................................................... 90 

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EudraCT Number:  2015-004467-36 
7.1.1 
Screening Evaluations: within 28 days prior to administration of 
SRA737 (first dose of SRA737 for PK between Day -7 and Day -4)91 
7.1.2 
Screening Evaluations: within 7 days prior to administration of 
SRA737 (the first dose of SRA737 for PK between Day -7 and 
Day -4) .......................................................................................... 93 
7.2 
Evaluations During the Trial ......................................................................... 93 
7.2.1 
First Dose of SRA737 for PK (Day -7 to Day -4) ............................ 93 
7.2.2 
Standard Evaluations for each Cycle ............................................. 95 
7.3 
Safety Follow-up visit ................................................................................... 97 
7.4 
Long Term Follow-Up .................................................................................. 98 
7.5 
Missed Evaluations ...................................................................................... 98 
7.6 
Schedule of Events ...................................................................................... 99 
7.7 
Stage 2 Schedule of Secondary and Exploratory Assessments ................. 105 
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................... 106 
8.1 
SRA737 Pharmacokinetics ........................................................................ 106 
8.2 
Genetic Alterations in Tumor Tissue OR circulating Tumor DNA ................ 107 
8.3 
Triplet Biopsies .......................................................................................... 107 
8.4 
PBMCs for Exploratory Biomarkers Analyses ............................................ 108 
8.5 
Comet Assay ............................................................................................. 108 
9 
ASSESSMENT OF EFFICACY ............................................................................................. 108 
9.1 
Measurement of disease ............................................................................ 108 
9.2 
Timing and Type of Tumour Assessments ................................................. 108 
9.2.1 
Baseline Evaluations ................................................................... 109 
9.2.2 
Evaluations During Study ............................................................ 109 
9.3 
Tumour Response ..................................................................................... 110 
9.3.1 
Recording of Response in the eCRF ........................................... 110 
9.3.2 
other Definitions of Outcome ....................................................... 110 
10 
ASSESSMENT OF SAFETY ................................................................................................. 110 
10.1 
Adverse Event Definitions .......................................................................... 110 
10.1.1 
Adverse Event ............................................................................. 110 
10.1.2 
Serious adverse events ............................................................... 111 
10.1.3 
Suspected, unexpected, serious adverse reactions ..................... 112 
10.1.4 
Determining adverse event causality ........................................... 113 
10.1.5 
Expectedness .............................................................................. 114 
10.2 
Evaluating and Recording Adverse Events ................................................ 114 
10.2.1 
Screening failures ........................................................................ 114 

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10.2.2 
Documentation of Adverse Events ............................................... 114 
10.2.3 
Monitoring and Follow-up of AEs and SAEs ................................ 114 
10.3 
Immediate Adverse Event Reporting .......................................................... 115 
10.3.1 
Events exempt from being reported as SAEs to the 
Pharmacovigilance Department ................................................... 116 
10.4 
Recording of Adverse Events and Serious Adverse Events in eCRFs ........ 116 
10.5 
Urgent Safety Measures ............................................................................ 117 
10.6 
Pregnancy Reporting ................................................................................. 117 
11 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................... 118 
11.1 
Analysis Populations .................................................................................. 119 
11.1.1 
Safety Evaluable Population ........................................................ 119 
11.1.2 
Response Evaluable Population .................................................. 119 
11.1.3 
Pharmacokinetic Evaluable Population ........................................ 119 
11.1.4 
Pharmacodynamic Evaluable Population ..................................... 120 
11.2 
Statistical Analysis ..................................................................................... 120 
11.2.1 
Presentation of Data .................................................................... 120 
11.2.2 
Safety .......................................................................................... 120 
11.2.3 
Efficacy Analyses ........................................................................ 120 
11.2.4 
Pharmacokinetics ........................................................................ 122 
11.2.5 
Pharmacodynamics ..................................................................... 123 
11.2.5.1 
Tumor Profiling ........................................................... 123 
11.2.5.2 
Triplet Tumor Biopsies ............................................... 123 
11.2.5.3 
PBMCs ....................................................................... 123 
11.2.5.4 
Comet Assay .............................................................. 123 
11.2.5.5 
Additional PDn Assays ............................................... 124 
11.3 
Sample Size ............................................................................................... 124 
12 
ADMINISTRATION ................................................................................................................ 124 
12.1 
Protocol deviations and amendments ........................................................ 124 
12.2 
Serious breach of GCP .............................................................................. 125 
12.3 
Obtaining written informed consent ............................................................ 125 
12.4 
Completion of the electronic case report form ............................................ 126 
12.5 
End of Study .............................................................................................. 127 
12.6 
Trial performance, monitoring, auditing and inspection .............................. 128 
12.7 
Source document verification ..................................................................... 128 
12.8 
Record retention ........................................................................................ 129 

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12.9 
Ethical considerations ................................................................................ 129 
12.10 Publication Policy and Press Releases ...................................................... 130 
13 
REFERENCES ....................................................................................................................... 131 
14 
APPENDICES ........................................................................................................................ 136 
APPENDIX 2:  ASSESSMENT OF DISEASE RESPONSE ............................................................... 137 
APPENDIX 3.  NEW YORK HEART ASSOCIATION (NYHA) SCALE ............................................. 150 
APPENDIX 4.  CONTRACEPTIVE GUIDANCE FOR WOMEN OF CHILDBEARING POTENTIAL 
(WOCBP) AND MALE PARTNER OF WOCBP ................................................................... 151 
APPENDIX 5.  QT PROLONGING DRUGS AND DRUGS METABOLIZED BY CYP1A2 ................ 153 
APPENDIX 6.  GENETIC PREDICTORS OF SRA737 SENSITIVITY ............................................... 157 
 
List of Tables 
Table 1.  Potentiation of DNA-damaging agents in cancer cells by SRA737 ....................... 42 
Table 2.  Non-Clinical Pharmacokinetics of SRA737 ........................................................... 49 
Table 3.  Dose Escalation Decision Making ........................................................................ 66 
Table 4.  Treatment Schedules ........................................................................................... 75 
Table 5.  Gemcitabine/Cisplatin and Gemcitabine Alone Dose Modifications for 
Hematologic Toxicity .......................................................................................... 81 
Table 6.  Recommendations for Modifying Study Drug on Day 8 in Stage 1 and Day 15 in 
Stage 2 for Hematologic Toxicity ....................................................................... 82 
Table 7.  Dose Modifications for Toxicities of Stomatitis or Diarrhea ................................... 83 
Table 8. Schedule of Events for Stage 1 ........................................................................... 100 
Table 9. Schedule of Events for Stage 2 (Dose Escalation and Cohort Expansion) .......... 102 
Table 10. Schedule for Stage 2 Secondary and Exploratory Assessments ....................... 105 
 
List of Figures 
Figure 1.  Schematic of key roles of Chk1 in the DNA damage response ............................ 28 
Figure 2. SRA737 potentiates the efficacy of low-dose gemcitabine in HT29 and SJSA-1 
xenografts in mice in a dose dependent manner. ............................................... 32 
Figure 3.  SRA737 (formerly CCT245737) potentiates the efficacy of gemcitabine in HT29 
xenografts in mice in a dose dependent manner ................................................ 44 
Figure 4.  SRA737 (formerly CCT245737) potentiates the efficacy of a single cycle of the 
combination of gemcitabine and carboplatin in Calu6 NSCLC xenografts .......... 45 
Figure 5.  SRA737 plus gemcitabine inhibits tumor growth and extends survival in a 
gemcitabine-insensitive patient-derived xenograft model of bladder cancer. ...... 46 
Figure 6.  Effect of SRA737 (formerly CCT245737; 12.5 to 100 mg/kg PO) on 
gemcitabine-induced Chk1 S296 autophosphorylation in HT29 human tumor 
xenografts in mice (ICR EXP 1569) ................................................................... 47 
Figure 7.  Original Study Design Schema (Protocol v1.0-4.0) .............................................. 62 

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EudraCT Number:  2015-004467-36 
Figure 8.  Amendment v5.0 Study Design Schema ............................................................. 63 
Figure 9. Amendment v6.0 Study Design Schema .............................................................. 63 
Figure 10.  Stage 1 Treatment Schedule (SRA737/Gemcitabine/Cisplatin) ......................... 76 
Figure 11.  Stage 2 Treatment Schedule (SRA737/Gemcitabine) ....................................... 77 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
A 
ADMET 
adsorption, distribution, metabolism, excretion, and toxicity 
 
AE 
adverse event 
 
AUC 
area under the curve 
 
AUC0-t 
area under the curve from time zero to last measured concentration 
 
AUCinf 
area under the curve from time zero to infinity 
 
AUCtau 
area under the curve from time zero to tau (tau = dosing interval) 
B 
BP 
blood pressure 
 
BSA 
body surface area 
C 
95% CI 
95% confidence interval 
 
C1D1 
Cycle 1 Day 1 
 
CBC 
Complete blood count (full blood count) 
 
Chk1 or 2 
Checkpoint kinase 1 or 2 
 
CI 
Chief Investigator  
 
Cmax 
maximum observed plasma concentration 
 
Cmin 
minimum observed plasma concentration 
 
CR 
complete response 
 
CRA 
Clinical Research Associate 
 
CRUK 
Cancer Research UK (previous sponsor of this trial with investigational 
medicinal product CCT245737 now known as SRA737) 
 
CT 
computerized tomography 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
ctDNA 
circulating tumor deoxyribonucleic acid 
 
CYP 
Cytochrome P450 
D 
Day 
calendar day 
 
DCR 
disease control rate 
 
DDR 
DNA damage response 
 
DLT 
dose-limiting toxicity 
 
DNA 
deoxyribonucleic acid 
 
DOR 
duration of response 
E 
EC 
Ethics Committee 
 
EC50 
half maximal efficacious concentration 
 
ECG 
Electrocardiogram 
 
ECHO 
Echocardiogram 
 
eCRF 
electronic case report form 
 
EDC 
electronic data capture 
 
ESMO 
European Society for Medical Oncology 
F 
FDG  
Fluorodeoxyglucose 
 
FIH 
First-in-human 
 
FOLFIRINOX 
leucovorin, fluorouracil, irinotecan, oxaliplatin 
G 
G or G-alone 
gemcitabine alone 
 
GC 
gemcitabine + cisplatin 
 
GCP 
Good Clinical Practice 
 
GI 
Gastrointestinal 
 
GLP 
Good Laboratory Practice 
H 
h  
Hour 
 
HGSOC 
High-grade serous ovarian cancer 
 
HPV 
human papilloma virus 
I 
IC50 
half maximal inhibitory concentration 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
 
ICD 
informed consent document 
 
ICH 
International Conference on Harmonisation  
 
ICR 
Institute for Cancer Research 
 
IMP 
investigational medicinal product 
 
IRB 
Institutional Review Board 
 
ITF 
Investigator Trial File 
 
IV 
Intravenously 
L 
LTFU 
Long term follow-up 
M 
MEC 
minimum effective concentration 
 
min 
minute(s) 
 
MHRA 
Medicines and Healthcare products Regulations Agency  
 
MRI 
magnetic resonance imaging 
 
MTD 
maximum tolerated dose 
 
MVAC 
methotrexate, vinblastine, doxorubicin, cisplatin 
N 
NCCN 
National Comprehensive Cancer Network 
 
NCI 
National Cancer Institute 
 
NE 
not evaluable 
 
NGS 
next generation sequencing 
 
NOAEL 
No observed adverse effect level 
 
NSCLC 
Non-small cell lung cancer 
 
NYHA 
New York Heart Association 
O 
OD 
oncogenic driver 
 
ORR 
overall response rate 
 
OS 
overall survival 
P 
PARP 
poly ADP ribose polymerase  
 
PBMC 
peripheral blood mononuclear cell 
 
PD 
progressive disease or disease progression 
 
PDn 
pharmacodynamics 
 
PET 
positron emission tomography 
 
PFS 
progression-free survival 
 
PI 
Principal Investigator 
 
PK 
pharmacokinetics 
 
PO 
oral (orally) 
 
PPI 
proton pump inhibitors 
 
PR 
partial response 
Q 
QT, QTc 
QT interval, corrected QT interval 
 
QTcF 
QTc interval corrected for heart rate using Fridericia’s formula 
R 
RBC 
Red blood cell 
 
REC 
Research Ethics Committee 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
 
RNAi 
ribonucleic acid interface 
 
RP2D 
recommended Phase II dose 
 
RS 
replication stress 
S 
SAE 
serious adverse event 
 
SCLC 
small cell lung cancer 
 
SD 
stable disease 
 
SFU 
Safety follow-up 
 
Sierra Oncology 
Sierra Oncology, Inc.  
 
SmPC 
Summary of Product Characteristics 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
 
SRA737 (investigational 
medicinal product) 
Previously known as CCT245737 
 
STS 
soft tissue sarcoma 
T 
t1/2 
terminal elimination half-life 
 
 
 
 
TEAE 
treatment-emergent adverse event 
 
TK 
toxicokinetics 
 
TS 
tumor suppressor 
 
Tmax 
time to reach Cmax 
 
TTP 
Time to progression 
 
TTR 
Time to response 
U 
ULN 
upper limit of normal 
 
USM 
urgent safety measure 
W 
WBC 
white blood cell 
 
WHO 
World Health Organisation 
 
WOCBP 
women of child bearing potential 

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PROTOCOL ACCEPTANCE PAGE 
Title: 
A Phase 1/2 trial of oral SRA737 (a Chk1 inhibitor) given in combination with 
gemcitabine plus cisplatin or gemcitabine alone in subjects with advanced 
cancer 
Protocol Number 
SRA737-02 
Version (Date) 
7.0 (03-Aug-2018) 
 
 
Investigator Signature: 
I have reviewed the protocol and agree to conduct the study as outlined herein and in compliance with 
Good Clinical Practices and all applicable regulatory requirements.  I understand that neither I nor any 
member of my staff may modify this protocol without obtaining written concurrence of Sierra Oncology, 
Inc. (Sierra Oncology), and that Sierra Oncology and the institutional review board/independent ethics 
committee must approve any substantive changes to the protocol in writing before implementation. 
I agree not to divulge to anyone, either during or after termination of the study, any confidential 
information acquired regarding the investigational product and Sierra Oncology processes or methods.  
All data pertaining to this study will be provided to Sierra Oncology.  I understand that any presentation 
or publication of study data must be reviewed by Sierra Oncology, before release, as specified in the 
protocol. 
I certify that neither I nor any member of my staff have been disqualified or debarred by the US Food 
and Drug Administration or any European regulatory body for clinical investigations or any other 
purpose. 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 

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1 
PROTOCOL SYNOPSIS 
Name of 
sponsor/company: 
Sierra Oncology, Inc. 
Name of product: 
SRA737 
Full title of study and 
protocol number and 
phase: 
SRA737-02:  A Phase 1/2 trial of oral SRA737 (a Chk1 inhibitor) given in 
combination with gemcitabine plus cisplatin or gemcitabine alone in 
subjects with advanced cancer. 
Short Title of Study: 
SRA737-02:  A Phase 1/2 trial of SRA737 in combination with 
gemcitabine plus cisplatin or gemcitabine alone in subjects with 
advanced cancer. 
Study objective(s): 
Primary Objectives:   
• 
To establish the safety profile of SRA737 administered in 
combination with gemcitabine ± cisplatin  
• 
To determine the maximum tolerated dose (MTD) of SRA737 
administered in combination with gemcitabine 
• 
To define a recommended Phase 2 dose (RP2D) of SRA737 in 
combination with gemcitabine 
Secondary Objectives:   
• 
To characterize the pharmacokinetic (PK) profile of SRA737 
administered in combination with gemcitabine ± cisplatin 
• 
To assess clinical activity of SRA737 in combination with 
gemcitabine.  Activity of SRA737 in combination with gemcitabine + 
cisplatin will also be explored as feasible based on the number of 
subjects enrolled. 
Exploratory Objectives:   
• 
To assess the relationship between tumor response and the 
presence of selected genetic alterations as detected in tumor tissue 
or circulating tumor deoxyribonucleic acid (ctDNA) 
• 
To explore possible clinical predictors of outcomes 
• 
To investigate the pharmacodynamics (PDn) of SRA737 in 
combination with gemcitabine in tumor tissue  
• 
To investigate the PDn of SRA737 in combination with gemcitabine 
in surrogate tissues such as blood or peripheral blood mononuclear 
cell (PBMCs)  
Study design: 
This is a multicenter, first-in-human, Phase 1/2, open-label, dose 
escalation trial, in subjects with advanced solid tumors. 
The trial will consist of 2 stages: 
• 
Stage 1:  A SRA737 and gemcitabine + cisplatin Dose Escalation 
Phase.  Upon implementation of Protocol Amendment Version 5.0 
(hereafter referred to as Amendment v5.0), further dose-escalation in 
this stage was halted and Stage 2 began.  Ten subjects with solid 
tumors were enrolled in the SRA737 + gemcitabine + cisplatin Dose 
Escalation Phase (Stage 1) of the study.   
• 
Stage 2:  A SRA737 and gemcitabine Dose Escalation Phase to 
establish the MTD, and a Cohort Expansion Phase  
In the Stage 2 Dose Escalation Phase, approximately 30 to 40 
subjects with solid tumors in cohorts of 3 to 6 subjects will receive 
escalating doses of SRA737 in combination with varying doses of 
gemcitabine in 28-day cycles to establish the MTD.  Upon reaching 

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the MTD for SRA737, or earlier (eg, when minimum efficacious dose 
range has been achieved or evidence of anti-tumor activity 
observed), gemcitabine may be escalated to a maximum dose of 
600 mg/m2 (with corresponding decreases in the SRA737 dose, as 
necessary for safety). 
In the Cohort Expansion Phase, approximately 20 prospectively-
selected genetically-defined subjects will be enrolled in each of 4 
indication-specific cohorts: high-grade serous ovarian cancer 
(HGSOC), small cell lung cancer (SCLC), soft tissue sarcoma (STS), 
and cervical/anogenital cancer. These subjects will be treated at the 
MTD or at a lower dose as selected by the sponsor.   
Subjects may continue treatment as long as none of the treatment 
discontinuation criteria are met (see Section 5.6).   
Subjects who are not evaluable for dose-limiting toxicity (DLT) 
assessments may be replaced.   
Number of 
investigational sites: 
This is a multicenter study.   
Planned number of 
subjects: 
It is estimated that approximately 140 subjects will be required to 
complete this trial.  The final number of subjects enrolled in this trial will 
depend on the number of dose levels explored. 
Sample size 
justification: 
The sample size for this study is based on assumptions of allometric 
scaling and the estimated number of dose levels required to establish the 
MTD and the optimal number of subjects needed to further evaluate the 
safety profile of the MTD/RP2D and schedule in this Phase 1/2 study. 
For the Cohort Expansion Phase, the sample size of 20 subjects enrolled 
in each indication-specific expansion cohort was chosen such that 0 of 
20 responses observed excludes an objective response rate (ORR) 
of 16% in the 95% confidence interval (CI).    
Study population: 
Dose Escalation Phase:  Subjects with advanced solid tumors. 
Cohort Expansion Phase:  Prospectively-selected genetically-defined 
subjects with HGSOC, SCLC, STS, or cervical/anogenital cancer. 
Test product, dose, and 
mode of administration: 
SRA737 is a highly potent and selective orally administered checkpoint 
kinase 1 (Chk1) inhibitor.  In this first-in-human trial, the starting dose of 
SRA737 in Stage 1 was 20 mg/day on Day 2, 3, 9 & 10 of each 21-day 
cycle.  The starting dose of SRA737 for Cohort 1 of Stage 2 Dose 
Escalation Phase was 40 mg/day.  
Treatment regimen(s): 
All subjects will receive a single dose of SRA737 between Day -7 and 
Day -4 for the purposes of PK evaluation.  The sponsor reserves the 

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option to remove this requirement once sufficient intensive single-dose 
PK data has been obtained, if applicable.  
Stage 1: 
• 
Gemcitabine:  Administered intravenously (IV) over 30 minutes on 
Days 1 and 8 of each 21-day cycle. The starting dose of gemcitabine 
for Cohort 1 was 1250 mg/m2.   
• 
Cisplatin:  Administered IV over 2 hours following gemcitabine on 
Day 1 of each cycle with pre- and post-infusion hydration.  The 
starting dose of cisplatin for Cohort 1 was 80 mg/m2. 
• 
SRA737:  Taken PO daily on Days 2, 3, 9 and 10 of each 21-day 
cycle. The starting dose for Cohort 1 was 20 mg. 
Stage 2: 
• 
Gemcitabine: Administered IV over 30 minutes on Days 1, 8, and 15 
of each 28-day cycle. The starting dose and schedule for the first 
cohort 1 of Stage 2 was 300 mg/m2. The dose and schedule may be 
adjusted based on accumulating data. 
• 
SRA737:  Taken PO daily on Days 2, 3, 9, 10, 16, and 17 of each 
28-day cycle. The starting dose of SRA737 for the first cohort of 
Stage 2 was 40 mg. The dose and schedule may be adjusted based 
on accumulating data. 
Inclusion criteria: 
Dose Escalation and Cohort Expansion: 
1. Written (signed and dated) informed consent and be capable of 
co-operating with treatment and follow up. 
2. In the Dose Escalation Phase, subjects with a locally advanced 
or metastatic, histologically or cytologically proven solid tumor, 
relapsed after or progressing despite conventional treatment for 
which no conventional therapy is considered appropriate by the 
investigator or is declined by the subject.   
3. Life expectancy of at least 12 weeks. 
4. World Health Organization (WHO) performance status of 0-1 
(Appendix 1). 
5. Hematological and biochemical indices within the ranges shown 
below measured within 1 week prior to the subject receiving their 
first dose of SRA737 (or gemcitabine if the SRA737 dose for PK 
is omitted). 
Laboratory Test 
Value Required 
Hemoglobin 
≥ 90 g/L 
Absolute neutrophil count 
≥ 1.5 × 109/L 
Platelet count 
≥ 100 × 109/L 
Bilirubin 
≤ 1.5 × upper limit of normal 
(ULN) unless due to Gilbert’s 
syndrome in which case up to 
3 × ULN is permissible 
Alanine aminotransferase and 
aspartate aminotransferase 
and Alkaline Phosphatase  
≤ 2.5 × ULN unless raised due 
to tumor in which case up to 
5 × ULN is permissible 
Serum Creatinine 
≤ 1.5 × ULN 

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Electrolytes: magnesium, 
potassium and calcium 
If electrolyte levels are low, it 
must be demonstrated that 
they can be normalized and 
maintained using supplements 
prior to the subject beginning 
study treatment. Supplement 
use should continue while on 
study as appropriate. 
 
6. Subjects who are 18 years or older at the time consent is given. 
7. Subjects must have archival tumor tissue available for tumor 
profiling OR accessible tumor and willingness to consent to a 
biopsy for the collection of tumor tissue.  Refer to Section 7.1.1 
for more information. 
 
Cohort Expansion: 
8. Subjects in the indication-specific cohort expansion must have 
histologically or cytologically proven advanced malignancy of the 
types specified in Inclusion Criterion 11, for which no 
conventional therapy is considered appropriate by the 
investigator or is declined by the subject. 
9. Have measurable disease according to Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) criteria. 
10. Subjects must have predicted sensitivity to Chk1 inhibition based 
on factors including: genetic profiling of tumor tissue or ctDNA, 
HPV status, and germline BRCA1 and BRCA2 gene status. All 
subjects will have genetic profiling from tumor tissue or ctDNA; 
profiling will be performed prospectively if required to evaluate 
Chk1 sensitivity or otherwise performed retrospectively. 
a. For subjects with HGSOC, documented somatic or germline 
BRCA1 and BRCA2 wild-type status will confer eligibility 
without requirement for prospective genetic profiling. If 
documented BRCA status is not available, genetic profiling 
may be performed prospectively to determine eligibility. 
b. Subjects with SCLC are eligible without requirement for 
prospective genetic profiling on the basis of very high 
prevalence of cancer related alterations in the tumor 
suppressor genes (eg, TP53 and RB1) in this population. 
c. For subjects with STS, and any others for whom genetic 
profiling is performed prospectively, eligibility will be 
determined by the sponsor’s review of genetic abnormalities 
detected in genes in the following categories, as detailed in 
Appendix 6: 
− 
Key tumor suppressor genes regulating G1 cell cycle 
progression/arrest such as RB1, TP53, etc. For relevant 
cancers, positive human papilloma virus (HPV) status is 
also considered for eligibility. 
− 
The DNA damage response pathway including ATM, 
BRCA1, BRCA2, mismatch repair genetic alterations 
and/or high microsatellite instability. 

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− 
Genetic indicators of replicative stress such as gain of 
function/amplification of Chk1 or ATR or other related 
gene. 
− 
Oncogenic drivers such as MYC, CCNE1, etc. 
d. For subjects with anogenital cancer, known HPV positive 
status will confer eligibility without requirement for 
prospective genetic profiling. If HPV status is not known or 
not positive, genetic profiling (or HPV testing where 
appropriate) may be performed prospectively to determine 
eligibility. Subjects with cervical cancer or squamous cell 
carcinoma of the anus are eligible without requirement for 
prospective genetic profiling based on the very high 
prevalence of HPV positivity in these populations. 
 
11. Subjects must meet one of the following criteria: 
a. HGSOC, defined by the following: 
i. 
Histologically confirmed high-grade serous ovarian, 
fallopian tube, or primary peritoneal cancer. 
ii. 
Platinum-resistant or refractory disease (defined as in 
Section 2.2.1), or if the subject is intolerant to platinum 
therapy.   
b. Small Cell Lung Cancer 
i. 
Must have received at least 1 but no more than 3 prior 
regimens for advanced disease, unless otherwise 
approved by sponsor 
c. Soft Tissue Sarcoma 
i. 
Including undifferentiated pleiomorphic sarcoma / 
malignant fibrous histiocytoma (MFH) (including high-
grade spindle cell sarcoma / pleomorphic 
liposarcomas), leiomyosarcoma, and dedifferentiated 
liposarcomas. Other types of STS may be eligible with 
sponsor’s approval.  
ii. 
Must have received at least 1 but no more than 3 prior 
regimens for advanced disease, unless otherwise 
approved by sponsor 
d. Cervical/Anogenital Cancer 
i. 
Including all cervical carcinoma and 
advanced/metastatic squamous cell carcinoma of the 
anus, penis, vagina, and vulva.  
iii. 
Must have received at least 1 but no more than 3 prior 
regimens for advanced disease, unless otherwise 
approved by sponsor 
Exclusion criteria: 
1. Have received prior or current anticancer therapy within the 
noted time periods prior to receiving SRA737 or have not 
recovered from toxicity consistent with exclusion criterion 5: 
a. Radiotherapy (except for symptom control and where the 
lesions will not be used as measurable disease), 
chemotherapy, therapy with poly ADP ribose polymerase 

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(PARP) inhibitors, other targeted therapies, or other 
IMPs within 2 weeks  
b. Nitrosoureas or Mitomycin C within 6 weeks 
c. Any prior treatment with a Chk1 inhibitor, or prior treatment 
with an ATR inhibitor within 6 months  
2. No more than 3 previous treatment regimens for advanced 
disease (not applicable to HGSOC expansion cohort), unless 
otherwise approved by sponsor.  Prior gemcitabine therapy is 
permitted as previous therapy. 
3. Other malignancies within the past 2 years with the exception of 
adequately treated tumors that are associated with an expected 
5-year disease-free survival of ≥ 95%. 
4. If, in the opinion of the investigator, the subject is highly likely to 
experience clinically significant myelosuppression, based on 
previous experience with chemotherapy. 
5. Ongoing toxic manifestations of previous treatments greater than 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Grade 1.  Exceptions to this are 
alopecia or certain toxicities, which in the opinion of the 
investigator and the sponsor’s Medical Monitor should not 
exclude the subject. 
6. History of allergy to gemcitabine. 
7. New or progressing brain metastases.  Subjects with brain 
metastases that have been asymptomatic and radiologically 
stable over an 8-week period and have not been treated with 
steroids during that time may be included with approval from the 
sponsor.     
8. Women of childbearing potential (WOCBP) or women who are 
already pregnant or lactating.  However, those subjects who 
have a negative serum or urine pregnancy test before enrollment 
and agree to use 2 forms of contraception as per Appendix 4 or 
agree to sexual abstinence, effective from the first administration 
of SRA737, throughout the trial and for 6 months afterwards are 
considered eligible.  
9. Male subjects with partners of child bearing potential, unless 
they agree to take measures not to father children by using a 
barrier method of contraception defined per Appendix 4, effective 
from the first administration of SRA737 through the trial and for 
6 months after their final SRA737 dose.  Men with pregnant or 
lactating partners must be advised to use barrier method 
contraception (eg, condom plus spermicidal gel) to prevent 
exposure of the fetus or neonate. 
10. Major surgery from which the subject has not yet recovered. 
11. At high medical risk because of nonmalignant systemic disease 
including active uncontrolled infection. 
12. Known to be serologically positive for hepatitis B, hepatitis C or 
human immunodeficiency virus. 
13. Serious cardiac condition, such as concurrent congestive heart 
failure, prior history of class III/ IV cardiac disease (New York 
Heart Association [NYHA] - refer to Appendix 3), left ventricular 
ejection fraction < 45% at baseline, history of cardiac ischemia 
within the past 6 months, or prior history of cardiac arrhythmia 
requiring treatment, unless approved by the sponsor. 

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14. Prior bone marrow transplant or have had extensive radiotherapy 
to greater than 25% of bone marrow within the previous 8 weeks. 
15. Peanut allergy unless this restriction is removed by the sponsor 
(refer to Section 6.1 for additional details).   
16. QTcF > 450 msec in adult males and > 470 msec in adult 
females. 
17. Impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of SRA737 (eg, ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome). 
18. Not able to swallow capsules without chewing or crushing. 
19. Is a participant or plans to participate in another interventional 
clinical trial, whilst taking part in this Phase 1/2 study of SRA737.  
Participation in an observational trial or interventional clinical trial 
which does not involve administration of an IMP and which would 
not place an unacceptable burden on the subject in the opinion 
of the investigator and sponsor would be acceptable. 
20. Any other condition which in the investigator’s opinion would not 
make the subject a good candidate for the clinical trial. 
Overview of 
assessments: 
As part of Pre-Screening the following will be performed: written informed 
consent; blood and available suitable archival or fresh tissue will be 
collected for tumor profiling for cohort expansion subjects, or confirmed 
as available for collection at baseline for dose escalation subjects. Up to 
28 days prior to the first scheduled dose, the following will be 
performed/obtained: demographic information, medical history, and 
concomitant medications will be recorded. Serious adverse events 
(SAEs) will be collected starting on the date of informed consent.  
Radiological assessment will be performed within 4 weeks from the first 
dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted) 
and repeated every 6 weeks in Stage 1. In Stage 2, assessments will be 
performed every 8 weeks and then in long-term follow-up every 16 
weeks. Assessments may be performed more frequently, when clinically 
indicated.  Cardiac assessments (echocardiogram [ECHO] and 
electrocardiogram [ECG]) will also be conducted. Optional triplet tumor 
biopsies may be collected within 28 days prior to receiving the first 
SRA737 dose. 
Within 7 days of the first dose of SRA737 (or gemcitabine if the SRA737 
dose for PK is omitted), the following assessments will be completed:  
complete physical examination, clinical disease assessment, SAE and 
concomitant medication, WHO performance status and local laboratory 
assessment of blood (for hematology, biochemistry, and pregnancy 
testing),   
At the single-dose PK run-in on Day -7 to Day -4 visit, concomitant 
medication, vital signs (including temperature, blood pressure, and 
pulse), height, weight, body surface area (BSA), and WHO performance 
status will be collected.  Blood samples will be obtained predose for 
hematology, biochemistry, pregnancy testing, troponin I or T, as well as 
for tumor markers and tumor profiling.  Adverse events (AEs) will be 
collected starting at the administration of SRA737.  Archival tissue will be 
submitted for tumor profiling. PK samples will be collected at up to 10 
time points over a 48-hour time period on Day - 7 to - 4 (first dose of 
SRA737 for PK).  The sponsor may reduce the requirement for PK 
sampling, including modification or elimination of the Day -7 to Day -4 

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visit once sufficient data to evaluate the single-dose PK of SRA737 have 
been collected and analyzed. 
Dosing will begin on Day 1 with the following procedures occurring at 
regular intervals.   
• 
Adverse event and concomitant medication:  On an ongoing basis 
• 
Symptom-directed physical exam (if medically indicated):  Day 1 of 
each cycle  
• 
Radiological disease assessment:  Every 6 weeks after Day 1 for 
Stage 1 and every 8 weeks after Day 1 for Stage 2 
• 
Clinical disease assessment:  Every 6 weeks after Day 1 for Stage 1 
and every 4 weeks after Day 1 for Stage 2 
• 
Tumor markers (serum or urine) (if applicable):  every 6 weeks from 
Cycle 1 Day 1 for Stage 1 and every 4 weeks from Cycle 1 Day 1 for 
Stage 2 
• 
WHO Performance Status and weight/BSA:  Day 1 of each cycle 
• 
Vital signs:  Days 1 and 8 for Stage 1 and Days 1, 8, and 15 for 
Stage 2 
• 
Local laboratory assessment of blood (for hematology, biochemistry, 
troponin I or T) and urine (urinalysis) – see Section 7.2.2 for detailed 
schedule  
• 
ECHO:  Cycle 2 Day 1 
• 
ECG:  Day 1 of Cycles 1 and 2, and then predose Day 1 at each 
third subsequent cycle, and Day 1 of any cycle with intra-subject 
dose escalation 
• 
Pharmacokinetics Samples for PK will be taken at the following 
timepoints in Cycle 1: pre-dose on Day 1, pre-dose on Day 10, up to 
6 time points post-dose on Day 10. For Stage 2 only, additional 
samples will be taken pre-dose on Day 8 and pre-dose on Day 15. 
Compliance review of subject diary card 
Subjects who discontinue treatment will complete the Safety Follow-up 
(SFU) visit 30 days (± 7 days) after the last dose.  Assessments required 
at the SFU visit include AEs and concomitant medication collection, 
symptom-directed physical exam, vital signs, weight, WHO performance 
status, ECG, ECHO, laboratory assessment of blood (for pregnancy 
testing, hematology, biochemistry, Troponin T or I, tumor markers if 
applicable]), urinalysis, radiological and clinical disease assessment (if 
applicable), and subject diary card review.   
Subjects without disease progression (PD) at the time of SRA737 
discontinuation will continue in Long-Term Follow-Up and undergo 
disease evaluations every 16 ± 2 weeks in Stage 2 (or 6 weeks for 
Stage 1) and have the following assessments:  radiological and clinical 
disease evaluation, SAEs determined as related to SRA737 by the 
investigator, first subsequent anticancer therapy, and tumor markers (if 
applicable) until disease progression or initiation of subsequent cancer 
therapy. Additional contact may be made as requested by the sponsor or 
the investigator to obtain disease and survival updates on an as needed 
basis until the subject discontinues from the study.   
Criteria for evaluation: 
 
Dose-Escalation: 
An enrolled subject will be evaluable for dose escalation review if within 
Cycle 1, the subject received at least 3 of the 4 (75%) planned doses in 
Stage 1 or 5 of the 6 (83%) planned doses in Stage 2 of SRA737 and all 

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doses of gemcitabine or the subject received less than these planned 
IMP doses due to drug-related toxicity (unless not applicable due to the 
sponsor having elected to evaluate an alternative schedule).   
Efficacy: 
All enrolled subjects who have measurable disease, receive at least 75% 
(Stage 1) or 83% (Stage 2) of SRA737 in 1 cycle (or the equivalent if the 
sponsor elects to evaluate an alternative dosing schedule), and have a 
baseline assessment of disease plus at least 1 postbaseline disease 
assessment will be evaluable for response.  All subjects who enroll into 
the Cohort Expansion Phase will be evaluable for response if they have 
measurable disease, receive at least 1 cycle of study medication as 
defined above, have a baseline assessment of disease plus at least 1 
postbaseline disease assessment and are confirmed as having met the 
genetic selection requirements. 
In addition, subjects who have measurable disease and received at least 
83% of SRA737 (if the sponsor elects to evaluate an alternative dosing 
schedule) in 1 cycle but developed PD, intolerable toxicity, or death prior 
to the postbaseline assessment will also be considered evaluable and 
will be classified as non-responders. 
Safety: 
All enrolled subjects who receive at least 1 dose of SRA737 will be 
evaluable for safety. 
Other: 
Pharmacokinetics: All enrolled subjects who receive at least 1 dose of 
SRA737 and provide at least 1 evaluable PK concentration will be 
evaluable for PK.   
Pharmacodynamics:  All enrolled subjects who receive at least 1 dose of 
SRA737 and have evaluable data for each specific PDn assessment will 
be evaluable for PDn. 
Statistical methods and 
analyses: 
Data will be presented in a descriptive fashion.  Variables will be 
analyzed to determine whether the criteria for the trial conduct are met.   
Baseline characteristics will be summarized for all enrolled subjects.   
Treatment administration will be described for all cycles.  Dose 
administration, dose modifications or delays and the duration of therapy 
will be described. 
The analysis of all efficacy endpoints will be based on the Response 
Evaluable Population and will be evaluated using RECIST v1.1 criteria.   
An estimate of the  ORR (defined as the proportion of subjects who 
achieved best response of complete response [CR] or partial response 
[PR]) and its 1-sided 95% exact binomial confidence interval (95% CI) for 
the recommended dose group(s) will be determined.  Additionally, the 
ORR and disease control rate along with the associated 2-sided 95% CI 
will be determined for each dose cohort (within each of the following 
variables: category of genomic alteration and number of categories of 
genomic alterations, schedule, expansion versus dose escalation 
subjects, Stage 1 or Stage 2). Additional subgroups of interest may also 
be identified, and the ORR will be estimated, as described in the 
Statistical Analysis Plan.  
Duration of response (DOR) is defined the interval from the first evidence 
of objective response (of PR or CR) to the earlier of the first 
documentation of PD or death from any cause.  Duration of response will 
be right-censored for subjects who at least achieve a PR based on the 
censoring conventions defined for progression-free survival (see Section 
11.2).  Analysis of DOR will be performed using the Kaplan-Meier 

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method.  Medians and other quartiles for DOR will be estimated in 
addition to the corresponding 2-sided 95% CI. 
Pharmacokinetic parameters will be determined using 
non-compartmental method(s).  Pharmacokinetic parameters such as 
AUCtau, Cmin, Cmax, Tmax, t½, will be estimated and reported, as 
appropriate.   
Pharmacodynamic parameters utilizing tumor and surrogate tissue to 
analyze biomarkers to identify possible predictors of clinical outcome will 
be further defined in the statistical analysis plan. 
 

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2 
INTRODUCTION 
TRIAL STATUS 
The study was designed with two stages (Stage 1 and Stage 2); each stage has a dose 
escalation phase and an expansion phase (refer to protocol Section 3.2). Stage 1 explored a 
combination of SRA737 + gemcitabine + cisplatin and Stage 1 was permanently discontinued at 
the dose escalation phase upon initiation of Protocol Amendment version 5.0 (hereafter referred 
to as Amendment v5.0) which allowed Stage 2 to supersede further exploration of the Stage 1 
triplet regimen.  Thus, Stage 1 was discontinued after 10 subjects across 3 gemcitabine dose 
levels (with constant SRA737 and cisplatin doses) had received the triplet combination in the 
dose escalation phase (refer to protocol Section 2.4.2 for a clinical summary). 
Stage 2 of the study explores the combination of SRA737 + gemcitabine.  The dose escalation 
phase of Stage 2 consists of cohorts of 3 to 6 subjects in a rolling 6 design (refer to protocol 
Section 3.3).  
As of 06 Jul 2018, 35 subjects have been treated in the UK in Stage 2 dose escalation with no 
dose-limiting toxicities (DLTs) reported with SRA737 dose levels shown below, each given in 
combination with low-dose gemcitabine (refer to protocol Section 2.4.2).  
SRA737-02 Stage 2 Dose Escalation (n=35 as of 06 Jul 2018) 
Cohort 
Dose Level  
SRA737 (mg) / gemcitabine (mg/m2) 
Number of 
Subjects 
Cumulative 
Number of 
Subjects 
1 
40 / 300 
5 
5 
2 
80 / 100 
4 
9 
3 
150 / 100 
4 
13 
4 
300 / 100 
4 
17 
5 
300 / 50 
3 
20 
6 
500/100 
4 
24 
7 
500/50 
4 
28 
8 
500/150 
4 
(enrollment 
ongoing) 
32 
9 
600/100 
3 
(enrollment 
ongoing) 
35 
 

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The 500 mg SRA737 + 100 mg/m2 gemcitabine and 500 mg SRA737 + 50 mg/m2 gemcitabine 
dose levels were completed in May 2018 without a DLT and the dose escalation proceeded to 
open a 600 mg SRA737 + 100 mg/m2 cohort and 500 mg SRA737 + 150 mg/m2 cohort (refer to 
protocol Section 2.4.2 for details).  Subsequent escalation cohorts may receive higher doses of 
SRA737 and/or gemcitabine, and alternative treatment schedules may also be explored if 
deemed appropriate (refer to protocol Section 3.3). 
Based on the preclinical efficacy studies and preliminary PK data, an efficacious concentration 
of SRA737 has been achieved and expansion cohorts will be initiated in parallel with the 
escalation cohorts at a dose level of 500 mg SRA737 + 100 mg/m2 gemcitabine (ie, the current 
highest dose level completed without DLT in the escalation phase) or a higher dose level based 
on emerging clinical data from the ongoing escalation phase (refer to Section 2.3.1.1).  Four 
expansion cohorts of approximately 20 subjects each are planned in high-grade serous ovarian 
cancer (HGSOC), small cell lung cancer (SCLC), soft tissue sarcoma (STS), and 
cervical/anogenital cancer.  These subjects may be enrolled at sites in countries including the 
UK and Spain.  Subjects entering the expansion phase will be treated at the highest dose level 
determined to be safe and tolerable in the concurrent escalation phase.  Any subject may, at the 
discretion of the investigator and with the agreement of the sponsor, be offered treatment at the 
higher dose of SRA737 and/or gemcitabine once that higher dose level has been shown to be 
safe and approved by the Cohort Review Committee.   
2.1 
BACKGROUND 
2.1.1 
DNA DAMAGE/CHK1 BIOLOGY 
The maintenance of genomic integrity is critical for cell survival and proliferation (Negrini 2010).  
Genomic integrity is compromised by deoxyribonucleic acid (DNA) damage arising from either 
intrinsic processes (such as oxidative stress or genomic instability) or exogenous sources such 
as environmental mutagens and chemotherapy.  Consequently, organisms have developed a 
myriad of intra- and inter-cellular mechanisms to address this genomic damage – collectively 
known as the DNA damage response (DDR).  Cells respond to DNA damage by activating a 
number of cell-cycle checkpoints as part of the DDR to facilitate cell cycle arrest, DNA repair or 
apoptosis (Kaufmann 2007, Meek 2009).  Genotoxic antitumor drugs causing DNA damage also 
cause activation of G1/S, S and G2/M cell-cycle checkpoints and the DDR.  This cancer cell 
response can potentially limit the efficacy of chemotherapeutic agents (Dai 2010, Garrett 2011, 
Zhou 2000). 

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The DDR to double strand breaks is predominately mediated through the PI3K-related kinase 
family member, ATM kinase, and that to single strand breaks, stalled replication forks and cross 
links mediated though ATR kinase (Weber 2015).  In general, activation of ATR leads to 
downstream phosphorylation and activation of checkpoint kinase-1 (Chk1).  One of the functions 
of Chk1 is to prevent cells harboring DNA damage from continuing through the cell-cycle, until 
DNA repair is completed (Weber 2015). 
Chk1 has been shown to activate the S and G2/M checkpoints by modulating the expression 
and function of CDC25 A and C, respectively, and as such acts as a critical effector of two out of 
three cell cycle checkpoints (Dai 2010, Xiao 2003, Sorensen 2012).  In addition, Chk1 has an 
additional important role in the S phase checkpoint where it stabilizes and preserves replication 
fork complexes following replication stress, preventing catastrophic replication fork collapse 
(Dai 2010, Feijoo 2001, Curtin 2012, Figure 1).  Chk1 is also involved in homologous 
recombination repair of DNA through activation of Rad51 (Sorensen 2005) and in regulation of 
mitosis through direct phosphorylation of Aurora B (Peddibhotla 2009).   

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Figure 1.  Schematic of key roles of Chk1 in the DNA damage response  
 
Source:  Curtin 2012. 
Preclinical studies using Chk1 ribonucleic acid interface (RNAi) and selective Chk1 inhibitors 
provide evidence that certain chemotherapeutic agents such as topoisomerase 1 inhibitors and 
anti-metabolites (Garrett 2011, Walton 2012, Lowenberg 2011) show enhanced activity in 
combination with Chk1 inhibitors.  Chk1 inhibitors are expected to prevent cells entering cell 
cycle arrest thereby enhancing the activity of genotoxic agents by preventing the cell from 
pausing the cell cycle to allow for repair of DNA damage.  Both gemcitabine and etoposide have 
been shown to cause cell cycle arrest in human colon cancer cell lines at 24 and 48 hours post 
administration, and this arrest could be overcome by Chk1 inhibition (Walton 2012).   
As noted above, Chk1 has an important role in stabilizing replication fork complexes following 
replication stress, preventing catastrophic replication fork collapse (Dai 2010, Feijoo 2001, 
Curtin 2012, Figure 1). Replication stress (RS) involves dysregulated origin firing and the 
stalling of DNA replication forks that can lead to DNA damage and genomic instability along with 

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an increased frequency of transcription replication collisions, elevated oxidative stress, and 
depletion of the nucleotide supply.  
Chk1 is an essential effector of the cellular response to RS. Highly proliferating cancer cells 
experience elevated intrinsic RS, thus, tumor cells become highly reliant on Chk1 to manage RS 
and its downstream consequences in order to maintain proliferation and survival.  Chk1 
activation stabilizes replication forks, abrogates origin firing, arrests the cell cycle and mediates 
DNA repair. Therefore, inhibition of Chk1 is expected to be synthetically lethal in tumor cells with 
increased RS.  
Chk1 inhibitors (along with inhibitors of the upstream kinase ATR) are now in early phase trials 
both as monotherapies and in combination (see Section 2.5). 
2.1.2 
IDENTIFYING CORRELATES OF CHK1 SENSITIVITY (REPLICATION STRESS) 
Tumor cells frequently harbor genomic alterations that result in increased intrinsic RS including 
mutations in genes involved in proliferation, cell cycle control, DNA replication and repair. Loss 
of function mutations in tumor suppressors (TS), such as TP53 and RB1 as well as DNA 
damage repair (DDR) genes such as ATM or BRCA1, contribute to genetic instability and RS.  
Similarly, gain of function alterations in oncogenic drivers (OD) like MYC, CCNE1 or KRAS also 
generate genomic instability and RS through cell cycle and replication origin dysregulation.  
Finally, viral infection such as human papillomavirus (HPV) can also elevate RS through 
inactivation of TS genes and enhancement of cell cycle and DNA repair machinery.    
Genetics have proven to be powerful predictors of clinical response to a variety of agents and 
genetic alterations are currently being used in a variety of trials for prospective patient 
recruitment.  Preclinical and preliminary clinical data has shown genetic alterations in TS, DDR 
or OD genes are associated with greater efficacy of Chk1 inhibition.  Detailed examples of 
alterations in TS, DDR or OD genes enhancing Chk1i sensitivity are detailed below.  A complete 
list of genes shown to influence Chk1i sensitivity and RS levels can be found in Appendix 6.     
• 
Oncogenic drivers such as MYC and RAS are frequently amplified and/or hyperactivated 
in a range of tumors and have been strongly implicated in contributing to RS and 
potently enhancing sensitivity to Chk1 inhibitors (Gaillard 2015). Moreover, SRA737 and 
its analogues demonstrate robust single agent activity in tumor models with MYC or 
MYCN overexpression (Cole 2011; Derenzini 2015).  

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• 
TS alterations result in defective G1/S cell cycle checkpoints, arising through inactivation 
of the p53 and Rb pathways, and can result in synthetic lethality in the context of Chk1 
inhibition given Chk1’s role in controlling the S and G2M checkpoints.  Rb and p53 
pathway deficiencies can arise through direct inactivating mutation or deletion of genes 
encoding RB1 and TP53, or through mutation/deletion of other genes in the pathway, 
including CDKN1A, CDKN2A, or hyperactivation of MDM2 (Negrini 2010).  HPV infection 
also results in G1/S loss due to inactivation of p53 and Rb1. 
• 
Multiple DDR mutations contribute to genomic instability (Negrini 2010) and RS.  
Interestingly, similar to what is observed with poly ADP ribose polymerase (PARP) 
inhibitors, Chk1 phosphorylates BRCA2 and Chk1 inhibitors are synthetically lethal in 
cell lines deficient in BRCA2 (Chen and Sanchez 2004; Chen 2009).  Beyond the BRCA 
genes, studies have demonstrated that loss of several Fanconi anemia genes involved 
in homologous recombination repair and inter-strand crosslink repair result in enhanced 
sensitivity to Chk1 inhibition (Chen 2009).  Loss of function in other genes in these and 
related DNA repair processes, such as RPA1 and POLD1 generate synthetic lethal 
backgrounds for Chk1 inactivation (Chen 2009; Hocke 2016).  
2.1.3 
EXOGENOUS SOURCES OF REPLICATION STRESS AND GEMCITABINE 
SYNERGY 
Exogenous sources of RS, such as chemotherapeutic agents can be utilized to heighten RS 
and increase the efficacy of Chk1 inhibition.  The critical role of Chk1 in mediating cellular 
responses to RS affords the opportunity to combine SRA737 with sub-therapeutic 
concentrations the RS-inducing agent, gemcitabine. 
Extensive preclinical data, as well as clinical data, supports the synergistic interaction between 
Chk1 inhibition and gemcitabine.  Gemcitabine, a nucleotide analogue and inhibitor of 
ribonucleotide reductase, targets proliferating cells by inducing RS through induction of stalled 
replication forks and double-strand breaks.  Low concentrations of gemcitabine cause a 
prolonged S-phase and induce hallmarks of RS without inducing overt cytotoxicity. Preclinical 
experiments have shown that clinically relevant doses as well as very low, subtherapeutic doses 
of gemcitabine when combined with Chk1i, result in significant tumor growth inhibition. The 
clinical activity noted at subcytotoxic doses is thought to be a consequence of depletion of 
deoxyribonucleoside triphosphate pools, particularly deoxyadenosine triphosphate (dATP) 
(Heinemann et al. 1990; Shewatch et al 1994; Caffo et al 2016). The combination of 

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gemcitabine with Chk1 inhibition results in cell death independent of an abrogated G2-M 
checkpoint or premature mitotic entry, suggesting synergistic induction of replication 
catastrophe (Koh et al 2015; Montano et al. 2017). 
Extensive preclinical data, as well as clinical data, supports the synergistic interaction between 
Chk1 inhibition and gemcitabine. A reverse genetic siRNA screen of 1006 genes identified 
CHEK1 (encodes Chk1 kinase) and ATR (Chk1 pathway kinase) as targets whose loss of 
function is most synergistic with gemcitabine in tumor cells (Smith 2014).  Consistent with this 
observation, numerous small molecule inhibitors of Chk1 have been demonstrated to potentiate 
gemcitabine in vitro and in vivo (reviewed in Manic 2015).  SRA737 has been previously shown 
to increase the cytotoxic potential of gemcitabine in several tumor cell lines and in an HT29 
colorectal xenograft (Walton 2016).   
We have extended these findings in extensive pair-wise combination studies demonstrating 
profound cytotoxic potentiation of low concentrations of gemcitabine and SRA737 in a panel of 
15 cancer cell lines (data on file). Importantly, the cytotoxic effects of the combination are 
sustained at low nanomolar concentrations of gemcitabine, and synergy/efficacy is observed 
over a broad concentration range. 
In vivo tumor growth inhibitory synergy was observed combining SRA737 with low-dose 
gemcitabine (40 mg/kg) in colorectal HT29 and osteosarcoma SJSA-1 xenograft models (Figure 
2) and pharmacodynamics (PDn) effects were demonstrated in HT29 tumor xenograft tumors 
isolated from mice treated with a single IV dose of gemcitabine (40 mg/kg) followed 24 hr later 
with a single PO dose of SRA737 or vehicle (Figure 2; unpublished data). Low-dose 
gemcitabine induced Chk1 activity as evident by the increase of autophosphorylation of Chk1 at 
S296, while SRA737 inhibited this increase in a dose-dependent manner resulting in a reduction 
of S296 levels.  At the same time, SRA737 increased markers of replication fork stalling and 
collapse such as pS33 RPA32 and γH2AX, as well as ATR-mediated phosphorylation of Chk1 
at S317 and S345. In addition, these increased cell toxic effects are reflected in pancreas tumor 
xenografts, wherein gemcitabine induced γH2AX (a marker of DNA damage and apoptosis) 
levels were potentiated and reached equivalent levels over a gemcitabine dose range of 
40 mg/kg to 240 mg/kg when dosed in combination with a Chk1 inhibitor (Montano et al., 2017). 

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Figure 2. SRA737 potentiates the efficacy of low-dose gemcitabine in HT29 and SJSA-1 
xenografts in mice in a dose dependent manner. 
 
Mice bearing subcutaneous colorectal HT29 (left) or osteosarcoma SJSA-1 (right) tumors were 
treated with vehicle or gemcitabine (IV; green arrows) plus or minus vehicle or SRA737 (PO; blue 
arrows) at indicated doses when initial tumor volumes were approximately 100 mm3. Note: In both 
HT29 and SJSA-1 tumor models, monotherapy SRA737 lacks tumor inhibitory growth effects using 
the indicated dosing schedule (data not shown). 
2.1.4 
LOW-DOSE GEMCITABINE 
Gemcitabine is a nucleoside analogue and is used extensively for the treatment of a wide 
variety of cancers. It is typically administered IV over 30 minutes and is classified as mildly 
emetogenic and requires antiemetic medication.  Gemcitabine’s dose and administration 
schedule varies based on indication and its therapeutic use.  When used as a radio-potentiator 
for muscle invasive bladder cancer with intent to cure, for example, the gemcitabine dose can 
be more than 20-fold or even 30-fold lower than a standard dose of gemcitabine given as a 
single agent for its direct cytotoxic effect.  One Phase 1 study identified a maximum tolerated 
dose (MTD) of gemcitabine of 27 mg/m2 when administered twice-weekly with concurrent 
radiotherapy (Kent et al, 2004).  This regimen achieved a very high rate of bladder preservation 
and is currently being tested in a multi-center randomized Phase 2 study (NCT00777491).  A 
more recent pooled analysis of individual data from eight Phase I–II trials of concurrent 

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gemcitabine and radiotherapy for the treatment of muscle-invasive bladder cancer 
demonstrated outcomes that appear to be at least as good as with cystectomy alone while 
historically, neither radiation therapy alone nor chemotherapy alone could match the survival 
results achieved with surgical resection (cystectomy) (Caffo et al, 2016). Although the regimens 
tested across these 8 studies varied, 81% of the patients received an intended weekly dose of 
gemcitabine of 100 mg/m2 (32.1%) or less (48.9%).  Similar approaches have been pursued in 
lung and pancreatic cancer and other settings (van Putten et al, 2003).   
The parallel between low-dose gemcitabine when used as a radiosensitizer or a sensitizer to 
Chk1 inhibition, based on the preclinical evidence and proposed mechanism of action suggest 
that there may be parallels in the clinic with regard to the dose of gemcitabine required to 
achieve a safe and active regimen when given in combination with SRA737. This hypothesis is 
further supported by the clinical study evaluating the Chk1 inhibitor GDC-0575 combined with 
low-dose gemcitabine (500 mg/m2 weekly) which demonstrated evidence of significant tumor 
responses in patients with STS, triple negative breast cancer and non-small cell lung cancer 
(Italiano 2017). 
In summary, preclinical and clinical data supports the hypothesis that sub-therapeutic doses of 
gemcitabine strongly synergize with active doses of SRA737 which should lead to clinical 
efficacy. To test this hypothesis, low-dose gemcitabine in combination with SRA737 is being 
explored in stage 2 of this study.  
2.2 
BACKGROUND ON COHORT EXPANSION INDICATIONS 
Collectively, the available data suggests that tumors with high levels of intrinsic RS are likely to 
be sensitive to Chk1 inhibition and that this sensitivity should be further enhanced by the 
addition of gemcitabine, an exogenous inducer of RS. Moreover, the heightened intrinsic RS in 
cancer cells is hypothesized to increase sensitivity to RS-inducing chemotherapy in combination 
with Chk1 inhibition thereby increasing the therapeutic window.   
Genetics have proven to be a powerful predictor of clinical response to a variety of agents and 
genetic alterations are currently being used in a variety of trials for prospective patient 
recruitment. Patients whose tumors contain genetic alterations in TS, DDR or OD genes may be 
the most likely to benefit from Chk1 inhibition. The prevalence of genetic alterations varies 
depending on the tumor type but collectively, the data described above supports the likelihood 
that patients with tumors such as HGSOC, SCLC, certain subtypes of STS and the 

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cervical/anogenital (HPV) tumors, all of which harbor high levels of genomic instability, may be 
uniquely sensitive and therefore will be included in the expansion phase of this clinical trial. 
 
2.2.1 
OVARIAN CANCER 
Ovarian cancer is the eighth most common cancer worldwide, with 239,000 new cases 
diagnosed in 2012 and 152,000 deaths worldwide (Ferlay 2013).  About 75% of women with 
ovarian cancer are diagnosed with Stage 3 or Stage 4 disease and 75% of women with 
advanced stage disease suffer relapse or die from their disease despite treatment (Jemal 2011). 
Nearly all ovarian cancers originate in the surface epithelium of the ovaries or fallopian tubes, 
with the papillary serous histology subtype accounting for approximately 75% of those, and of 
which a significant majority (90%) are high grade (Cannistra 2004).   
Initial therapy typically consists of cytoreductive surgery and 6–8 cycles of platinum and taxane 
based chemotherapy.  PARP inhibitors have shown substantial benefit as maintenance therapy 
when administered to patients who have completed their initial chemotherapy regimen.  
The choice of subsequent therapy for patients who relapse is based on the treatment-free 
period and chemotherapy agents already utilized.  Patients are further categorized as having 
platinum sensitive, resistant or refractory disease.  Primary refractory is defined as disease 
progression during therapy or within 1 month of the last dose of the first line of platinum-based 
chemotherapy. Platinum resistant is defined as those who are not primary refractory but have 
disease progression within 6 months of the last dose of platinum-based chemotherapy. 
Patients with platinum-resistant disease have a poor prognosis with a short expected median 
overall survival (OS) of less than 12 months. Four different agents, weekly or 3-weekly 
paclitaxel, topotecan, pegylated liposomal doxorubicin and gemcitabine, have been shown to 
have some activity in Phase 3 trials, with overall response rates of less than 15% and a median 
progression-free survival (PFS) of 3 to 4 months.  Occasionally, platinum drugs continue to be 
used in the platinum-resistant population with, for example, a dose-dense regimen.  However, 
as no agent has proven to be superior to another, the selection of therapy is mostly based on 
toxicity, clinical situation of the patient and convenience of administration.  Randomized trials of 
combination chemotherapy have shown no advantage in this population and have shown 
compound toxicity.  Accordingly, sequential single-agent therapy is currently the recommended 

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management for this group of patients, as per European Society for Medical Oncology (ESMO) 
guidelines for newly diagnosed and relapsed epithelial ovarian carcinoma (Ledermann 2013). 
New approaches which leverage the underlying biology, especially if adverse effects can be 
minimized without the addition of cytotoxic chemotherapy are warranted.  The underlying 
biology of HGSOC includes high levels of genomic instability mainly due to defects in 
homologous recombination (e.g. mutation in BRCA genes) as well as high rates of TP53 
mutations suggesting a defective G1/S checkpoint (Landen 2008; Kurman 2011).   
The Cancer Genome Atlas profiled over 400 HGSOC patient samples and reported TP53 
mutations in 96% of samples.  Additionally, key oncogenes such as MYC, KRAS and CCNE1 
were altered in at least 40% of patient samples.  BRCA1 and BRCA2 were found to be altered 
in roughly 12% of samples (TCGA 2011).  The progression of genomic instability in HGSOC, 
could make this cancer type highly susceptible to Chk1 inhibition. 
Of particular interest, approximately 20% of patients with HGSOC have CCNE1 amplification 
which is associated with resistance to platinum-based therapy and insensitivity to PARP 
inhibitors (Kanska  2016).  It is hypothesized that CCNE1 amplification may sensitize tumor cells 
to Chk1 inhibition via increased replication stress due to increased S-phase entry, increased 
DNA replication and increased transcriptional activity (Zeman 2014). Supporting this hypothesis 
are preliminary pre-clinical data suggesting CCNE1 amplified, BRCA wild-type, HGSOC patient-
derived xenograft (PDX) tumor models resistant to platinum-based therapy and PARP inhibition 
are responsive to SRA737 monotherapy (data not shown).  
Additional support is provided by preliminary clinical data with the Chk1 inhibitor LY2606368 in 
patients with HGSOC, squamous cell carcinoma of the head and neck and squamous cell 
carcinoma of the anus; demonstrating that treatment benefit is correlated with tumor genomic 
profiles indicative of high cyclin E expression (Lee 2016; Martinez  2017).   
The BRCA wild-type population has been shown to be enriched for CCNE1 overexpression 
through CCNE1 gene amplification and/or mRNA upregulation and/or cyclin E protein 
overexpression (Lee 2018). In order to evaluate SRA737 in this population an expansion cohort 
of subjects with BRCA wild-type, platinum-resistant or refractory HGSOC will be enrolled in this 
study. 

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2.2.2 
SMALL CELL LUNG CANCER 
Lung cancer is the most common cancer worldwide, with 1,825,000 new cases diagnosed in 
2012 and 1,590,000 deaths worldwide (Ferlay 2013).  Small cell lung cancer accounts for about 
10% to 15% of all lung cancers, with non-small cell lung cancer (NSCLC) accounting for 70 to 
80%. SCLC, which originates from neuroendocrine-cell precursors, is distinguished from 
NSCLC by its rapid doubling time and the early development of widespread metastases. 
As per guidelines of the European Society for Medical Oncology (ESMO) (Früh 2013) treatment 
of stage IV SCLC is palliative, with combination chemotherapy being the main treatment option. 
Overall response rates (ORRs) with combination chemotherapy are close to 70%, however, 
median progression-free survival (PFS) is only 5.5 months and a median OS less than 10 
months. Response rates to second-line treatment are typically around 10% in resistant disease 
and 20% in sensitive disease; dependent on the treatment-free interval. The clinical benefit of 
further systemic therapy in the case of patients with resistant disease and early relapse (<6 
weeks) is not clear as outcomes are poor. Participation in a clinical trial or supportive care is 
recommended for patients with relapsed or progressive disease. 
Despite recent advances, mainly in the use of radiation therapy, the median survival time of 
8-10 months for patients with extensive state SCLC has remained approximately the same over 
the last 30 years and exploring novel treatments for these patients remains an area of unmet 
medical need. Several novel agents have recently been evaluated in patients with SCLC.  
Immune checkpoint inhibition, for example via pembrolizumab was explored in a Phase Ib trial 
for 135 patients who had progressed on platinum-based chemotherapy and were screened for 
PD-L1 expression, with 27% testing positive (Ott et al, 2015). Ultimately, 17 patients were 
enrolled with 25% achieving a partial response. Other examples include aurora A kinase 
inhibitors, such as alisertib, which was tested in a Phase I/II trial of 60 patients with relapsed or 
refractory SCLC, of whom 21% had a partial response on therapy (Melichar et al, 2015).  
Another novel agent is rovalpituzumab tesirine, an antibody-drug conjugate designed to bind to 
the delta-like protein 3 (DLL3), has recently been investigated in a Phase Ia/Ib trial in SCLC. In 
29 DLL3-positive patients with SCLC who had progressed after first- or second-line therapy, 
34% of patients had a partial response and 31% achieved disease stability (Pietanza et al, 
2015).  
Genetically, 85-90% of all SCLC tumors have genetic alterations in the sponsor’s defined tumor 
suppressor genes (George 2015).  In general, the sponsor-defined DDR genes are individually 

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altered in less than 5% of tumors; however, due to their non-overlapping occurrences about 
37% of SCLC tumors harbor a DDR defect (POLE and SMARCA4 are two exceptions with 
alterations in 12.5% and 9.5% of tumors respectively) (Zehir 2017). The above described 
genetic alterations in SCLC make this indication an ideal therapeutic target for a Chk1 inhibitor, 
such as SRA737 in combination with gemcitabine. Due to the presence of cancer related 
alterations in the tumor suppressor genes (eg, TP53 and RB1) in the majority (approximately 
90%) of patients with SCLC, enrollment in the SCLC cohort of the study is not dependent on 
prospective genetic testing. 
2.2.3 
SOFT TISUE SARCOMA 
Sarcomas are a group of rare malignant tumors of connective tissues, capable of differentiation 
into many different cell types such as connective tissues (lipocytes, fibrous supporting 
structures, muscle, etc.), visceral tissues, and bone. These tumors can occur in almost any 
anatomic site, although they are reported to be more frequent in the extremities and are typically 
classified by origin in soft tissue or bone.  
Soft tissue sarcomas  are reported to account for <1% of all adult malignancies and bone 
sarcomas for <1% of all adult malignancies respectively (Ducimetière 2013). It is estimated that 
adult STS and visceral sarcomas occur with an estimated age-standardized incidence ranging 
from 3-5/100,000/year in Europe (Stiller 2013). 
Soft tissue sarcoma is a biologically heterogeneous malignancy with over 100 histological 
subtypes (Fletcher 2013). Generally, STSs can be classified into two broad categories: those 
driven by complex karyotypes and those by specific translocations.  The genotype of the former 
category is generally more sporadic; however, alterations in the p53 pathway are common for 
multiple histological subtypes such as leiomyosarcomas and undifferentiated pleomorphic 
sarcomas.  Unlike STS of complex karyotypes, STS driven by translocations are 
transcriptionally dysregulated and have very few genetic alterations making it difficult to 
prospectively select patients genetically.  
Historically, there have been few systemic treatment options for this relatively rare disease.  
ESMO guidelines (2014) specify surgery as the standard treatment of all patients with an adult 
type, localized STS. Some lesions may also be treated with surgery followed by radiation 
therapy.  

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For patients whose disease is not fully resectable or whose disease has recurred, traditional 
cytotoxic agents, such as anthracyclines, alkylating agents, and taxanes are employed although 
they have limited clinical benefit beyond the first-line setting.  Across all STS subtypes, median 
overall survival remains approximately 12–18 months for those with locally advanced or 
metastatic disease. The development of targeted therapies has led to recent approval of four 
new treatments for advanced STS in the EU and US. Among these, olaratumab is most notable 
for its improvement in overall survival for patients with anthracycline-naïve disease. The other 
three novel agents, trabectedin, pazopanib and eribulin, have been approved for the treatment 
of specific histologic subtypes of STS in the second-line setting after progression on 
anthracyclines (In 2017).  
Recently, encouraging preliminary results were reported for a clinical study evaluating the oral 
Chk1 inhibitor GDC-0575 combined with low-dose gemcitabine (500 mg/m2 every 2 weeks) with 
evidence of significant tumor responses in STS (PR lasting 52 weeks in leiomyosarcoma and 
CR lasting 24 weeks in undifferentiated pleomorphic sarcoma) (Cousin 2016). 
Further progress in STS management will rely on subtype-specific therapies and validation of 
biomarkers to tailor therapy (In 2017). 
Genetic alterations in the p53 pathway are common for STS not harboring translocations.  For 
example, over 50% of leiomyosarcomas and undifferentiated pleomorphic sarcomas have 
defects in TP53 (Zehir 2017).  Certain classes of liposarcomas have also shown very high rates 
of p53 pathway dysfunction.  As such, genetic mutations in non-translocated STS make this 
indication an ideal therapeutic target for a Chk1 inhibitor such as SRA737, in particular in 
combination with gemcitabine, which is hypothesized to further enhance the activity of SRA737. 
2.2.4 
CERVICAL/ANOGENITAL CANCER (HUMAN PAPILLOMA VIRUS RELATED 
CANCERS) 
Human papilloma virus (HPV) is the most common sexually transmitted virus that affects the 
genital tract of males and females. Cervical cancer is the most prevalent HPV-related cancer 
and the fourth most common cancer in women, with approximately 528,000 new cases and 
more than 266,000 deaths resulting from cervical cancer annually worldwide (Globocan 2012). 
The biology of HPV has been extensively studied and its link with malignancies has been well 
established, specifically with cancers involving the anogenital (cervical, vaginal, vulvar, penile, 
anal) tract and also those involving the head and neck. HPV, including high-risk types, such as 

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HPV genotypes 16 and 18, cause approximately 30% of all cancers worldwide (de Martel 2012) 
and are the estimated cause of 100% cervical cancer cases, 90% of anal cancers, 35% of 
oropharyngeal cancers and 40% of vaginal cancers, vulvar cancers, and penile cancers 
worldwide (Gilison 2008). 
Not only are the biology and histology of anogenital cancers similar, but so are the treatment 
options and outcomes for those who are not cured with surgery or multi-modality therapy.  
Early-stage cervical cancer, like other early-stage HPV-related cancers, may be appropriately 
treated with either radical surgery and/or chemoradiation.  
In metastatic or recurrent cervical cancer, paclitaxel and cisplatin combined with bevacizumab is 
considered the preferred first-line regimen. In patients progressing following first-line therapy, 
different cytostatic agents, including vinorelbine, topotecan, gemcitabine or nanoparticle 
albumin-bound paclitaxel have been evaluated, but response rates are low and no 
recommendation has been given concerning the most effective second-line treatment 
(Marth 2017).   
Similar treatment dilemmas exist for other metastatic or recurrent HPV-related cancers and very 
few recent advances have been reported.  However, encouraging preliminary results have been 
observed in an early phase trial of the PD1 inhibitor nivolumab in metastatic cervical cancer 
(Hollebecque 2017).  
Also notable were recent reports of single agent activity in anal cancer for the Chk 1 inhibitor 
LY2606368 (Bendell 2015). Following the initial report of a response in an anal cancer patient in 
the Phase 1 study, a Phase 2 study in 24 anal cancer patients was conducted that 
demonstrated 5 objective responses including 1 CR and 4 PRs in an otherwise unselected 
patient population (Martinez 2017). LY2606368 differs from SRA737 in that it is not selective for 
Chk1 and equipotent against both Chk1 and Chk2, despite the lack of anticancer activity 
associated with inhibition of Chk2. 
Chk1 functions as an essential effector kinase in the cellular response to endogenous RS, and 
tumor cells with elevated RS become highly reliant on Chk1 for survival.  Chk1 inhibitors, such 
as SRA737 have been shown to exacerbate RS and result in replication catastrophe. Non-
genetic alterations, such as HPV infection, also induce the high RS phenotype through the 
action of viral proteins including E6 and E7.  This synergy makes these cancers an ideal 

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therapeutic target for a Chk1 inhibitor, such as SRA737, in particular in combination with 
gemcitabine, which is hypothesized to further enhance the activity of SRA737. 
2.3 
INVESTIGATIONAL MEDICINAL PRODUCT: SRA737  
SRA737 (the investigational medicinal product [IMP] formerly known as CCT245737) is a 
potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a serine-threonine 
kinase enzyme that acts as a central regulator of the DDR network.   
The agent was developed through collaboration between The Institute of Cancer Research 
(ICR) Cancer Therapeutics Unit, Sareum Ltd and Cancer Research Technology Ltd.  SRA737 
was acquired by Sierra Oncology, Inc.  in September 2016.  The agent is also being 
investigated as monotherapy in subjects with solid tumors (NCT02797964).    
2.3.1 
STARTING DOSE RATIONALE: SRA737 
Murine toxicity studies indicated a SRA737 MTD of 75 mg/kg/day (~ 225 mg/m2/day) as a 
single-agent or in combination with cisplatin and gemcitabine.  The ICH S9 guidance suggests 
using an equivalent dose 1/10th that of the rodent MTD as an initial clinical dose.  Consequently, 
a Human Equivalent Dose of 22.5 mg/m2/day (0.61 mg/kg/day) equating to an absolute dose of 
36 mg (for a 60 kg subject) could be utilized.  For the further assurance of subject safety, a 
lower starting dose of 20 mg was selected.    
Using similar allometric scaling, pharmacologically-active concentrations of SRA737 are 
expected at clinical doses of approximately 80 to 160 mg.    
For additional information concerning SRA737, refer to the Investigator’s Brochure. 
2.3.1.1 
Dose Justification for Stage 2 Expansion Phase 
Data from murine efficacy studies investigating the activity of various doses of SRA737 in 
combination with low-dose gemcitabine (40 mg/kg) indicate profound activity at the minimum 
administered SRA737 dose of 25 mg/kg (IMPD v3.0; Section 2.2.1.2.2.1.1 p33; Figure 2.2.1-
10). 
The Cmin (C24h) of 200 nM (~76 ng/mL) modelled following administration of this dose of SRA737 
to mice has been determined as the minimum effective concentration (MEC) for the 
SRA737/low-dose gemcitabine combination dosing regimens examined thus far, noting that 
further SRA737 murine dose decrement studies are ongoing. 

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Preliminary clinical PK data from the SRA737-02 study, supported by modelling of the more 
extensive SRA737-01 PK dataset, suggests that the murine MEC will be exceeded for 
approximately 18 hours post-dosing at 150 mg and for 24 hours at doses of 300 mg or greater 
(again, noting the ongoing murine efficacy studies designed to determine whether the MEC is 
lower than that presently estimated). 
 
Data from patients enrolled in the Dose Escalation cohorts receiving SRA737 in combination 
with low-dose gemcitabine (Stage 2 of this study) indicate that the administration of 500 mg 
SRA737 in combination with 100 mg/m2 gemcitabine was well-tolerated and no DLTs have been 
observed in patients in Stage 2 of this study to date (refer to Section 2.4.2 for details).  Based 
on the preliminary PK data from the Stage 2 escalation cohorts, the efficacious concentration 
has been achieved at these clinical doses.  Together these safety and PK data supported the 
initiation of expansion cohorts at the 500 mg SRA737 + 100 mg/m2 gemcitabine dose level, or a 
higher dose level based on emerging clinical data from the ongoing escalation phase. 
2.3.2 
NON-CLINICAL PHARMACOLOGY 
2.3.2.1 
Efficacy/Primary pharmacology 
SRA737 is a potent and selective inhibitor of Chk1 (half maximal inhibitory concentration 
[IC50] < 10 nM) with minimal activity against Chk2.  Off-target kinase screening studies has also 
confirmed the selectivity of SRA737 across the broader kinome.  
0
6
1 2
1 8
2 4
1
1 0
1 0 0
1 ,0 0 0
C lin ic a l S tu d y  S R A 7 3 7 -0 2
S R A 7 3 7  M e a n  (±  S E M ) P la s m a  P h a rm a c o k in e tic s
T im e  (h )
P la s m a  [S R A 7 3 7 ] (n g /m L )
3 0 0  m g (n = 1 )
1 5 0  m g (n = 4 )
8 0  m g (n = 4 )
4 0  m g (n = 5 )
M u rin e   M E C (e s t.)

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In vitro, SRA737 at 0.1 to 0.5 µM inhibited Chk1 autophosphorylation induced by genotoxic 
chemotherapy and prevented downstream signal transduction.  Dose-dependent inhibition of 
chemotherapy-induced checkpoint arrest (data not shown) and a potentiation of these agents 
was observed (Table 1).  SRA737 alone caused cytotoxicity; however, at concentrations 
approximately 10-fold higher than those shown to be synergistic in these cell lines. 
Table 1.  Potentiation of DNA-damaging agents in cancer cells by SRA737 
Human Cancer Cell 
Line 
Tissue of 
Origin 
Genotoxic drug 
Potentiation (fold) 
HT29 
Colon 
Gemcitabine 
7.9 (±2.1, n=6) 
HT29 
Colon 
SN38a 
1.8 (±0.3, n=3) 
SW620 
Colon 
Gemcitabine 
16.9 (±3.4, n=7) 
SW620 
Colon 
SN38a 
3.1 (±0.9, n=3) 
Calu6 
NSCLC 
Gemcitabine 
9.1 (±1.5, n=3) 
Calu6 
NSCLC 
SN38 
1.3 (±0.08, n=3) 
MiaPaCa-2 
Pancreas 
Gemcitabine 
23 (±10, n=3) 
MiaPaCa-2 
Pancreas 
SN38a 
3.1 (±0.4, n=3) 
a = The active metabolite of irinotecan. 
In the colon cancer cell lines, exposure to gemcitabine or SN38 alone increased ATR-mediated 
Chk1 phosphorylation, autophosphorylation of Chk1, downstream phosphorylation of CDK1 and 
resulted in a small increase in γH2AX foci.   
Consistent with its mechanism of action, the administration of SRA737 with these agents 
inhibited Chk1 autophosphorylation and CDK1 phosphorylation, induced a large increase in 
γH2AX foci and cleaved PARP as a result of abrogation of the DDR response to chemotherapy.  
Little effect on ATR-mediated Chk1 phosphorylation was noted, supporting SRA737’s pathway 
selectivity.  
Subsequently, SRA737 was combined in an optimized dose combination matrix with 
gemcitabine in a 15-cell line panel including: 5637, TCCSUP, and J82 (bladder); HT29 and 
SW620 (colon); CAL-27 and FaDu (head and neck squamous carcinoma); Calu-6 and NCI-
H520 (lung); KURAMOCHI, OV90, and OVCAR-3 (ovarian); MIA PaCa-2, Panc 03.27, and 
SNU-324 (pancreatic).  Combination indices (CI) values were calculated as determined by Chou 
and Talalay (1984) across the combination dose matrix and the mean and range best CI values 
across the panel were 0.25 (0.06 – 0.87). CI values <0.7 indicate synergy, CI values between 
0.7 and 1.3 indicate additivity, and CI values >1.3 are antagonistic.  Fourteen of the 15 cell lines 

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had best CI values less than 0.7 indicating the profound synergy of the combination verses 
either agent alone across numerous types of cancer cell lines.  
The efficacy of SRA737 in combination with cytotoxic agents was then examined in various 
mouse tumor xenograft studies, including in combination (i) with gemcitabine in HT29 and 
SW620 colon cancer and Calu6 NSCLC models; (ii) with gemcitabine and carboplatin in the 
Calu6 model; (iii) with irinotecan in the HT29 model and (iv) with ionizing radiotherapy in the 
HT29 and SW620 models. The efficacy of SRA737 in combination with gemcitabine was also 
investigated in gemcitabine-resistant bladder carcinoma patient-derived xenograft model. 
For all combinations with cytotoxic chemotherapy SRA737 was administered at 24 and 48 hours 
after the cytotoxic agent (Walton 2012) at doses ranging variously from 50 to 150 mg/kg.   
Importantly, some degree of increased antitumor efficacy over cytotoxic chemotherapy alone 
was observed in all combinations but, as observed in the in vitro cytotoxicity studies, the 
potentiation of cytotoxicity by SRA737 appeared greater in combination with gemcitabine than 
irinotecan.   
Data from a gemcitabine combination study in an HT29 colon cancer model, showed a striking 
dose dependent potentiation of gemcitabine efficacy by SRA737, including complete tumor 
stasis or minor regression at the higher investigated doses (Figure 3).  Progression-free survival 
was also substantially improved in subject animals receiving the SRA737 plus gemcitabine 
combination therapy.  

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Figure 3.  SRA737 (formerly CCT245737) potentiates the efficacy of gemcitabine in HT29 
xenografts in mice in a dose dependent manner 
 
 
A further murine xenograft study investigating the activity of SRA737 in combination with 
gemcitabine and cisplatin in the Calu6 NSCLC model was also performed.  Markedly improved 
tumor growth inhibition was noted in subject animals receiving the triple combination therapy 
compared with the gemcitabine/cisplatin doublet combination or SRA737 alone (Figure 4).  An 
approximate 50% increase in PFS for the triplet combination was also noted.   

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Figure 4.  SRA737 (formerly CCT245737) potentiates the efficacy of a single cycle of the 
combination of gemcitabine and carboplatin in Calu6 NSCLC xenografts   
 
 
Gemcitabine plus or minus SRA737 was examined in a bladder carcinoma patient-derived 
xenograft model.  The combination of SRA737 with gemcitabine resulted in 64% tumor growth 
inhibition compared to vehicle treatment and significantly increased survival in a highly 
aggressive gemcitabine-resistant bladder carcinoma PDX model (Figure 5). These results 
suggest that this combination may be substantially more efficacious than gemcitabine alone in 
certain settings. 
 
 

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Figure 5.  SRA737 plus gemcitabine inhibits tumor growth and extends survival in a 
gemcitabine-insensitive patient-derived xenograft model of bladder cancer. 
 
Note, **  = Log-rank (Mantel-Cox) test Gem(100)+SRA737(100) vs Gem(100) (P=0.011) or Vehicle 
(P=0.016).  One mouse was found dead on D9 and another sacrificed on D13 in the combination 
treatment group. SRA737 dosed as scheduled in combination resulted in no tumor growth inhibition 
or improvement in time to tumor volumes 1500 mm3 compared to vehicle. 
A PDn assessment of HT29 and SW620 xenografts tumors demonstrated that gemcitabine 
induced tumor Chk1 autophosphorylation (pS296).  This autophosphorylation was significantly 
inhibited by administration of SRA737 at doses as low as 12.5 mg/kg (Figure 6).   

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Figure 6.  Effect of SRA737 (formerly CCT245737; 12.5 to 100 mg/kg PO) on 
gemcitabine-induced Chk1 S296 autophosphorylation in HT29 human tumor xenografts 
in mice (ICR EXP 1569) 
 
 
An exploratory correlation of these PDn findings with pharmacokinetic (PK) data, suggests that 
a total circulating plasma concentration above 100 nM (equating to a free (unbound) 
concentration of ~ 20 nM) may be required to significantly inhibit Chk1 in vivo for an entire 24-
hour period in mice.  Continuous inhibition of Chk1 activity in combination with gemcitabine for a 
period of 48 hours is necessary for maximal potentiation (Garrett 2011). 
In summary, SRA737 has demonstrated significant antitumor activity (including some tumor 
stasis and minor regression) in a variety of murine and patient-derived xenograft studies in 
combination with gemcitabine, gemcitabine and carboplatin and irinotecan and radiotherapy 
(data not shown).  Analysis of various DDR markers confirmed this activity was directly related 
to SRA737’s mechanism of action.   
2.3.3 
IN VITRO ADMET AND NONCLINICAL PHARMACOKINETICS 
SRA737 has been assessed in an initial package of in vitro absorption, distribution, metabolism, 
elimination, and toxicity (ADMET) studies, including comparative metabolism in nonclinical 
species and human hepatocytes; inhibition of human cytochrome P450 (CYP) enzymes; 
profiling in the CEREP pharmacological off-targets panel; plasma protein binding and Caco-2 
permeability assessment.  In vitro cardiac channel studies were also undertaken.  More detailed 
information on these various studies is available in the current version of the Investigator’s 
Brochure. 

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2.3.3.1 
In Vitro Metabolism 
The in vitro metabolism of SRA737 has been compared in human, mouse, rat, dog, minipig, and 
monkey hepatocytes. 
The rank order of stability from most stable to least stable for the species was rat ≈ mouse > 
monkey ≈ human >> dog >> minipig. In the human hepatocyte preparation, approximately 66% 
of the parent remained after 4 hours of incubation compared to 75% and 7% in the rat and 
minipig preparations, respectively. 
Twelve components were identified as putative metabolites of SRA737 formed by oxygenation, 
dehydrogenation, N-dealkylation, glucuronidation, sulfation, acetylation, or a combination 
thereof. The metabolic profile in monkey hepatocytes was most similar to human hepatocytes 
with all eight human SRA737 metabolites also observed in the monkey, with six at equal or 
greater abundance. No human-specific metabolites were observed.  
2.3.3.2 
In Vitro Safety and Developability Assessments 
2.3.3.2.1 
Cytochrome P450 inhibition 
No significant inhibition of major CYP enzymes (1A2, 2A6, 2C9, 2C19, 2D6 and 3A4) was 
observed at the highest concentration of SRA737 investigated (IC50 > 10-50 µM), suggesting 
that the compound is unlikely to mediate significant metabolic drug-drug interactions. 
2.3.3.2.2 
CYP Induction 
The ability of SRA737 to induce the major inducible CYP enzymes (1A2, 2B6 and 3A4) in 
cultured human hepatocytes was assessed by qRT-PCR.  Minimal, concentration-dependent 
increases in CYP1A2 mRNA levels (up to 7-fold at 30 µM SRA737; EC50 = 3-7 µM) were 
observed.  While the response was less than 10% of the positive control (omeprazole, 50 µM), 
these in vitro data suggest SRA737 may minimally affect the metabolism of concomitantly 
administered drugs that are predominately metabolized by CYP1A2. 
2.3.3.2.3 
Off-target Profiling Screen  
The potential off-target binding activity of SRA737 against a range of 80 pharmacological 
targets (including the hERG and related cardiac channels) was determined in the CEREP 
Express Profiler assay package.   

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Partial agonism of the 5HT2B receptor was the only finding of note, although an absence of 
particularly potent nor complete agonist activity (half maximal efficacious concentration 
[EC50] = 2.1 µM; 46% maximal effect of serotonin) likely renders this observation of limited 
toxicological significance in the intended patient population. 
2.3.3.2.4 
Plasma Protein Binding 
Moderate, concentration-independent plasma protein binding of SRA737 (1 and 10 µM) has 
been noted in minipig (fbound = 80%), dog (69%), monkey (87%), and human plasma (87%). High 
protein binding was observed in mouse plasma (94%).  
2.3.3.2.5 
Permeability  
SRA737 displays high permeability (A > B = 25 × 10-6 cm/s; 10 µM) and a low efflux ratio (0.80) 
in a standard Caco-2 cell model of human intestinal permeation.  These data suggest that the 
compound is not an avid substrate for efflux transporters such as P-gp, and that favorable 
absorption following oral administration to humans is likely. 
2.3.4 
IN VIVO PHARMACOKINETICS 
The PK of SRA737 have been determined in the mouse, rat, dog, and monkey following oral 
(PO) and intravenous (IV) administration (Table 2).  Very favorable absolute oral bioavailability 
(%F) was noted, particularly in the mouse (105%) and monkey (90-104%), consistent with the 
moderate metabolism and favorable permeability noted in in vitro models.  An acceptable 
terminal elimination half-life (t1/2) was also observed in each species.  Further studies in mice 
confirmed dose linearity in pertinent PK parameters over the range of 50 to 300 mg/kg PO. 
Table 2.  Non-Clinical Pharmacokinetics of SRA737 
Species 
Dose 
t1/2 (h) 
Cmax (µg/mL) 
AUC (0-t) 
(µg•h/mL) 
%F 
Mouse 
IV (10 mg/kg) 
2.9 
- 
3.77 
105 
PO (10 mg/kg) 
2.9 
0.61 
3.94 
Rat 
IV (5 mg/kg) 
1.0 
- 
1.38 
42 
PO (10 mg/kg) 
4.6 
0.19 
1.17 
Dog 
IV (1 mg/kg) 
2.8 
- 
0.20 
86 
PO (10 mg/kg) 
3.5 
0.13 
0.85 
Monkey 
IV (1 mg/kg) 
5.3 
- 
1.52 
- 
PO (2mg/kg) 
5.0 
0.50 
2.73 
90 

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PO (10 mg/kg) 
5.1 
2.64 
15.8 
104 
 
Taken together, the compound’s favorable solubility, permeability, metabolic stability, and 
demonstrable oral bioavailability in nonclinical species is suggestive of favorable oral absorption 
in humans. 
2.3.5 
SAFETY PHARMACOLOGY 
An extensive program of safety pharmacology studies designed to investigate the cardiac safety 
of SRA737 has been undertaken.  
2.3.5.1 
In Vitro Cardiac Safety Assessments 
Initial data from human cardiac ion patch clamp assays indicated moderate inhibition of the 
hERG channel (IC50 = 6.2 µM [2.4 µg/mL] and 4.2 µM [1.6 µg/mL] free drug concentration), with 
no significant inhibition of the other ion channels at 10 µM (3.8 µg/mL).   
A subsequent study of SRA737 (3–30 µM [1.1-11.4 µg/mL]) in an isolated rabbit Purkinje fiber 
model was demonstrated a statistically-significant increase in action potential duration and an 
increase in Vmax at 30 µM. 
2.3.5.2 
In Vivo Cardiac Safety Assessments 
The cardiac safety of SRA737 (0, 0.3, 3 and 30 mg/kg; administered sequentially via 10-minute 
IV infusion) was assessed in anesthetized female guinea pigs (n = 5).  A single animal died 
following administration of 30 mg/kg and QT prolongation (> 10% compared to baseline) was 
noted at the highest dose.  Poor control of anesthesia was noted in this study. 
The cardiac safety of SRA737 was further assessed in a benchmark, non-Good Laboratory 
Practice (GLP) study in conscious, telemetered female beagle dogs (0, 30 and 80 mg/kg PO; 
n = 3 per dose).  No adverse effects on cardiovascular parameters were noted at doses up to 
and including 80 mg/kg, corresponding to a mean circulating plasma concentration of 3,4 µg/mL 
(~ 8,700 nM; 3 hours postdose).   
The effect of SRA737 on cardiac parameters was also investigated in male and female minipigs 
following single PO administration at 50 or 75 mg/kg (n = 2/sex/dose level).  One male animal 
(50 mg/kg) experienced multiple frequent premature ventricular complexes at approximately 1 
hour postdose. although these findings were thought unrelated to drug.  No other SRA737-

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related changes were noted.  Significant maximal plasma exposure (Cmax) of approximately 
0.64 µg/mL and 2.3 µg/mL in male and female animals, respectively, at the 50 mg/kg dose, and 
2.3 µg/mL and 2.9 µg/mL in male and female animals, respectively, at the 75 mg/kg dose can 
be inferred from other studies. 
The cardiovascular effect of SRA737 was also investigated in male and female cynomolgus 
monkeys following single and repeat oral administration at 2, 10 or 20 mg/kg/day (n=3-
5/sex/dose level) in a GLP 28-day toxicity study. Although there were instances of sinus 
tachycardia and bradycardia-(both of which are known findings in cynomolgus monkeys), due to 
the sporadic nature of these findings and the absence of a treatment or dose relationship, these 
observations were considered unrelated to SRA737. There were no other SRA737-related 
effects on electrocardiogram (ECG) waveform or intervals. Mean circulating plasma levels at the 
approximate time ECGs were recorded (~ 4 hours post-dose) were 1.6 µg/mL in males and 
females. 
2.3.5.3 
Cardiovascular Safety Summary 
When taken together, data from this program of in vitro and in vivo studies suggests that 
SRA737 possesses no significant nonclinical cardiac liabilities at likely free therapeutic plasma 
concentrations, including in the benchmark in vivo studies in jacketed minipigs and telemetered 
beagle dogs, and in the 28-day GLP monkey toxicity study.  Consequently, there appears 
minimal risk that SRA737 will mediate clinically meaningful cardiac liabilities in humans.  
Nonetheless, standard cardiovascular safety assessments are included in the ongoing Phase I 
clinical studies. 
2.3.6 
TOXICOLOGY 
The toxicology of SRA737 has been assessed in a number of clinical-trial enabling studies 
including 28-day repeat-dose toxicity studies in the mouse, minipig, and monkey and a triple 
combination study in the mouse.  More detailed information on this suite of studies is available 
in the current version of the SRA737 Investigator Brochure. 
2.3.6.1 
28-Day Mouse Study 
The toxicity and population toxicokinetics (TK) of SRA737 were assessed in a GLP 28-day, 
repeat-dose, oral toxicology study in CD-1 mice.  Subject animals were administered compound 
daily at doses of 0, 10, 40 or 75 mg/kg/day (~ 30, 120 or 215 mg/m2/day). 

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The findings of this study were broadly consistent with those expected for a compound with 
SRA737’s cell cycle mechanism; namely, dose-dependent hematological changes, including 
significantly decreased red and white blood cell parameters (RBC, WBC), atrophy of the femoral 
and sternal marrow, decreased thymic weight, and a concordant increase in splenic weight 
likely due to compensatory extramedullary hematopoiesis.  Partial or complete reversal of these 
findings was noted over the 14-day recovery period.  Of note, given the compound’s mechanism 
of action, was the absence of adverse macro- or microscopic findings in the gastrointestinal (GI) 
tract in this 28-day study.  (It should be noted that apoptosis of cells in the GI tract was noted at 
high drug doses [> 150 mg/kg] in an earlier dose-range finding study). 
An apparently irreversible tubular atrophy of the testis was also observed at the high dose.  
Although considered an adverse finding, the relevance of these changes to adult human cancer 
patients appears limited. 
Drug exposure was broadly dose proportional, with the mean maximal circulating plasma 
concentrations of SRA737 (Cmax) of 4.0 and 5.5 µg/mL (~ 10.6 and 14.5 µM), and total exposure 
(AUC0-t) of 45.5 and 68.6 µg•h/mL in female and male animals respectively at the 75 mg/kg 
dose (Day 28). 
The MTD in this study was 75mg/kg/day. 
2.3.6.2 
Three-Cycle Mouse Triple Combination Study 
A further study was conducted in CD-1 mice to investigate the toxicity and TK of SRA737 when 
administered in combination with IV gemcitabine and cisplatin on an intermittent schedule over 
18 days.  Male and female animals were administered SRA737 PO at 40, 75 or 150 mg/kg/day 
on Days 2, 3, 9, 10, 16 and 17 of dosing, in combination with cisplatin (12 mg/kg IV Day 1) and 
gemcitabine (100 mg/kg IV on Days 1, 8 and 15; “triplet combination”).     
The toxicological findings in this combination study mirrored those noted in the monotherapy 
toxicity study, namely a decrease in RBC parameters (although of a magnitude less that 
observed previously); decreased eosinophils; sporadic marrow pallor and hypocellularity; 
decreased thymic weight and evidence of extramedullary hematopoiesis including increased 
spleen and liver weights and testicular changes.  Partial or complete recovery of these findings 
was observed over the 28-day recovery period, with some minor exceptions.  Reversible 
intestinal epithelial degeneration was also noted in the high dose triplet combination group.  No 
changes in WBC or clinical chemistry parameters was observed. 

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Importantly, only the reversible marrow toxicity, consequent splenomegaly, and the high-dose 
intestinal observations were deemed to have been exacerbated by administration of SRA737 
over those observed following administration of the cisplatin/gemcitabine control group alone. 
The MTD of SRA737 in combination with cisplatin and gemcitabine on an intermittent schedule 
was 75 mg/kg/day, equivalent to its MTD when administered as a single agent (daily for 
28 days). 
At this dose, the PK of the compound was broadly equivalent to those observed in the 
single-agent toxicology study, suggesting an absence of profound drug-drug interactions with 
gemcitabine and cisplatin.  Mean maximal plasma concentrations (Cmax) of 4.4 and 5.1 µg/mL, 
and AUC0-t of 46.2 and 59.7 µg•h/mL were noted in female and male animals respectively at the 
75 mg/kg dose (D16). 
2.3.6.3 
28-Day Minipig Study 
This GLP study was designed to assess the toxicity and TK of SRA737 following daily PO 
administration to minipigs for 28 consecutive days at doses of 0, 10, 40 or 75 mg/kg/day 
(~ 350, 1,400 or 2,625 mg/m2).  No recovery animals were included.  
Toxicological findings in this study were broadly consistent with those observed in the mouse 
study (including hematological and lymphoid changes), and in keeping with the compound’s 
mechanism of action, although often at a greater severity than previously noted.   
Six animals were prematurely terminated over the course of the study due to moribundity (viz: 
all high dose and two mid dose males terminated in Week 4, and one high dose female 
terminated in Week 3).  Significant lymphoid depletion predisposing to secondary infection of 
the liver, GI tract, and lung, or septicemia was noted in the premature decedent animals.   
A decrease in RBC parameters (including hemoglobin, RBC and reticulocyte count, and packed 
cell volume) were noted in male and female animals at 40 or 75 mg/kg/day at the end of the 
dosing period.  A slight to minimal increase in hematopoiesis was also noted in the femur, 
sternum, spleen and liver of most animals in these dose groups. 
Decreased white blood cell counts were also observed at the higher doses in female animals as 
was lymphoid atrophy of the spleen, thymus and other organs.  Minimal single cell necrosis in 
the gastrointestinal tract of these animals was also noted. 

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Low grade tubular atrophy of the testis and of the prostate was noted sporadically in male 
animals, with minimal to moderate ovarian toxicity noted in females.  Again, the toxicological 
relevance of these findings in immature minipigs to adult cancer patients is not considered 
development limiting. 
The highest non-severely toxic dose in this study was 10 mg/kg/day (~ 350 mg/m2/day). 
At this dose, maximal plasma concentrations ranged from 0.5–0.6 µg/mL and AUC0-t 
approximated 6.5 µg•h/mL in the male and female animals collectively on Day 28. 
2.3.6.4 
28-Day Monkey Study 
This GLP study was designed to assess the toxicity and toxicokinetics of SRA737 following daily 
oral administration to monkeys for 28 consecutive days at doses of 0, 2, 10, or 20 mg/kg/day 
(~ 0, 24, 120, or 240 mg/m2/day). A subset of animals in the control, and mid and high dose 
groups were retained on study for a two-week non-dosing recovery period. 
SRA737 was well tolerated at all dose levels with SRA737-related findings limited to a minimal 
non-regenerative decrease in red cell mass in males at doses ≥10 mg/kg/day and females at 
20 mg/kg/day, and reversible minimal decreases in lymphocytes and transient minimal 
increases in glucose concentration in females at 20 mg/kg/day; none of these changes had 
correlating microscopic findings and were considered to be non-adverse. There were no 
SRA737-related effects on any other parameter evaluated in this study. 
The no-observed-adverse-effect-level (NOAEL) was 20 mg/kg/day (~ 240 mg/m2/day). At this 
dose, mean maximal plasma concentrations (Cmax) of 3.2 and 2.3 µg/mL, and total exposure 
(AUC0-t) of 20.7 and 24.2 µg.h/mL were noted in male and female animals, respectively, on 
Day 28. 
2.3.6.5 
Toxicology Summary 
In summary, the toxicology findings were broadly similar between the mouse and minipig and 
consistent with SRA737’s mechanism of action.  Specifically, dose-dependent toxicological 
findings related to bone marrow toxicity, including variously decreased red and white cell 
parameters with increased medullary or extramedullary hematopoiesis and atrophy of lymphatic 
organs including the thymus was noted.  These findings were reversible on cessation of drug 
administration. 

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Toxicological findings in the monkey indicated SRA737 had the potential to cause findings 
similar to those observed in mouse and minipig, although at much greater plasma exposures. 
Toxicological findings in the GI tract were also observed in the minipig and in early mouse and 
monkey studies and changes in reproductive organs, particularly the testes, were also observed 
in the minipig and mouse, but not the monkey.  These latter changes were not reversible in the 
mouse; however, the relevance of these findings in sexually immature animals to adult cancer 
patients appears limited. 
As the combination agents in this study (gemcitabine ± cisplatin) also possess known 
hematological and GI toxicities, and some exacerbation of myelosuppression was observed in 
the murine triple combination toxicity study, the clinical combination of SRA737, gemcitabine 
and cisplatin may lead to augmented hematological and other toxicities in patients. 
2.4 
CLINICAL EXPERIENCE  
SRA737 had not been administered to humans prior to the concurrent initiation of this study and 
the ongoing monotherapy study. 
Several Chk1 and Chk1/2 inhibitors have however previously been investigated clinically.  The 
development of several first generation inhibitors was terminated due to unfavorable 
pharmaceutical properties and/or unmanageable toxicities including off-target cardiovascular 
liabilities.  Several second-generation Chk1 inhibitors are now in development.  
LY2606368, an unselective Chk1/Chk2 inhibitor administered by intravenous infusion is 
currently the most advanced second-generation agent.  This compound is currently the subject 
of a number of Phase 1 and 2 clinical studies both as monotherapy and in combination with 
various chemotherapeutic agents and radiotherapy.  Interim data from a number of these 
studies suggests that (putatively on-target) myelosuppression including high-grade neutropenia, 
is dose-limiting.  Favorable initial activity has also been noted with a PR rate of 38% in a study 
of 13 patients with HGSOC (Lee 2016). 
GDC-0575 an orally available Chk1 inhibitor is also currently being investigated in a Phase 1 
clinical trial in refractory solid tumors and lymphoma (refer to Section 2.2.3).   

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Dose escalation is ongoing in the SRA737 Phase 1 monotherapy trial and has been safely 
advanced through six single patient dose cohorts of 20, 40, 80, 160, 300 and 600 mg/day, 
administered on a continuous daily oral dosing regimen in 28-day cycles. 
Further information on SRA737 is available in the current version of the Investigator’s Brochure. 
2.4.1 
SRA737-01 (MONOTHERAPY) 
The SRA737-01 trial is a first-in-human (FIH) trial of SRA737 administered orally with 
continuous daily dosing as monotherapy. 
As of 02 July 2018, 69 subjects have been enrolled and received at least a single dose of 
SRA737.  Dose level cohorts at 20, 40, 80, 160, 300, 600 and 1000 mg once daily were 
completed without DLTs.  Two DLTs have been observed at the 1300 mg once daily dose, each 
being an inability to receive 75% of the planned SRA737 dose due to Grade 1/2 GI intolerability.  
After 1000 mg once daily dose level cohort was completed without DLT, a cohort receiving 
500 mg twice daily was added to determine if a twice daily dosing schedule can improve GI 
tolerability, given the half-life of SRA737 is approximately 10 hours.  One DLT was experienced 
by a subject in the 500 mg twice daily cohort; this was inability to receive 75% of the planned 
SRA737 dose due to grade 4 thrombocytopenia with grade 3 neutropenia and anemia. Cohort 
expansion subjects initially received 1000 mg once daily, however based on overall tolerability 
and gastrointestinal AEs (nausea, vomiting, and diarrhea), new subjects enrolled in expansion 
cohorts are receiving a dose of 800 mg once daily as of 15 Jun 2018.  
At the time of this amendment (7.0), AE data were available for a total of 61 subjects treated up 
to 02 July 2018. The majority (>90%) of the reported AEs were Grade 1 or Grade 2 in severity 
and the most commonly observed treatment emergent AEs (≥ 20%; all reported causalities) 
were fatigue and GI events (diarrhea, nausea, vomiting).  Additional AEs observed in ≥ 15% but 
< 20% of subjects included constipation and decreased appetite.  Serious AEs that were at least 
possibly related to SRA737 by investigator’s assessment and occurred in single subjects 
included: at the 1300 mg once daily dose level: Grade 3 neutropenia; at the 1000 mg once daily 
dose level: Grade 3 heart failure/cardiomyopathy (possible stress-related cardiomyopathy), 
asymptomatic Grade 3 QTc prolongation, Grade 3 pyrexia and Grade 2 nausea; at the 500 mg 
twice daily dose level: Grade 4 thrombocytopenia with Grade 3 neutropenia and anemia. 
Serious AEs of Grade 3 skin rash that were at least possibly related to SRA737 occurred in 2 
subjects, one at the 1000 mg once daily dose level and the other at 500 mg twice daily. 

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2.4.2 
SRA737-02 (IN COMBINATION WITH GEMCITABINE AND CISPLATIN OR 
GEMCITABINE ALONE) 
The SRA737-02 trial is a FIH trial of SRA737 administered orally intermittently in combination 
with cytotoxic chemotherapy.   
Enrollment to Stage 1 has concluded with 10 subjects enrolled across 3 cohorts.  Enrollment is 
currently proceeding in the low-dose gemcitabine combination in Stage 2 Dose Escalation 
cohorts.   
In Stage 1, DLTs (hematology toxicities/rash) in Cohorts 1 and 2 led to the reduction in the 
gemcitabine dose from a starting dose of 1250 mg/m2 in Cohort 1 to 875 mg/m2 in Cohort 2 and 
subsequently to 600 mg/m2 in Cohort 3.  Each of the 3 cohorts also received cisplatin at a dose 
of 80 mg/m2 and SRA737 at a dose of 20 mg.  No DLTs were observed in Cohort 3 of Stage 1.    
Further enrollment to Stage 1 was superseded by the activation of Stage 2 following 
Amendment 5.0 which introduced the low-dose approach to the gemcitabine combination.  As of 
06 Jul 2018, no DLTs have been observed in Stage 2 across the 35 subjects treated in dose 
escalation cohorts with dose levels as described in “Trial Status” contained in Section 2.   
At the time of this amendment (7.0), AE data were available for 33 subjects treated in Stage 2 
up to 27 June 2018. The majority (94%) of the reported AEs were Grade 1 or Grade 2 in 
severity.  Most commonly observed treatment-emergent AEs (≥ 20% of subjects) were: nausea, 
diarrhea, vomiting, fatigue, anemia, ALT increased, headache, influenza-like illness, 
neutropenia, back pain, and thrombocytopenia.  Two SAEs were considered by the investigator 
to be at least possibly related to SRA737: a Grade 1 fever (80 mg SRA737 + 100 mg/m2 
gemcitabine dose level cohort) which the subject recovered after 1 day and continued on 
treatment, and a Grade 2 deep vein thrombosis (150 mg SRA737 + 100 mg/m2 gemcitabine 
dose level cohort) which was resolved with sequalae after 2 days and SRA737 was withdrawn.     
The 500 mg SRA737 + 100 mg/m2 gemcitabine and 500 mg SRA737 + 50 mg/m2 gemcitabine 
dose level cohorts were completed in May 2018 without a DLT and the dose escalation 
proceeded to open a 500 mg SRA737 + 150 mg/m2 cohort in parallel with a 600 mg SRA737 + 
100 mg/m2 cohort.   

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2.5 
RATIONALE FOR THE PROPOSED TRIAL:  
Although progress has been made in many areas of clinical oncology, the treatment options for 
patients with cancer remain limited and continue to represent an area of high unmet medical 
need. In the continually evolving science of cancer drug development, combination therapies 
that leverage the mechanism of action of each agent represent a potentially important strategy 
for treating the highly complex biology of cancer. In addition, the ability to select patients for 
treatment based on relevant underlying genetic components of their disease provides a means 
for improving the potential for patient benefit without increasing overall risk.  
Consistent with this paradigm, this clinical trial has been designed to evaluate SRA737 in 
combination with low-dose gemcitabine. The recommended Phase 2 dose (RP2D) for the 
combination will be defined, while also evaluating which patients are most likely to benefit from 
the combination. Four indications have been selected as being most likely to represent potential 
areas for SRA737/gemcitabine efficacy, and the diagnostic test will be explored as a means to 
identify patients with the greatest likelihood of benefit from treatment. 
2.6 
BENEFIT/RISK ASSESSMENT   
SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Chk1, a central 
regulator of the DDR network.  The compound abrogates gemcitabine-induced G2/M arrest of 
HT29 human colon cancer cells at nanomolar concentrations and potentiates the anti-
proliferative and apoptotic activities of a range of DNA-damaging agents in human lung, 
pancreatic and colon cancer cell lines.  SRA737 has also shown chemosensitizing efficacy of 
gemcitabine or gemcitabine + carboplatin in a number of murine xenograft models.  In addition, 
the compound possesses the requisite PK, toxicological, and pharmaceutical properties for 
further clinical investigation. 
As described in Section 2.1.4, gemcitabine has the ability to greatly potentiate the cytotoxicity 
observed with SRA737 and other Chk1 inhibitors in preclinical models.  This effect is retained 
even when very low doses of gemcitabine are used.  Although tolerability of the combination of 
SRA737 and gemcitabine has been studied in mice and in a formal toxicology study in mini-
pigs, the optimal doses of gemcitabine and SRA737 when administered together in humans is 
not known and is the focus of this current study.  It is hypothesized that a very low dose of 
gemcitabine, well below what might be considered active as a single agent, might be sufficient 
to develop an active combination regimen with an optimal benefit-risk profile. 

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Given the strength of the data, the safety and preliminary activity of escalating doses of SRA737 
in combination with gemcitabine ± cisplatin in subjects with advanced solid tumors will be 
investigated.  The safety and activity of SRA737 in combination with gemcitabine will be further 
evaluated in expansion cohorts of prospectively-selected genetically-defined subjects with 
HGSOC, SCLC, STS and cervical/anogenital cancer. The indications selected for the expansion 
cohorts have been identified both on the scientific hypothesis of greater likelihood for benefit, as 
well as the high unmet medical need in these populations where alternative therapies are 
required. 
In a Phase 1 monotherapy trial of SRA737 (SRA737-01), subjects receive continuous daily 
doses in 28-day cycles. This trial is ongoing, and dose level cohorts of up to 1000 mg once daily 
have been completed without any DLT (refer to Section 2.4.1). These initial clinical findings are 
supported by the favorable tolerability and broad implied therapeutic window observed in the 
pivotal monkey toxicology study. The most likely target organs for SRA737 toxicity are the bone 
marrow and GI tract, which will be closely monitored in the ongoing studies. Although no 
significant nonclinical cardiac liabilities have been observed during the pivotal toxicity studies, 
cardiovascular safety assessments are included in the clinical study.  
During the conduct of the study, the sponsor is committed to perform ongoing review of safety 
data with careful oversight of the subject’s safety by the Cohort Review Committee. The 
protocol includes guidelines for the reduction, interruption and discontinuation of study treatment 
in the event of adverse events (Section 5.4 and Section 5.6). 
Based on the non-clinical and clinical information currently available, the balance between 
anticipated efficacy/benefits and the potential safety risks for SRA737 in combination with 
gemcitabine remains favorable.  

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3 
TRIAL DESIGN 
3.1 
CLINIAL TRIAL OBJECTIVES AND ENDPOINTS 
3.1.1 
PRIMARY OBJECTIVES AND ENDPOINTS 
Primary Objectives 
Endpoints 
To establish the safety profile of SRA737 
administered in combination with 
gemcitabine ± cisplatin.  
Safety parameters (referencing National Cancer 
Institute – Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] v4.03) including: 
incidence, seriousness, severity and causality of 
each adverse event (AE) to SRA737, cisplatin, 
and/or gemcitabine, timing of AE onset, AE 
duration, and AEs leading to interruption, 
modification, or discontinuation of study treatment, 
and primary reason for discontinuation of study 
treatment if other than disease progression [PD], 
laboratory (eg, clinical chemistry, hematology, 
urinalysis) and vital sign data. 
To determine the MTD of SRA737 
administered in combination with 
gemcitabine.  
The highest dose at which ≤ 33% of subjects have 
a dose-limiting toxicity (DLT) in a cohort of up to 
6 subjects. 
To define a RP2D of SRA737 administered 
in combination with gemcitabine. 
A safe and well tolerated dose and schedule that 
provides high exposure, based on all available PK, 
PDn, and safety parameter data from all cycles of 
therapy. 
 
3.1.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary Objectives 
Endpoints 
To characterize the PK profile of SRA737 
administered in combination with 
gemcitabine ± cisplatin. 
Plasma concentration-time profiles of SRA737 
based on PK parameters including but not limited 
to AUCinf, AUCtau, Cmin, Cmax, time to reach Cmax 
(Tmax), t½. 
To assess clinical activity of SRA737 in 
combination with gemcitabine.  Activity of 
SRA737 in combination with 
gemcitabine + cisplatin will also be explored 
as feasible based on the number of subjects 
enrolled. 
• 
ORR as measured by Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST 
v1.1) 
• 
Duration of response (DOR) 
• 
Disease control rate (DCR) 
• 
Time to response (TTR) 
• 
PFS 
• 
Time to Progression (TTP) 
• 
OS 
 

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3.1.3 
EXPLORATORY OBJECTIVES AND ENDPOINTS 
Exploratory Objectives 
Endpoints 
To assess the relationship between 
response and the presence of selected 
genetic alternations detected in tumor tissue 
or circulating tumor deoxyribonucleic acid 
(ctDNA). 
Objective response rate as measured by RECIST 
v1.1 and gene alterations in tumor tissue or ctDNA 
at baseline as measured by next generation 
sequencing (NGS). 
To explore possible clinical predictors of 
outcomes. 
Characteristics such as performance status, prior 
therapy, indication and other known or potential 
prognostic or predictive factors. 
To investigate the PDn of SRA737 in 
combination with gemcitabine in tumor 
tissue.  
Proof of target engagement and changes in 
mechanism of action biomarkers between baseline 
and on treatment with SRA737, including, but not 
limited to:  pSer296 Chk1, pS317 Chk1, and total 
Chk1.  
To investigate the PDn of SRA737 in 
combination with gemcitabine in surrogate 
tissues such as blood or peripheral blood 
mononuclear cell (PBMCs).  
Proof of target engagement and changes in 
mechanism of action biomarkers between baseline 
and on treatment with SRA737, including but not 
limited to:  Comet assay, pS296 Chk1, 
pS317 Chk1, pS345 Chk1, total Chk1, 
gammaH2AX and RAD51.  
 
3.2 
DESIGN OF CLINICAL TRIAL 
This is a multicenter, first-in-human, Phase 1/2, open-label, dose-escalation trial in subjects with 
advanced solid tumors.   
The trial will consist of 2 stages: 
• 
Stage 1:  SRA737 + gemcitabine + cisplatin Dose Escalation Phase.    
Upon implementation of Amendment v5.0, dose escalation in Stage 1 was halted. Ten 
subjects with solid tumors in cohorts of 3 to 6 subjects were enrolled in Stage 1 of the study.  
Subjects receiving the triplet combination when Amendment v5.0 was implemented 
continued to follow the treatment regimen and schedule of assessments for Stage 1 defined 
in Section 5 and Section 7, respectively. 
• 
Stage 2:  SRA737 + gemcitabine Dose Escalation and Cohort Expansion Phases 
Stage 2 began upon activation of Amendment v5.0.   
In the Dose Escalation Phase, approximately 30-40 subjects with solid tumors in cohorts of 
3 to 6 subjects will receive escalating doses of SRA737 in combination with varying doses of 
gemcitabine in 28-day cycles to establish the MTD.  Upon reaching the MTD for SRA737, or 
earlier (eg, when minimum efficacious dose range has been achieved or evidence of anti-
tumor activity observed), gemcitabine may be escalated to a maximum dose of 600 mg/m2 
(with corresponding decreases in the SRA737 dose, as necessary for safety).  

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In the Cohort Expansion Phase, approximately 20 prospectively-selected genetically-defined 
subjects will be enrolled in each of the 4 indication-specific cohorts: HGSOC, SCLC, STS, or 
cervical/anogenital cancer. These subjects will be treated at the MTD or a lower dose 
selected by the sponsor.   
The original study design schema is presented in Figure 7,an amended study design schema 
(with implementation of Amendment v5.0) is presented in Figure 8, and a further amended study 
design schema (with implementation of Amendment v6.0) is presented in Figure 9. 
Figure 7.  Original Study Design Schema (Protocol v1.0-4.0) 
 
 

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Figure 8.  Amendment v5.0 Study Design Schema 
 
Figure 9. Amendment v6.0 Study Design Schema 
 
High-grade serous ovarian 
cancer 
Small cell lung cancer 
Sarcoma 
Cervical/anogenital cancer 

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3.3 
DOSE ESCALATION SCHEME 
Dose escalation rules are described in Section 3.3.2. The goal of Stage 1 and Stage 2 Dose 
Escalation is to identify the doses and schedule of these agents given in combination that 
provide the optimal balance of safety and potential for efficacy.  The main objective is to 
escalate the dose of SRA737 across sequential cohorts until an MTD is reached.  Depending on 
emerging safety, PK, PDn, and preliminary efficacy data, the cytotoxic dose(s) (gemcitabine 
and/or cisplatin in Stage 1; gemcitabine in Stage 2) may be de-escalated or the frequency of 
their administration reduced.  For example, this approach could be pursued if toxicity precludes 
further escalation at dose levels with insufficient SRA737 exposure to produce the desired PDn 
effects. This approach could also be pursued in the absence of toxicity sufficient to preclude 
further escalation, that is, simultaneous with SRA737 dose escalation.    
Subjects will be recruited to cohorts according to a rolling 6 design.  In Stage 2, 3 to 6 evaluable 
subjects will be entered at each dose level and receive escalating or varying doses of SRA737 
and gemcitabine for the determination of MTD and safety and toxicity profile.  Alternative 
schedules of either agent in Stage 2 may also be tested if deemed appropriate.  Once the first 
subject has completed the observation period of 7 days after the first dose of gemcitabine 
subsequent subjects may start treatment at the same time, unless otherwise determined by the 
sponsor, based on emerging data from the study.  
• 
If a DLT (in 1 of 6 subjects) occurs at a concentration of SRA737 below 100 nM at Cmin 
24 hour (level below which we would not expect to see Chk1 inhibition from preclinical 
models), the dose of SRA737 may continue to be escalated in 100% increments.  After 
reaching a concentration of SRA737 above 100 nM at Cmin 24 hour, the dose of SRA737 
will be escalated in less than 100% increments, typically 25-75% increments, depending 
on the clinical data.  Dose escalation of SRA737 will cease once the MTD has been 
reached (defined in Section 3.5), unless the sponsor elects to stop prior to this.  Refer to 
Section 3.3.2 for dose escalation rules. 
• 
The sponsor may elect to escalate the dose of gemcitabine, for example if the minimum 
efficacious dose range for SRA737 has been reached or evidence of anti-tumor activity 
observed. The maximum possible dose of gemcitabine will be 600 mg/m2. 
• 
Alternative dosing/schedules for SRA737 and gemcitabine may be considered, as 
described in Section 5.1.   

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Subjects who receive fewer than 5 of the 6 (< 83%) planned doses of SRA737 in Stage 2 in 
Cycle 1 (from Cycle 1 Day 1 [C1D1] onwards) or do not receive all doses of gemcitabine in 
Cycle 1 for reasons other than IMP-related toxicity will not be evaluable for assessment of DLT 
and may be replaced in the cohort unless the sponsor elects to evaluate an alternative dosing 
schedule.  Reported safety information for these subjects will, however, be considered to guide 
the percentage change in dose levels. 
3.3.1 
COHORT REVIEW PROCESS 
A review of safety data and other supporting data required to make a recommendation with 
regard to dose escalation will be conducted prior to opening any new cohort.  Dose assignment 
for each cohort will be carried out, using all available data, by the sponsor in conjunction with 
the chief investigator (CI), and principle investigators (PIs).  Cohort Review Meetings will be 
held to determine if the dose level has been tolerated by the subjects, to determine if it is safe to 
escalate to a higher dose, and to determine the next dose level.  These reviews will be triggered 
when sufficient subjects have completed their first cycle of treatment at a particular dose.  
These meetings will be led by the sponsor and will include, at a minimum, the CI or his designee 
and a representative from each site with a subject in the cohort under discussion.  The safety 
data, including a list of DLTs and all AEs, will be reviewed along with all other available data 
such as PK and/or PDn data.   
Other topics to be discussed could include, but are not limited to whether the data suggest that 
testing of an alternative schedule should begin and if so, what initial dose and schedule would 
be tested. 
3.3.2 
DOSE ESCALATION DECISION RULES 
Dose levels of SRA737 and gemcitabine (and, for Stage 1, cisplatin) for subsequent cohorts will 
be determined, following a Cohort Review Meeting held when at least 3 evaluable subjects have 
completed the DLT observation window, or earlier if required for the safety of the subjects (eg, 
2 subjects with DLTs observed in the first 2 subjects).   
Decision criteria for dose escalation for Stage 2 are as follows: 
• 
If the data are available from a minimum of 3 subjects who have been treated in a cohort 
and no DLTs have been observed at that dose level, then dose escalation of SRA737 or 
gemcitabine can be considered.  Electively, a simultaneous reduction of the gemcitabine 
dose may also be undertaken.  

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• 
If the data are available from 3 subjects who have been treated in a cohort and 1 DLT has 
been observed at that dose level, then the cohort will be expanded to include 6 subjects. 
• 
If 2 DLTs have been observed at any dose level, the dose of gemcitabine, SRA737, or both 
will be de-escalated.  This could be accomplished with a lower dose for each administration 
or a less frequent administration of either agent during a cycle (eg, gemcitabine on Days 1 
and 15, and SRA737 on Days 2, 3, 16, and 17). 
• 
The next lower dose level will be expanded to include up to 6 subjects.  If this dose level is 
confirmed to be tolerable: 
• 
It may be defined as the MTD.   
• 
Alternatively, if the gemcitabine dose had been de-escalated and if the lower dose 
level of gemcitabine with SRA737 is confirmed to be safe in 3 to 6 subjects, further 
escalation of SRA737 is allowed for subsequent cohorts.   
• 
Or, if the SRA737 dose had been de-escalated to the next lower dose level or an 
intermediate dose level and confirmed to be safe in 3 to 6 subjects, further escalation 
of gemcitabine is allowed for subsequent cohorts.   
Table 3.  Dose Escalation Decision Making 
Number of 
Subjects with 
DLT(s) 
Action 
0/3 
Increase to next SRA737 or gemcitabine dose level 
1/3 
Treat up to 3 more subjects at same SRA737 and gemcitabine dose 
level 
≥2/3* 
Stop enrollment at that dose level, de-escalate and test a lower dose 
level.  Define the MTD or pursue an alternative dose escalation 
strategy as described above. 
Once a DLT has been seen or the cohort expanded up to 6 subjects 
1/6 
Continue dose escalation with up to 100% increment if SRA737 
below 100 nM at Cmin 24 hour, or 
For SRA737 above 100 nM at Cmin 24 hour, escalated in less than 
100% increments (typically 25-75%), depending on the clinical data. 
≥2/6* 
Stop enrollment at that dose level, de-escalate and test a lower dose 
level; Define the MTD or pursue an alternative dose escalation 
strategy as described above.  
*No additional subjects will be added to a cohort after a second DLT is observed. 
 

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3.4 
DEFINITION OF DOSE-LIMITING TOXICITY 
Due to anticipated overlapping hematological toxicities with chemotherapy and SRA737, 
hematological toxicities assessed as associated with chemotherapy should also be assessed for 
the relationship to SRA737.   
The DLT window is defined from the first Day -7 to -4 dose until the end of Cycle 1 (up to 
35 days). 
A DLT is defined as any highly probably or probably IMP-related (SRA737, gemcitabine, 
cisplatin) event of: 
• 
Grade 4 neutropenia or thrombocytopenia that lasts for > 7 days despite withholding dosing 
and/or providing supportive care (eg, hematopoietic growth factors) 
Note:  In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood 
count must be performed at least on Day 7 after the onset of the event to determine if a DLT 
has occurred.  The investigator must continue to monitor the subject closely until resolution 
to ≤ Grade 3. 
• 
Febrile neutropenia 
• 
A ≥ Grade 3 thrombocytopenia with ≥ Grade 3 bleeding 
• 
A ≥ Grade 3 nonhematological toxicity with the following possible exceptions if agreed by the 
sponsor after discussion during the Cohort Review Meeting: 
o Alopecia of any grade 
o Grade 3 or 4 nausea or vomiting, in subjects that have not received optimal treatment 
with antiemetics  
o Grade 3 or 4 diarrhea, in subjects that have not received optimal treatment with 
antidiarrheal medication 
o Transient, asymptomatic Grade 3 biochemical abnormalities if agreed by the sponsor’s 
Medical Monitor and the CI 
o Grade 3 fatigue, unless there is an increase by at least 2 grades from baseline 
(classed as grade prior to first dose of SRA737 [or gemcitabine if the SRA737 dose for 
PK is omitted])  
• 
Inability to receive all doses (Stage 2) of gemcitabine dose in Cycle 1 due to IMP-related 
toxicity (unless not applicable due to the sponsor having elected to evaluate an alternative 
dosing schedule) 
• 
Inability to receive 5 of the 6 (83%, Stage 2) planned doses of SRA737 (or the equivalent if 
the sponsor elects to evaluate an alternative dosing schedule) in Cycle 1 due IMP-related 
toxicity 

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Dose-limiting toxicities defined above will be considered for the purposes of dose escalation 
decisions; however, should cumulative toxicity become apparent this will also be taken into 
consideration when determining either the next dose level or the RP2D(s). 
All DLTs must be reported to the sponsor or sponsor’s designee within 24 hours of site staff 
becoming aware of the DLT, including any change made to the grade or causality of an AE that 
may alter its DLT status, as this may affect dose escalation decision making. 
3.5 
DEFINITION OF MAXIMUM TOLERATED DOSE AND RECOMMENED PHASE 2 
DOSE 
If 2 out of up to 6 subjects at the same dose level experience a DLT, as defined in Section 3.4, 
the MTD will be determined as a lower dose level. 
The R2PD will be defined at the end of the study and will take all clinically relevant toxicity, PK 
and PDn data into account.  The RP2D will be a dose equal to or less than the MTD. 
3.6 
COHORT EXPANSION SCHEME 
To further evaluate the safety profile and to preliminarily explore efficacy, prospectively-selected 
genetically-defined subjects will be enrolled in 4 indication-specific expansion cohorts to be 
treated with SRA737 and gemcitabine at the MTD or a lower dose selected by the sponsor.  
Each expansion cohort will enroll approximately 20 subjects from the following indications: 
HGSOC, SCLC, STS, and cervical/anogenital cancer. 
Determination of the MTD is likely to occur prior to the initiation of the expansion cohorts; 
however, enrollment for expansion cohorts may begin prior to the completion of dose escalation 
and determination of MTD or RP2D, if there is evidence of anti-tumor activity or the minimal 
plasma concentration of SRA737 is maintained above a threshold of 100 nM (the level at which 
sustained Chk1 inhibition is anticipated) at 24 hours after dosing (Cmin 24h). Eligible subjects 
may be enrolled in the Cohort Expansion at the highest dose level determined to be safe and 
tolerable in the Dose Escalation Phase.  If a subject who meets the eligibility criteria for the 
expansion cohorts enrolls to a Dose Escalation Cohort, that subject will count toward the 
sample size of 20 for that indication specific cohort.  Subjects in expansion cohorts may be able 
to undergo intra-subject dose escalation to receive higher doses of SRA737 and/or gemcitabine 
depending on results from the ongoing escalation phase (see Section 3.7). 

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The goal of the expansion cohorts is to assess SRA737 in combination with gemcitabine across 
subjects who have a range of genomic profiles of interest as described in inclusion criterion 10.  
As this is an early stage clinical trial, the role of diagnostic testing is being explored and refined 
in an effort to improve likelihood of patient benefit. In order to ensure the genetic selection 
component reflects the current scientific understanding and is also consistent with an effective 
exploration of the testing as it relates to patient benefit, the sponsor may refine particular 
genomic profile requirements in any expansion cohort based on observations of tumor response 
and clinical benefit in the ongoing study and/or other emerging clinical and nonclinical data.  
The sponsor may also select for alternative genomic profiles in the event profile(s) not 
associated with tumor responses are overrepresented in subjects already enrolled. For 
example, if no responses have been seen in subjects with deleterious KRAS and TP53 
mutations across tumor types, the sponsor may elect to restrict further enrollment of subjects 
with this particular genomic profile. Also, the sponsor may select subjects such that sufficient 
numbers of genetic variants within an indication are studied (for example BRCA mutant and 
BRCA wild-type). The maximum enrollment in each of these indication cohorts will be 
maintained at approximately 20 subjects total.   
3.7 
INTRA-SUBJECT DOSE ESCALATION FOR STAGE 2 
Any subject that remains on treatment at a lower dose level of SRA737 may, at the discretion of 
the investigator and with the agreement of the sponsor, be offered treatment at the higher dose 
of SRA737 once that higher dose level in combination with the corresponding dose of 
gemcitabine has been shown to be safe.  While a specific safety threshold has not been defined 
by the protocol, subjects who are permitted to escalate their SRA737 dose must not have 
experienced significant SRA737-related toxicity at the prior dose level.  There is no limit on the 
number of intra-subject dose escalations of SRA737 for a subject although only one dose level 
increase can be undertaken each cycle.  Similar intra-subject dose escalation may be 
undertaken for gemcitabine should gemcitabine escalation be carried out as described in 
Section 5.2. 
3.8 
 SUBJECT EVALUABILITY 
3.8.1 
DLT EVALUABLE 
All subjects receiving at least 5 out of the 6 (83%) planned doses of SRA737 and all doses of 
gemcitabine (or the equivalent if the sponsor elects to evaluate an alternative dosing schedule) 

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within Cycle 1 and those subjects receiving less than these planned doses of SRA737 due to 
IMP-related toxicity will be evaluable for dose review decisions. 
3.8.2 
REPLACEMENT OF SUBJECTS 
In the Dose Escalation Phase, if agreed by the sponsor, subjects will be replaced if they receive 
fewer than 5 of the 6 (83%) planned doses of SRA737 and/or not all doses of gemcitabine (or 
the equivalent if the sponsor elects to evaluate an alternative dosing schedule) during the DLT 
period for reasons other than IMP-related toxicity. 
In the Cohort Expansion Phase, subjects who are not response evaluable (as defined in 
Section 11.1.2) will be replaced in order to achieve approximately 20 response-evaluable 
prospectively-selected genetically-defined subjects in each indication-specific expansion cohort.   
4 
SUBJECT SELECTION AND ENROLLMENT 
Subjects who have consented to participate in the trial must first be entered in the electronic 
data capture (EDC) system by site staff and be allocated a subject number by the EDC system.  
Once the investigator or designated site representative has confirmed the eligibility of the 
subject, the site must submit a completed eligibility checklist, and receive confirmation of 
eligibility and confirmation of the assigned dose level from the sponsor or sponsor’s designee 
before the subject may be enrolled.   
4.1 
NUMBER OF SUBJECTS 
Approximately 140 subjects will be enrolled in this study. 
4.2 
SUBJECT SELECTION CRITERIA 
Subjects must fulfill the eligibility criteria listed in Sections 4.2.1 and 4.2.2 in order to participate 
in this study.   
4.2.1 
INCLUSION CRITERIA  
Dose Escalation and  Cohort Expansion: 
1. Written (signed and dated) informed consent and be capable of co-operating with 
treatment and follow-up. 
2. In the Dose Escalation Phase, subjects with locally advanced or metastatic, 
histologically or cytologically proven solid tumor, relapsed after or progressing despite 

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conventional treatment for which no conventional therapy is considered appropriate by 
the investigator or is declined by the subject.   
3. Life expectancy of at least 12 weeks. 
4. World Health Organization (WHO) performance status of 0-1 (Appendix 1). 
5. Hematological and biochemical indices within the ranges shown below measured within 
1 week prior to the subject receiving their first dose of SRA737 (or gemcitabine if the 
SRA737 dose for PK is omitted). 
Laboratory Test 
Value Required 
Hemoglobin 
≥ 90 g/L 
Absolute neutrophil count 
≥ 1.5 × 109/L 
Platelet count 
≥ 100 × 109/L 
Bilirubin 
≤ 1.5 × upper limit of normal (ULN) unless 
due to Gilbert’s syndrome in which case up to 
3 × ULN is permissible 
Alanine aminotransferase and aspartate 
aminotransferase and Alkaline Phosphatase    
≤ 2.5 × ULN unless raised due to tumor in 
which case up to 5 × ULN is permissible 
Serum Creatinine 
≤ 1.5 × ULN   
Electrolytes: magnesium, potassium and 
calcium 
If electrolyte levels are low, it must be 
demonstrated that they can be normalized 
and maintained using supplements prior to 
the subject beginning study treatment. 
Supplement use should continue while on 
study as appropriate. 
 
6. Subjects who are 18 years or older at the time consent is given. 
7. Subjects must have archival tumor tissue for tumor profiling OR accessible tumor and 
willingness to consent to a biopsy for the collection of tumor tissue.  Refer to Section 
7.1.1 for more information. 
Cohort Expansion: 
8. Subjects in the indication-specific cohort expansion must have histologically or 
cytologically proven advanced malignancy of the types specified in Inclusion 
Criterion 11, for which no conventional therapy is considered appropriate by the 
investigator or is declined by the subject. 
9. Have measurable disease according to RECIST v1.1 criteria. 

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10. Subjects must have predicted sensitivity to Chk1 inhibition based on factors including: 
genetic profiling of tumor tissue or ctDNA, HPV status, and germline BRCA1 and BRCA2 
gene status. All subjects will have genetic profiling from tumor tissue or ctDNA; profiling 
will be performed prospectively if required to evaluate Chk1 sensitivity or otherwise 
performed retrospectively. 
a. For subjects with HGSOC, documented somatic or germline BRCA1 and BRCA2 
wild-type status will confer eligibility without requirement for prospective genetic 
profiling. If documented BRCA status is not available, genetic profiling may be 
performed prospectively to determine eligibility. 
b. Subjects with SCLC are eligible without requirement for prospective genetic profiling 
on the basis of very high prevalence of cancer related alterations in the tumor 
suppressor genes (eg, TP53 and RB1) in this population. 
c. For subjects with STS, and any others for whom genetic profiling is performed 
prospectively, eligibility will be determined by the sponsor’s review of genetic 
abnormalities detected in genes in the following categories, as detailed in 
Appendix 6: 
− Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as 
RB1, TP53, etc. For relevant cancers, positive human papilloma virus (HPV) 
status is also considered for eligibility. 
− The DNA damage response pathway including ATM, BRCA1, BRCA2, mismatch 
repair genetic alterations and/or high microsatellite instability. 
− Genetic indicators of replicative stress such as gain of function/amplification of 
Chk1 or ATR or other related gene. 
− Oncogenic drivers such as MYC, CCNE1, etc. 
d. For subjects with anogenital cancer, known HPV positive status will confer eligibility 
without requirement for prospective genetic profiling. If HPV status is not known or 
not positive, genetic profiling (or HPV testing where appropriate) may be performed 
prospectively to determine eligibility. Subjects with cervical cancer or squamous cell 
carcinoma of the anus are eligible without requirement for prospective genetic 
profiling based on the very high prevalence of HPV positivity in these populations. 
11. Subjects must meet one of the following criteria: 
a. HGSOC, defined by the following: 
i. 
Histologically confirmed high-grade serous ovarian, fallopian tube, or primary 
peritoneal cancer. 
ii. 
Platinum-resistant or refractory disease (defined in Section 2.2.1), or 
intolerance of platinum therapy.  

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b. Small Cell Lung Cancer 
i. 
Must have received at least 1 but no more than 3 prior regimens for advanced 
disease, unless approved otherwise for the sponsor.  
c. Soft Tissue Sarcoma 
i. 
Including undifferentiated pleiomorphic sarcoma / malignant fibrous 
histiocytoma (MFH) (including high-grade spindle cell sarcoma / pleomorphic 
liposarcomas), leiomyosarcoma, and dedifferentiated liposarcomas.  Other 
types of STS may be eligible with sponsor’s approval. 
ii. 
Must have received at least 1 but no more than 3 prior regimens for advanced 
disease, unless approved otherwise for the sponsor. 
d. Cervical/Anogenital Cancer 
i. 
Including all cervical carcinoma and advanced / metastatic squamous cell 
carcinoma of the anus, penis, vagina, and vulva.  
ii. 
Must have received at least 1 but no more than 3 prior regimens for advanced 
disease, unless approved otherwise for the sponsor.  
4.2.2 
EXCLUSION CRITERIA 
1. Have received prior or current anticancer therapy within the noted time periods prior to 
receiving SRA737 and have recovered from toxicity consistent with exclusion criterion 5:  
a. Radiotherapy (except for symptom control and where the lesions will not be used as 
measurable disease), chemotherapy, PARP inhibitors, other targeted therapies, or 
other IMPs within 2 weeks 
b. Nitrosoureas or Mitomycin C within 6 weeks 
c. Any prior treatment with a Chk1 inhibitor, or prior treatment with an ATR inhibitor 
within 6 months. 
2. No more than 3 previous treatment regimens for advanced disease (not applicable to 
HGSOC expansion cohort), unless otherwise approved by sponsor.  Prior gemcitabine 
therapy is permitted as previous therapy. 
3. Other malignancies within the past 2 years with the exception of adequately treated 
tumors that are associated with an expected 5-year disease-free survival of ≥ 95%. 
4. If, in the opinion of the investigator, the subject is highly likely to experience clinically 
significant myelosuppression, based on previous experience with chemotherapy. 
5. Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1.  
Exceptions to this are alopecia or certain toxicities, which in the opinion of the 
investigator and the sponsor’s Medical Monitor should not exclude the subject.  
6. History of allergy to gemcitabine. 

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7. New or progressing brain metastases.  Subjects with brain metastases that have been 
asymptomatic and radiologically stable over an 8-week period and have not been treated 
with steroids during that time may be included with approval from the sponsor.   
8. Women of childbearing potential (WOCBP) or women who are already pregnant or 
lactating.  However, those subjects who have a negative serum or urine pregnancy test 
before enrollment and agree to use 2 forms of contraception as per Appendix 4 or agree 
to sexual abstinence, effective from the first administration of SRA737, throughout the 
trial and for 6 months afterwards are considered eligible.  
9. Male subjects with partners of child-bearing potential, unless they agree to take 
measures not to father children by using a barrier method of contraception defined per 
Appendix 4, effective from the first administration of SRA737, through the trial and for 
6 months after their final SRA737 dose.  Men with pregnant or lactating partners must be 
advised to use barrier method contraception (eg, condom plus spermicidal gel) to 
prevent exposure of a fetus or neonate. 
10. Major surgery from which the subject has not yet recovered. 
11. At high medical risk because of nonmalignant systemic disease including active 
uncontrolled infection. 
12. Known to be serologically positive for hepatitis B, hepatitis C or human 
immunodeficiency virus. 
13. Serious cardiac condition, such as concurrent congestive heart failure, prior history of 
class III/ IV cardiac disease (New York Heart Association [NYHA] - refer to Appendix 3), 
left ventricular ejection fraction < 45% at baseline, history of cardiac ischemia within the 
past 6 months, or prior history of cardiac arrhythmia requiring treatment, unless 
approved by the sponsor. 
14. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of 
bone marrow within the previous 8 weeks.   
15. Peanut allergy unless this restriction is removed by the sponsor (refer to Section 6.1 for 
additional details).   
16. QTcF > 450 msec in adult males and > 470 msec in adult females. 
17. Impairment of GI function or GI disease that may significantly alter the absorption of 
SRA737 (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or 
malabsorption syndrome). 
18. Not able to swallow capsules without chewing or crushing. 
19. Is a participant or plans to participate in another interventional clinical trial, whilst taking 
part in this Phase 1/2 study of SRA737.  Participation in an observational trial or 
interventional clinical trial which does not involve administration of an IMP and which 
would not place an unacceptable burden on the subject in the opinion of the investigator 
and sponsor would be acceptable. 

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20. Any other condition which in the investigator’s opinion would not make the subject a 
good candidate for the clinical trial. 
5 
DOSAGE AND TREATMENT ADMINISTRATION 
5.1 
TREATMENT SCHEDULE 
In both study stages, subjects will take a single PO dose of SRA737 prior to the start of Cycle 1, 
on a single day between Day -7 and Day -4 to assess PK parameters up to 48 hours postdose. 
The treatment schedule starting with Cycle 1 for Stage 1 and Stage 2 regimens is described in 
Table 4. 
Table 4.  Treatment Schedules 
 
Cycle 
Duration  
SRA737 Dosing 
Gemcitabine 
Dosing 
Cisplatin 
Dosing 
Stage 1 
SRA737+GC 
21 days 
Days 2, 3, 9 and 10 
Days 1 and 8 
Day 1 
Stage 2 
SRA737+G 
28 days 
Days 2, 3, 9, 10, 16 and 17 
Days 1, 8, and 15 
Not 
applicable 
SRA737+GC = SRA737 in combination with gemcitabine and cisplatin; SRA737+G = SRA737 in 
combination with gemcitabine alone. 
 
Stage 1 consists of SRA737 administered in combination with gemcitabine and cisplatin on a 
21-day cycle (Figure 10).  Subjects in Stage 1 have received: 
• 
Gemcitabine, administered IV over 30 minutes on Days 1 and 8.  The starting dose of 
gemcitabine for Cohort 1 was 1250 mg/m2/day 
• 
Cisplatin, administered IV over 2 hours following gemcitabine on Day 1 of each cycle with 
pre- and post-infusion hydration.  The starting dose of cisplatin for Cohort 1 was 
80 mg/m2/day.   
• 
SRA737, taken PO as described in Section 6.1.3, approximately 24 and 48 hours after the 
end of the Day 1 and Day 8 gemcitabine infusions (ie, on Days 2, 3, 9, and 10).  The starting 
dose of SRA737 for Cohort 1 was 20 mg/day.   
o If the dose of gemcitabine is not administered or is delayed by more than 7 
days, the doses of SRA737 will also be omitted or delayed by the same 
number of day to start 24 hours after the end of the gemcitabine infusion. 

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Figure 10.  Stage 1 Treatment Schedule (SRA737/Gemcitabine/Cisplatin) 
 
 
 
Stage 2 consists of SRA737 administered in combination with gemcitabine on a 28-day cycle 
(Figure 11).  Subjects in Stage 2 will receive: 
• 
Gemcitabine, administered IV over 30 minutes on Days 1, 8 and 15.  Gemcitabine will be 
administered at a starting dose for Cohort 1 of 300 mg/m2. The dose and schedule may be 
modified based on accumulating data. 
• 
SRA737, taken PO as described in Section 6.1.3, approximately 24 and 48 hours after the 
end of the Day 1, 8, and 15 gemcitabine infusions (ie, on Days 2, 3, 9, 10, 16, and 17).  The 
starting dose for dose escalation Cohort 1 was 40 mg/day.  
o If the dose of gemcitabine is not administered or delayed, the doses of 
SRA737 will also be omitted or delayed to start 24 hours after the end of the 
gemcitabine infusion. 

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Figure 11.  Stage 2 Treatment Schedule (SRA737/Gemcitabine) 
 
 
Treatment with SRA737 may continue until discontinuation of either gemcitabine + cisplatin or 
gemcitabine alone, PD, withdrawal of consent, unacceptable toxicity, or the investigator believes 
treatment with SRA737 should cease for any other reason.  Treatment duration for Stage 2 is 
further described in Section 5.3. 
Alternative dosing/schedules for SRA737 and gemcitabine including but not limited to those 
listed below will be considered by the sponsor based on emerging safety, PK, and PDn data 
during the study and following a discussion between sponsor, CI and PIs.   
• 
Gemcitabine on Days 1 and 15, and SRA737 at current dose level on Days 2, 3, 16, 
and 17. 
• 
Start dosing of SRA737 earlier, such as at 12 and 36 hours after the end of the 
gemcitabine infusion. 
• 
Reduce the frequency of dosing of SRA737 to 1 day rather than 2 days following 
chemotherapy. 
• 
Increase the frequency and/or duration of dosing of SRA737. 
• 
Twice-daily dosing of SRA737. 
5.2 
DOSE LEVELS 
The dose level of SRA737 will be assigned following discussion of all clinically relevant toxicity 
and available PK/PDn data from previous dose level(s) between the sponsor, the CI, and PIs. 

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Dose levels of SRA737 will be guided by the dose escalation rules as described in Section 3.  
With the implementation of Amendment v5.0, no further dose escalations were attempted in 
Stage 1.   
In Stage 2, the starting dose of SRA737 was 40 mg/day and the starting dose of gemcitabine 
was 300 mg/m2. Lower doses of gemcitabine will be permitted if necessary to allow for the 
maintenance of SRA737 dosing or the continuation of SRA737 dose escalation.  The de-
escalated gemcitabine dose level and schedule will be determined after a review and discussion 
of all clinically relevant safety data between the sponsor, CI, and PIs.   
Growth factor support will be permitted to allow for continued dose escalation of SRA737.   
Once the dose escalation of SRA737 is complete, or earlier, it may be decided to explore further 
dose escalation cohorts with a stepwise escalation of gemcitabine dose to a maximum of 
600 mg/m2, if fewer than 2 DLTs were observed at the previous dose level.  If this is pursued, 
prophylactic or early interventional use of granulocyte-colony stimulating factor (G-CSF) could 
be considered as well as enrolling only those subjects whose baseline absolute neutrophil count 
is ≥ 2.0 × 109/L.  
5.3 
DURATION OF STUDY TREATMENT 
5.3.1 
SRA737 
Treatment with SRA737 may continue until discontinuation of either gemcitabine + cisplatin or 
gemcitabine alone, PD, withdrawal of consent, unacceptable toxicity, or the investigator believes 
treatment with SRA737 should cease for any other reason.  Subjects will undergo the Safety 
Follow-up (SFU) visit 30 days after discontinuation of SRA737.   
5.3.2 
GEMCITABINE AND CISPLATIN 
Treatment with chemotherapy (gemcitabine alone or gemcitabine + cisplatin) may continue until 
discontinuation of SRA737, PD, withdrawal of consent, unacceptable toxicity, or the investigator 
believes treatment with chemotherapy should cease for any other reason.  The duration of 
chemotherapy treatment should follow local treatment guidelines specific to the subject’s 
indication, although, in general, cisplatin should be limited to 6 cycles or less to avoid 
cumulative toxicity.  While there is no protocol mandated cap on the number of gemcitabine 
cycles allowed, once a subject discontinues SRA737, his/her participation in the study will end 
after the SFU visit.  For subjects with an objective response who do not start new anticancer 

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therapy and remain on gemcitabine, they should stay in long-term follow-up (LTFU) until PD or 
start of another anticancer therapy.    
5.4 
DOSE MODIFICATIONS  
The schedule and/or dose may be reduced for all subjects depending on emerging safety 
information.  Decisions regarding treatment modification for individual subjects will be based on 
the following assessments: 
• 
Laboratory values and AE observations from the day of dosing, to determine if treatment 
can be administered or should be withheld; 
• 
Lowest (nadir) laboratory values and worst grade AE observations since the previous dose 
of study drug(s), to determine if a dose reduction is recommended. 
Decisions to delay or adjust the dose of SRA737 and/or gemcitabine ± cisplatin should be made 
conservatively, using the guidelines for the most severe AEs and the worst scenario of the 
recommended dose reduction(s).  Following dose reductions made due to hematological 
toxicity, the dose may be re-escalated when toxicity has resolved to appropriate levels (refer to 
Table 6). If the dose is reduced for reasons other than hematological toxicity it may be 
re-escalated if clinically appropriate, in consultation with the sponsor.  If any subject requires a 
delay in dosing for more than 28 days, the subject should be discontinued from treatment (see 
Section 5.6). 
5.4.1 
DOSE REDUCTIONS OF SRA737 
Granulocyte-colony stimulating factor may be administered for treatment of neutropenia to avoid 
dose delays and reductions of SRA737 and/or gemcitabine.  If G-CSF and/or reduction in the 
doses or frequency of chemotherapy is not successful or is not considered appropriate, 
consideration will be given to reducing the dose or frequency of SRA737 (eg, from 2 days to 1 
day following each dose of gemcitabine).   
If toxicity occurs at a concentration of SRA737 below 100 nM at Cmin 24 hour (level below which 
we would not expect to see Chk1 inhibition from preclinical models), no reduction of SRA737 is 
required.   
5.4.2 
DOSE MODIFICATIONS FOR GEMCITABINE AND CISPLATIN  
Standard dose reductions are provided below for common hematological and nonhematological 
toxicities for gemcitabine and cisplatin.  

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Following dose reductions made due to hematological toxicity, the dose may be re-escalated 
when toxicity has resolved to appropriate levels (refer to Table 6). If the dose is reduced for 
reasons other than hematological toxicity it may be re-escalated if clinically appropriate, in 
consultation with the sponsor. 
5.4.3 
TREATMENT MODIFICATIONS ON DAY 1 
If treatment is withheld on Day 1 in response to toxicity, all agents must be withheld.  
Hematological dose modification recommendations for SRA737 in combination with gemcitabine 
(± cisplatin) at Day 1 are described in Table 5. 

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Table 5.  Gemcitabine/Cisplatin and Gemcitabine Alone Dose Modifications for 
Hematologic Toxicity  
Observation 
Recommended Action 
Observation on Day 1 
• 
WBC ≥ 3.0 × 109/L AND  
• 
Neutrophils ≥ 1.5 × 109/L AND  
• 
Platelets ≥ 100 × 109/L 
Treat on time;  
For Cycle 2 and beyond, chemotherapy doses will 
be based on AEs observed in the previous cycle 
as described below 
• 
WBC < 3.0 × 109/L AND/OR  
• 
Neutrophils < 1.5 × 109/L AND/OR  
• 
Platelets < 100 × 109/L 
Withhold all study drugs for at least 1 week, or up 
to 28 days if required, until  
• 
WBC ≥ 3.0 × 109/L AND  
• 
Neutrophils ≥ 1.5 × 109/L AND  
• 
Platelets ≥ 100 × 109/L,  
• 
Then resume dosing per guidelines below 
Lowest (Nadir) Counts and AEs in Previous Cycle 
• 
Neutrophils ≥ 0.5 × 109/L OR < 0.5 × 109/L for 
≤ 7 days AND 
• 
Platelets ≥ 25 × 109/L 
No Change 
• 
Neutrophils < 0.5 × 109/L for > 7 days 
AND/OR 
• 
Platelets < 25 × 109/L 
First Occurrence:  Reduce gemcitabine to 75% of 
the previous dose and cisplatin by 1 dose level; 
no change to SRA737 dose. 
Second Occurrence:  Reduce gemcitabine to 75% 
of the previous dose and/or SRA737 to the dose 
level previously explored depending on whether 
toxicities have occurred at a concentration of 
SRA737 above 100 nM at Cmin 24 hoursa; reduce 
cisplatin by 1 dose level. 
Third Occurrence:  Reduce SRA737 to the dose 
level previously explored or reduce SRA737 
frequency. 
Fourth Occurrence:  Permanently discontinue 
study drugs unless the investigator considers 
continuation of treatment to be in the best interest 
of the subject and the sponsor’s Medical Monitor 
or designee approves continued treatment.  
Alternative dosing schedules may be utilized to 
allow improved tolerability. 
• 
Febrile neutropenia  
• 
Grade 3 or Grade 4 infection with ≥ Grade 3 
neutropenia 
• 
Thrombocytopenic bleeding (≥ Grade 3 
bleeding with ≥ Grade 3 thrombocytopenia) 
Note:  Dose levels for cisplatin include 80, 60, and 40 mg/m2.     
a. As communicated at the prior cohort review meeting. 
 
5.4.4 
TREATMENT MODIFICATIONS ON DAY 8 (AND DAY 15 IN STAGE 2) 
When treatment with gemcitabine is administered on Day 8 (and Day 15 in Stage 2), adjustment 
guidelines are described in Table 6. 

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Table 6.  Recommendations for Modifying Study Drug on Day 8 in Stage 1 and Day 15 in 
Stage 2 for Hematologic Toxicity 
Observation on Day 8 / 15 
Recommended Action 
Neutrophils ≥ 1.0 × 109/L  
AND 
Platelets ≥ 100 × 109/L 
Treat on time and administer full dose of gemcitabine 
and SRA737 
Neutrophils ≥ 0.5 to < 1.0 × 109/L  
AND/OR 
Platelets ≥ 50 to < 100× 109/L 
Treat on time and reduce gemcitabine dose to 75% of 
the previous dose; no change to SRA737 dose 
Neutrophils < 0.5 × 109/L  
AND/OR 
Platelets < 50 × 109/L 
AND/OR Febrile neutropenia 
AND/OR Thrombocytopenic bleeding 
(≥ Grade 3 bleeding with ≥ Grade 3 
thrombocytopenia) 
Withhold both study drugs for 1 week, or longer if 
required. 
• 
If neutrophils ≥ 1.0 × 109/L AND Platelets 
≥ 100 × 109/L within 7 days, resume dosing and 
reduce gemcitabine to 75% of the previous dose 
level.   
• 
If not recuperated within 7 days, re-assess at the 
time of the next scheduled dose, ie, either on 
Day 1 of the next cycle. 
 
Note: Following dose reductions made due to hematological toxicity, the dose may be re-
escalated when toxicity has resolved to appropriate levels. If the dose is reduced for reasons 
other than hematological toxicity it may be re-escalated if clinically appropriate, in consultation 
with the sponsor. 
 
5.4.5 
TREATMENT MODIFICATIONS DUE TO NONHEMATOLOGIC ADVERSE 
EVENTS 
On any day of any cycle, the presence of specific nonhematologic AEs should result in 
treatment modification in accordance with the guidelines provided below (Table 7). 

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Table 7.  Dose Modifications for Toxicities of Stomatitis or Diarrhea 
Grade 
Stomatitis 
Diarrhea 
Dose Reductions 
1 
Painless ulcers, erythema 
or mild soreness 
Increase of 2-3 stools/day or 
mild increase in loose watery 
colostomy output 
100% doses 
2 
Painful erythema, edema, 
or ulcers but can eat 
Increase of 4-6 stools, or 
nocturnal stools or mild increase 
in loose watery colostomy output 
Omit gemcitabine, 
cisplatin if relevant, and 
SRA737 until resolved, 
then resume at 100% 
doses 
3 
Painful erythema, edema, 
or ulcers and cannot eat 
Increase of 7-9 stools/day or 
incontinence, malabsorption, or 
severe increase in loose watery 
colostomy output 
Omit all IMPs until 
resolved, then reduce 
gemcitabine to 75% of 
previous dose and 
cisplatin (except for 
mucositis) by 1 dose 
level.  Consider reducing 
SRA737 to the dose level 
previously explored  
4 
Mucosal necrosis, 
requires parenteral 
support 
Increase of 10 or more 
stools/day or grossly bloody 
diarrhea, or grossly bloody 
colostomy output or loose watery 
colostomy output requiring 
parenteral support, dehydration 
Omit all IMPs until 
resolved, then reduce 
gemcitabine by 50% of 
the original dose, 
cisplatin (except for 
mucositis) by 1 dose 
level, and SRA737 to the 
dose level previously 
explored 
 
• 
Doses reduced for toxicity may be re-escalated if clinically appropriate, in consultation with 
the sponsor. 
• 
If doses must be omitted for Grade 2 toxicity twice in previous cycles, then commence next 
cycle chemotherapy at 75% lower dose level when treatment is resumed. 
5.4.5.1 
Renal Impairment 
Gemcitabine should be used with caution in subjects with a creatinine clearance (CrCl) 
< 30mL/min; however, no specific dosing recommendations for gemcitabine have been made.   
Dosing with cisplatin should be withheld if calculated CrCl is less than 60 mL/min.  Cisplatin 
induced nephrotoxicity is dose related and cumulative.  It manifests early by elevations in blood 
urea, creatinine, and wasting of potassium and magnesium.  Renal function, fluid and electrolyte 
balance must return to normal prior to subsequent doses.  Renal toxicity may be irreversible and 
is more prolonged and severe with repeated courses.  Avoid concomitant use of other 
nephrotoxic drugs. 

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5.4.5.2 
Neurotoxicity 
Grade 2 neurotoxicity requires a 50% dose reduction of cisplatin.  For Grade 3 or 4 
neurotoxicity, treatment should be discontinued. 
5.4.5.3 
Other Nonhematologic Toxicities 
For all other Grade 3 nonhematologic toxicities other than events assessed as related primarily 
to the underlying condition, withhold therapy for at least for 1 week and up to 28 days.  Once 
recovery occurs to Grade ≤ 1 or within 1 Grade of baseline, resume with a 75% dose of 
gemcitabine or 75% of gemcitabine dose and 1 reduced level of cisplatin unless the event was 
assessed as unlikely or not IMP-related.  Consider resuming SRA737 at the dose previously 
explored. 
For all other Grade 4 nonhematologic toxicities, withhold therapy for at least 1 week and up to 
28 days.  Therapy may be resumed if the event was assessed as unlikely or not IMP-related, 
the toxicity has recovered of to Grade ≤ 1 or within 1 Grade of baseline, and sponsor approval is 
granted.  If therapy is to be resumed, consider reducing the chemotherapy and/or SRA737 dose 
levels.  Consider discontinuing therapy if the above conditions are not met. 
5.5 
SUPPORTIVE CARE, CONCOMITANT MEDICATIONS, AND STUDY 
RESTRICTIONS 
5.5.1 
OPTIONAL AND ALLOWED CONCOMITANT MEDICATIONS 
Concomitant medication may be given as medically indicated.  Details (including name and start 
and stop dates of the concomitant medication given) must be recorded in the subject’s medical 
records and details entered into the electronic case report form (eCRF). 
5.5.1.1 
Granulocyte-colony Stimulating Factor  
Granulocyte-colony stimulating factor may be administered as medically indicated.  Treatment 
with G-CSF for subjects with ≥ Grade 3 neutropenia is recommended.  If G-CSF is not started 
for ≥ Grade 3 neutropenia, neutrophil levels must be closely monitored.  
5.5.1.2 
Palliative Radiotherapy 
Palliative radiotherapy may be given concomitantly for the control of bone pain or other 
symptoms.  These irradiated lesions will not be evaluable for response. 

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5.5.1.3 
Acid-reducing Agents 
Preliminary in vitro studies suggest that the SRA737 citrate drug product may possess some 
minimal to moderate pH-dependent solubility over the physiological range.  The effect of 
acid-reducing agents on the oral bioavailability of SRA737 in preclinical species or in humans is 
currently not known.  Consequently, administration of antacids or H2 antagonists should occur 
4 hours before or 2 hours after administration of SRA737.  Due to the long-acting duration of 
proton pump inhibitors (PPIs), there is no utility in separating SRA737 and PPI dose 
administrations.  Proton pump inhibitors should therefore be avoided if possible and used with 
caution if necessary. 
5.5.1.4 
Contraception Usage 
To be eligible for this study, WOCBP (as defined per Appendix 4) and male subjects with 
partners of child-bearing potential must follow the contraceptive requirements as described in 
Appendix 4, from the first administration of SRA737 through the trial and for 6 months 
afterwards.   
5.5.1.5 
QT Prolonging Drugs 
Preclinical data indicates that SRA737 possesses a minimal risk of clinically relevant 
prolongation of the QTc interval.  The potential for QT prolongation has not yet been evaluated 
in the clinical setting.  As a result, caution should always be used when continuing or initiating 
administration of QT prolonging drugs (https://www.crediblemeds.org) and the sponsor should 
be consulted for guidance in specific cases. A summary list applicable for this study is provided 
in Appendix 5. 
5.5.1.6 
Drugs Metabolized by Cytochrome P450 (CYP) Isoforms 
Preliminary in vitro data suggests SRA737 may minimally induce cytochrome P450 CYP1A2 
(Section 2.3.3.2.2). Consequently, investigators should be aware of this when continuing or 
initiating administration of drugs predominately metabolized by CYP1A2 while the subject is 
receiving SRA737. A summary list of such drugs is provided in Appendix 5. 
5.5.1.7 
Sun Protection 
SRA737 has a theoretical potential to elicit phototoxicity; therefore, subjects should use sun 
protection measures (eg, sunscreen, adequate garments) and avoid direct exposure to sunlight 
while receiving treatment. 

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5.5.1.8 
Treatment for Rash 
If rash develops following administration of study drug (SRA737 and gemcitabine), prompt 
treatment with antihistamines and/or topical or systemic steroids is recommended, as indicated. 
5.5.2 
EXCLUDED CONCOMITANT MEDICATIONS 
Subjects must not receive other anticancer therapy or investigational drugs while on the trial, 
with the exception of luteinizing hormone releasing hormone agonist therapy for the treatment of 
prostate cancer. 
Gemcitabine can cause increased prothrombin time  in subjects treated with warfarin, however 
the exact mechanism of drug interaction, if any, is not clear.  Nevertheless, subjects requiring 
anticoagulation should change from warfarin to low molecular weight heparin while they are on 
study. 
The following medication is not allowed and must be discontinued before starting study 
treatment and throughout therapy: 
• 
Warfarin 
• 
For subjects receiving cisplatin the following medications are not allowed and must be 
discontinued before starting study treatment and throughout therapy:  nephrotoxic drugs, 
aminoglycoside antibiotics, phenytoin and carbamazepine 
Refer to the summary of product characteristics (SmPC) for cisplatin and gemcitabine for further 
details. 
5.6 
DISCONTINUATION FROM TREATMENT 
Subjects can decline to continue receiving IMP but continue participation in the study.  If this 
occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from IMP and must discuss with the subject the options for continuation of 
Safety Follow-up and Long-term Follow-up assessments as described in Section 7.3 and 
Section 7.4 including different options for collection of data, including endpoints and AEs.   
Subjects may discontinue study treatment for the following reasons: 
• 
Disease progression 
• 
Unacceptable toxicity 
• 
Noncompliance with study procedures 

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• 
Treatment with prohibited concomitant medications 
• 
Intercurrent illness that interferes with study assessments 
• 
Withdrawal by the investigator for clinical reasons not related to SRA737 
• 
Pregnancy (of a subject during the study) 
• 
Start of new anticancer therapy 
• 
Treatment delay of more than 28 days  
The sponsor or sponsor’s designee should be notified within 24 hours if a subject is 
discontinued from study treatment.  
If the reason for discontinuation is the occurrence of an AE, the subject will be followed by the 
investigator for at least 30 days after discontinuation of study drug until such event(s) resolve, 
stabilize, and according to the investigator’s judgment, there is no need for further follow-up.  
Subjects who discontinue study treatment for reasons other than disease progression or death 
may continue on study until disease progression or death.  The reason for discontinuation from 
study treatment will be documented on the eCRF. 
5.7 
DISCONTINUATION FROM STUDY 
Subjects will be followed according to the procedures described in Section 7.4 until disease 
progression, initiation of subsequent cancer therapy, or the subject is discontinued from the 
study for any of the reasons described below. 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution.  All study related 
assessments and data collection will cease.  
The investigator must make every reasonable effort to complete study-specified Safety Follow-
up assessments at 30 ± 7 days after last SRA737 administration.  However, if the investigator 
removes a subject from the study or if the subject declines further participation prior to the 
planned Safety Follow-up visit, the Safety Follow-Up assessments should be performed before 
withdrawal from the study whenever possible.  All the results of the evaluations and 
observations, together with a description of the reasons for withdrawal from the study, must be 
recorded in the medical records and in the eCRF.  
Subjects may be discontinued from the study due to the following reasons: 

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• 
Sponsor’s decision to terminate the trial 
• 
Death or lost to follow-up 
• 
Withdrawal of consent 
 
6 
PHARMACEUTICAL INFORMATION 
6.1 
SRA737 
For information on SRA737 (the IMP previously known as CCT245737) including storage, 
handling, labelling, dispensing, and supply ordering, refer to the SRA737 Pharmacy Manual. 
SRA737 is supplied as its citrate salt in capsules containing 20 mg, 25 mg, 50 mg, and 100 mg 
of drug and higher dosage strengths when available (on a free base equivalent basis).  The 
capsules are presented in blister strips.  The primary and secondary packaging for the IMP will 
be labelled according to Eudralex Volume 4: Annex 13 ‘Investigational Medicinal Products’ of 
the European Union guide to Good Manufacturing Practice.   
Note:  The peanut allergy exclusion criterion (#15) is required because the current 
manufacturing facility of the SRA737 drug product cannot guarantee it is free from contact with 
nut products.  Drug manufacturing will be transitioned to a different facility in the future.  This 
exclusion criterion will not be applicable when the SRA737 drug product manufactured at the 
current facility is depleted and no longer available for subject dosing.  Refer to the SRA737 
Pharmacy Manual for more information. 
6.1.1 
STORAGE CONDITIONS FOR SRA737 
SRA737 must be stored according to the label (refrigerated at 2°C to 8°C) in its original 
packaging in a secure, limited access storage area in the site pharmacy.  Please refer to the 
labelling on the carton (primary package) and blister strip for the expiry date of the IMP. 
Subjects must be instructed to ensure that SRA737 is kept refrigerated and out of sight and 
reach of children (refer to the SRA737 Pharmacy Manual for more information). 
6.1.2 
DISPENSING 
Subjects are to be supplied with the required quantity of SRA737 capsules in the original 
blister pack to cover the prescribed dose until the next scheduled dispensing visit.  Blister 
packs must not be altered to reduce capsule numbers at dispensing.   

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6.1.3 
SRA737 ADMINISTRATION 
The SRA737 capsules must be swallowed whole (with water) and not chewed, crushed, 
dissolved or opened. 
SRA737 capsules should be taken on an empty stomach, at the same time each day.  Subjects 
should fast for 2 hours before administration and for 1 hour after administration.  Acid reducing 
medications should be avoided as described in Section 5.5.1.3.  SRA737 doses should be taken 
at the scheduled dosing time (ie, 24 hours after the preceding gemcitabine dose on the 2nd, 9th, 
and 16th day of each cycle and 24 hours after the preceding SRA737 dose on the 3rd, 10th, and 
17th day of each cycle) wherever possible. However, if necessary, it is acceptable for the dose 
to be taken 22-30 hours after the preceding dose of gemcitabine orSRA737.  After this time the 
subject should wait until the next scheduled time before taking the dose.  Subjects must be 
counseled to take their doses on time, without delay, on days prior to PK sampling.  Should a 
subject vomit after taking a scheduled dose, the subject should not re-take the dose and should 
wait until their next scheduled dose. 
6.2 
SRA737 ACCOUNTABILITY 
Accurate records of all IMP shipments, capsules dispensed,  all IMP returned by subjects, depot 
returns, and IMP destruction must be maintained by sites.  This inventory record must be 
available for inspection at any time by the sponsor or sponsor’s designee.  The IMP supplies are 
to be used only in accordance with this protocol and under the supervision of the investigator. 
Subjects will be asked to complete a study diary to document drug administration and to bring 
any remaining capsules with them to each study visit.  The investigator should make every effort 
to ensure subjects’ compliance to treatment. 
Destruction of IMP and depot returns are described in the SRA737 Pharmacy Manual. 
6.3 
GEMCITABINE AND CISPLATIN 
Gemcitabine and cisplatin will both be considered IMPs as subjects will not be prescribed either 
drug before enrollment on this trial.  Both drugs are available commercially.  The investigators 
will be responsible for supplying gemcitabine and cisplatin.  Prior to dispensing, the gemcitabine 
and cisplatin will be labelled by the Pharmacy according to Eudralex Volume 4: Annex 13 
‘Investigational Medicinal Products’ of the EU Guide to Good Manufacturing Practice.  Sufficient 

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quantities of either gemcitabine and/or cisplatin will be dispensed to cover the prescribed dose 
(as per Section 5.4.3). 
Gemcitabine and cisplatin will be dispensed from the hospital pharmacy on a per subject basis. 
Please refer to the relevant SmPC for the particular presentation of gemcitabine and cisplatin 
used for information on the formulation, administration, storage, stability and handling of the 
IMP. 
6.3.1 
GEMCITABINE RECONSTITUTION, STABILITY AND ADMINSTRATION 
Gemcitabine should be administered as per standard institutional guidelines.  For reconstitution 
and stability, please see the gemcitabine SmPC for more details. 
6.3.2 
CISPLATIN RECONSTITUTION, STABILITY AND ADMINSTRATION 
Cisplatin should be administered as per standard institutional guidelines.  For reconstitution and 
stability, please see the cisplatin SmPC for more details. 
6.4 
GEMCITABINE AND CISPLATIN ACCOUNTABILITY 
Pharmacy records are to be kept of the gemcitabine and cisplatin dispensed to study subjects, 
the expiry date and batch number used should be recorded.  These records must be available 
for inspection by the sponsor or sponsor’s designee at any time. 
7 
INVESTIGATIONS SCHEDULE 
In cases where a subject has investigations at a different hospital, for example weekly blood 
samples, then it is the investigator’s responsibility to ensure he/she receives and reviews the 
reported results.  These results must be available for source data verification.  Laboratory 
reference ranges, including effective dates, and evidence of laboratory accreditation must be 
obtained from all laboratories used, and updated if changed. 
7.1 
PRE-TREATMENT ENROLLMENT EVALUATIONS 
All required procedures must be performed only after obtaining informed consent unless the 
assessment was already performed within the allowable window as standard of care.  Details of 
all evaluations/investigations for enrolled subjects, including relevant dates, required by the 
protocol must be recorded in the medical records.   

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Please also refer to the tabulated Schedule of Events in Section 7.6. 
7.1.1 
SCREENING EVALUATIONS: WITHIN 28 DAYS PRIOR TO ADMINISTRATION 
OF SRA737 (FIRST DOSE OF SRA737 FOR PK BETWEEN DAY -7 AND DAY -4) 
Existing results such as radiological measurements may be used even where these 
investigations were performed prior to the subject’s provision of informed consent for the study if 
they were performed within the required time window. 
In Stage 2, the following will be performed/obtained as part of Pre-Screening (no time restriction 
relative to the start of dosing): 
• 
Written informed consent (as detailed in Section 12.3). 
• 
Submission of, or confirmation of availability of, suitable archival tumor tissue or fresh tumor 
tissue (such as with fine needle aspirate) for tumor profiling is required for all subjects.   
o For subjects being considered for enrollment to the Dose Escalation Phase, 
confirmation of the availability of suitable (as defined below) archival tumor tissue 
or planning for the acquisition of fresh tumor tissue after enrollment and before 
the start of treatment for retrospective tumor profiling is required.  If the subject 
is enrolled, archival tissue should be requisitioned for submission by C1D1. A 
decision to enroll a subject into the escalation phase, for whom no archival tissue 
is available for retrospective tumor profiling, may be made on a case by case 
basis after approval by the sponsor.   
o Subjects being considered for enrollment to the Cohort Expansion Phase must 
have predicted sensitivity to Chk1 inhibition based on factors including: genetic 
profiling of tumor tissue or ctDNA, HPV status, and germline BRCA1 and BRCA2 
gene status. All subjects will have genetic profiling from tumor tissue or ctDNA; 
profiling will be performed prospectively if required to evaluate Chk1 sensitivity or 
otherwise performed retrospectively.  If required, archival or fresh tissue should 
be submitted for prospective testing at the central laboratory as early as 
possible. 
– 
When archival material was collected more than 18 months ago, the need 
to collect fresh tumor tissue for participation in the study should be 
discussed with the sponsor.   
– 
Fresh tissue from triplet biopsies may also be collected from subjects 
during Cohort Expansion, if available, within 28 days prior to receiving the 
first SRA737 dose.  Note:  Triplet biopsies in Cohort Expansion are not 
mandatory.   
– 
Suitable archival tissue is defined as ≥ 40μm tissue, of which a minimum 
of 20% is of malignant origin, on approximately 11 unstained slides or in 
an FFPE block. 

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– 
Cytology would be an acceptable alternative to pathology for genomic 
analysis when clinically appropriate and technically feasible. 
o If results from a previously performed determination of tumor genetics are 
already available for a subject, the sponsor or sponsor’s designee must review 
and approve that data as being sufficient, based on both the type of assay used 
and the spectrum of genetic information available, to support enrollment without 
prospective confirmation by this study’s central laboratory.  In cases where the 
data is approved as sufficient to support enrollment, archival or fresh tumor 
tissue must still be submitted for retrospective testing by the central laboratory.    
The following evaluations must be completed within 28 days before the subject receives their 
first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), unless specified 
otherwise. 
• 
Demographic details. 
• 
Medical history including current diagnosis, prior treatment, concomitant 
conditions/diseases, previous cancers if appropriate, and baseline signs and symptoms, and 
concomitant treatment. 
• 
Radiological disease assessments appropriate to the subject’s disease must be performed.  
This may include:  radiological measurements (chest computerized tomography [CT] scan, 
liver CT scan, abdominal CT scan, magnetic resonance imaging [MRI], x-ray; a bone scan at 
Screening only, if clinically indicated).  Scans may be collected for potential central review. 
o Imaging should include all areas of known, suspected, or likely sites of disease. 
Note:  Radiological measurements should in general be conducted within 35 days of C1D1, 
and thus, should be repeated when the interval is > 35 days due to a delay in start of C1D1, 
or for any other reason.   
• 
ECG performed on any day within 28 days prior to administration of SRA737 for PK 
analysis. The QTc is to be calculated according to Fridericia’s formula: QTcF=QT / (RR)0.33 
(observed QT interval divided by cube root of RR interval). 
• 
Echocardiogram (ECHO) scan conducted within 28 days before the subject receives the first 
dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted). 
• 
Blood for exploratory ctDNA analysis will be collected from all subjects during Screening.  
When prospective ctDNA tumor profiling is performed to determine eligibility, blood samples 
for tumor profiling may be collected during Screening, or prior to Screening if necessary. 
• 
Tumor markers from serum or urine; if applicable (Stage 1 only) 
• 
All serious adverse events (SAEs) must be monitored and recorded in the eCRF from the 
time the subject consents to any protocol specific procedure (see Section 10 for further 
details). 
• 
Triplet biopsies (3 separate core needle biopsies) will be performed in subjects with 
accessible tumor and who provide additional consent for this procedure. Biopsies will be 

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taken in up to 1 subject, if available, per dose level in Dose Escalation, and subjects with 
accessible tumor and willingness to consent to a biopsy in Cohort Expansion. Biopsies 
should be obtained at the following time-points: Screening - up to 28 days prior to the first 
dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), Cycle 1 Day 2, 
immediately before SRA737 dosing (which should occur approximately 16-24 hours after the 
Cycle 1 Day 1 gemcitabine dose), Cycle 1 Day 2 at 4-6 hours post-SRA737 dose. Note:  
Triplet biopsies in Dose Escalation and Dose Expansion are not mandatory.    
 
7.1.2 
SCREENING EVALUATIONS: WITHIN 7 DAYS PRIOR TO ADMINISTRATION OF 
SRA737 (THE FIRST DOSE OF SRA737 FOR PK BETWEEN DAY -7 AND DAY -4) 
The following must be performed within 7 days before the subject receives the first dose of 
SRA737 (or gemcitabine if the SRA737 dose for PK is omitted): 
• 
Serious AEs (an assessment of any SAEs experienced since signing of the consent).   
• 
Concomitant treatment. 
• 
WHO performance status. 
• 
Complete physical examination including clinical disease assessment, as clinically relevant 
(ie, for subjects with clinically assessable disease). 
• 
Laboratory tests (blood/urine/tissue samples): 
o Hematology – complete blood count (CBC) with differential count.  
o Biochemistry – sodium, potassium, adjusted calcium, phosphate, chloride, 
magnesium, urea, creatinine, total protein, albumin, direct and indirect bilirubin, 
LDH, alkaline phosphatase, alanine aminotransferase and/ or aspartate 
aminotransferase, glucose (non-fasting), renal function (calculated creatinine 
clearance [Cockroft-Gault]).  
o Pregnancy testing (WOCBP only):  Serum or urine test is acceptable. 
• 
Enrollment of the subject on the study only once the investigator has confirmed eligibility 
and the sponsor approves (see Section 4.2). 
7.2 
EVALUATIONS DURING THE TRIAL 
Subjects should fast for 2 hours before and 1 hour after each dose of SRA737. 
7.2.1 
FIRST DOSE OF SRA737 FOR PK (DAY -7 TO DAY -4) 
The sponsor may eliminate or modify the requirements for the Day -7 to Day -4 visit once 
sufficient data to evaluate the single-dose PK of SRA737 have been collected and analyzed. If 
this occurs, the modified requirements will be documented by an update to the Laboratory 
Manual. 

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Subjects will remain as in-patient for 24 to 48 hours (if required to facilitate the collection of PK 
draws) after their first dose of SRA737 between Day -7 and Day -4.   
The following assessments will be conducted on the first day of SRA737 dosing unless 
performed within the preceding 3 days or unless noted otherwise below.  Dosing should be 
delayed if eligibility criteria are no longer met. 
• 
Adverse events and concomitant medications:  Adverse events must be monitored and 
recorded in the eCRF from the first dose of SRA737 administration (or gemcitabine if the 
SRA737 dose for PK is omitted).  At each visit, before each SRA737 administration, an 
assessment of any AE experienced since the previous visit must be made by the 
investigator, Research Nurse or suitably qualified member of the investigator’s team.   
o The start and stop dates of the AE together with the relationship of the event to 
the SRA737 must be recorded in the medical records.   
o All AEs must be graded according to NCI-CTCAE v4.03.  (See Section 10 for 
further details regarding AE reporting requirements). 
o Any concomitant treatment must be recorded in the medical records.  (See 
Section 10 for further details regarding AE reporting requirements.) 
• 
Height, weight, body surface area (BSA) will be required for gemcitabine and cisplatin dose 
calculation, WHO performance status, temperature, seated blood pressure (BP) and pulse 
rate.  If a subject’s BSA is > 2.2 m2, the dose can be calculated using a BSA of 2.2 m2 or the 
actual BSA can be used, depending on Institutional guidelines. 
• 
Laboratory tests (blood/urine/tissue collection for): 
o Hematology:  detailed in Section 7.1.2. Predose. 
o Biochemistry:  detailed in Section 7.1.2. Predose. 
o Troponin:  Troponin T or I (subject should be followed for the same parameter). 
Predose. 
o Tumor markers (serum or urine), if applicable based on standard institutional 
practice for the type of malignancy being followed (for example, PSA and CTCs 
for subjects with prostate cancer, CA-125 for subjects with ovarian cancer). 
Predose. 
o Urine pregnancy testing (WOCBP only):  Serum or urine test is acceptable. 
Predose. 
o Urinalysis – glucose, protein, and blood. Predose. 
o Blood collected and submitted for retrospective, exploratory Comet assay in up to 
3 subjects in Dose Expansion Cohort. Schedule in Section 7.7. 
o For subjects without adequate archival tissue, a biopsy to obtain fresh tumor 
tissue for tumor profiling must be performed prior to the first dose of SRA737 (or 

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gemcitabine if the SRA737 dose for PK is omitted), unless it was performed 
during Screening as described in Section 7.1.1.  For subjects with archival tissue, 
requisition of archival tissue for tumor profiling is required and submission of 
suitable archival tumor tissue should occur by C1D1, unless submitted during 
Screening.  Tumor profiling may include exploratory determination of 
microsatellite instability status, where relevant.  
• 
PK Assessments:  0 (predose), 1, 2, 4, 6, 8, 12, 24, and 48 hours after the first dose of 
SRA737 (or gemcitabine if the SRA737 dose for PK is omitted).  For subjects in the Dose 
Expansion Cohort, the12-hour time point may be omitted with sponsor’s approval.   
If the Day -7 to Day -4 visit is eliminated, the following assessments and sample collections 
should be added pre-dose on Cycle 1 Day 1: 
• 
Tumor markers (serum or urine), if applicable based on standard institutional practice for the 
type of malignancy being followed (for example, PSA and CTCs for subjects with prostate 
cancer, CA-125 for subjects with ovarian cancer). 
• 
Urine pregnancy testing (WOCBP only):  Serum or urine test is acceptable.  
• 
Height, weight, body surface area (BSA) will be required for gemcitabine and cisplatin dose 
calculation. If a subject’s BSA is > 2.2 m2, the dose can be calculated using a BSA of 2.2 m2 
or the actual BSA can be used, depending on Institutional guidelines 
• 
For subjects without adequate archival tissue, a biopsy to obtain fresh tumor tissue for tumor 
profiling must be performed prior to the first dose of SRA737 (or gemcitabine if the SRA737 
dose for PK is omitted), unless it was performed during Screening as described in Section 
7.1.1.  For subjects with archival tissue, requisition of archival tissue for tumor profiling is 
required and submission of suitable archival tumor tissue should occur by C1D1, unless 
submitted during Screening.  Tumor profiling may include exploratory determination of 
microsatellite instability status, where relevant.  
 
7.2.2 
STANDARD EVALUATIONS FOR EACH CYCLE 
The standard evaluations and sample collections for each cycle are listed below: 
• 
Adverse events and concomitant medications (detailed in Section 7.2.1). 
• 
Symptom directed physical examination:  if clinically indicated, predose Day 1 of each cycle. 
• 
WHO performance status at predose Day 1 of each cycle. 
• 
Temperature, pulse rate, seated BP at predose Day 1 and 8 of each cycle in Stage 1 or 
predose Day 1, 8 and 15 of each cycle Stage 2. 
• 
Weight and BSA must be repeated prior to Day 1 of each cycle to calculate the dose 
required for gemcitabine plus cisplatin or gemcitabine administration.  The dose of 
gemcitabine and cisplatin will only need to be recalculated should there be a 10% or greater 

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change in weight (unless required by local pharmacy procedures) or where doses are 
reduced because of toxicity.  
• 
Compliance:  Subjects will be provided with a diary card and will be instructed to record the 
time they take SRA737 as well as details of any missed doses.  At each visit, the subject’s 
most recent diary card should be collected and checked for completeness and compliance 
in taking SRA737. 
• 
ECG (locally read):  Day 1 predose for Cycles 1, 2, and then every third subsequent cycle. 
Also required in first cycle of intra-subject dose escalation. 
• 
ECHO scan:  Cycle 2 Day 1 only and then all subsequent cardiac monitoring should be 
done at investigator’s discretion.  The modality for this assessment should be consistent 
with the modality used at baseline (prior to the first dose of SRA737 [or gemcitabine if the 
SRA737 dose for PK is omitted]). 
• 
Laboratory tests (blood/urine samples):  Blood draws for laboratory tests will be performed 
at predose.  Samples should be collected on the days indicated below, unless an acceptable 
window for sample collection is stated, eg, within 72 hours prior to the first dose of 
gemcitabine each cycle for hematology, biochemistry, and troponin.  Subjects must be 
instructed not to take SRA737 prior to attending the clinic on those days they will be 
required to attend for routine blood samples.  SRA737 should only be taken once all clinic 
assessments have been completed: 
o Hematology and Biochemistry (detailed in Section 7.1.2):   72 hours prior to the 
first dose of gemcitabine of each cycle 
– 
Stage 1 Cycle 1 onwards:  Days 1 and 8.  
– 
Stage 2 Cycle 1 onwards:  Days 1, 8, and 15.  
Note:  Clinical hematology laboratory assessments should also be performed at 
Days 3, 10, and 18 or 19 in Cycle 1 only.  These samples may also be 
collected in subsequent cycles if clinically indicated due to toxicity.  In the 
case of intra-subject dose escalation, more frequent hematology laboratory 
assessments should be considered during the first cycle following escalation 
utilizing the same Cycle 1 assessment schedule.   
o Troponin:  Troponin T or I  
– 
Cycle 1 Days 1 (within 72 hours prior to dose) and on Day 8.  
– 
Cycle 2 Day 1 (within 72 hours prior to dose). 
– 
Cycle 6 Day 1 (within 72 hours prior to dose). 
o Urinalysis (glucose, protein and blood):  Day 1 of each cycle (may be performed 
up to 72 hours prior to the first dose of gemcitabine of each cycle). 
o Tumor markers (serum or urine), if applicable based on standard institutional 
practice for the type of malignancy being followed:  every 6 weeks (± 1 week) for 
Stage 1 and every 4 weeks (± 1 week) for Stage 2. 

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o Follow-up triplet biopsies (3 separate core needle biopsies) will be performed for 
appropriate subjects (Refer to “Triplet biopsies” in Section 7.1.1) on Cycle 1 
Day 2, immediately before SRA737 dosing (which should occur approximately 
16-24 hours after the Cycle 1 Day 1 gemcitabine dose), Cycle 1 Day 2 at 4-6 
hours post-SRA737 dose. Note:  Triplet biopsies in Dose Escalation and Dose 
Expansion are not mandatory.  See Section 8.3 for more information.   
o PBMC for exploratory biomarker analyses in up to 3 subjects per dose level in 
Dose Escalation at Cycle 1 Days 1, 2, and 3. 
o Blood for exploratory Comet assay in up to 3 subjects per dose level in Dose 
Escalation at Cycle 1 Days 1, 2, and 3.   
• 
PK Assessments (see Section 7.7):  Cycle 1 Day 1 at pre-dose, Cycle 1 Day 10 at pre-dose, 
and 1, 2, 4, 6, 8, and 12 hours after SRA737 dose.  For subjects in the Dose Expansion 
Cohort, the 12-hour time point may be omitted with sponsor’s approval.  For subjects in 
Stage 2, additional PK samples will be taken at Cycle 1 Day 8 at pre-dose and Cycle 1 
Day 15 at pre-dose. 
• 
Radiological disease assessments:  The same method of assessment as recorded at baseline 
is required throughout the trial (refer to Section 9 for more information) repeated every 
8 weeks (± 1 week) (every 6 weeks for Stage 1). 
• 
Clinical disease assessments (if applicable):  Repeated at every 6 weeks for Stage 1 and 
every 4 weeks (± 1 week) for Stage 2. 
7.3 
SAFETY FOLLOW-UP VISIT 
If a subject discontinues investigational product for any reason, the SFU visit evaluations should 
be performed 30 ± 7 days after the last dose of SRA737.  If the subject begins a new anticancer 
treatment within 30 days of the last administration of study drug, the SFU Visit should be 
performed prior to initiation of the new anticancer treatment, if possible.  The following 
investigations should be performed wherever possible: 
• 
Assessment of AEs (also see Section 7.2.1) and review of concomitant medications 
o Monthly follow up required ONLY for those AEs and SAEs considered drug 
related (highly probable, probable or possible) and present at Safety Follow-up 
visit.  Monthly follow-up to continue until resolution, return to baseline, 
stabilization or subject discontinues from study.   
• 
A symptom directed physical examination including WHO performance status, temperature, 
pulse rate, seated BP and weight; 
• 
Laboratory tests (blood/urine samples):   
o Hematology tests (detailed in Section 7.1.2).  
o Biochemistry tests (detailed in Section 7.1.2).  

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o Troponin T or Troponin I (where applicable, detailed in Section 7.1.2). 
o Urinalysis (detailed in Section 7.1.2).  
o Urine or serum pregnancy test. 
o Tumor markers (serum or urine), if applicable based on standard institutional 
practice for the type of malignancy being followed. 
• 
ECG (locally read). 
• 
ECHO scan (modality for this assessment should be consistent with the modality used at 
baseline). 
• 
Clinical and radiological (if applicable) assessment of disease:  Continue clinical disease 
assessments at every 4 weeks and radiological disease assessments at every 8 weeks 
unless PD was indicated on a previous study scan.  
• 
Compliance:  the subject’s most recent diary card must be collected and checked for 
completeness and compliance in taking SRA737.   
7.4 
LONG TERM FOLLOW-UP 
For subjects who have stopped study treatment but have not progressed and have not initiated 
subsequent cancer therapy, clinical, serum, and radiological disease assessments will continue 
to be captured every 16 weeks (± 2 weeks) until the subject withdraws from the study or until 
documented disease progression, or until the initiation of new anticancer therapy.  Additional 
contact may be made as requested by the sponsor or the investigator to obtain disease and 
survival updates on an as-needed basis until the subject discontinues from the study. The 
following data will be collected: 
• 
Serious adverse events assessed by the investigator as related to SRA737. 
• 
First subsequent cancer therapy (if applicable). 
• 
Tumor markers (serum or urine; if applicable), unless PD was previously documented. 
• 
Clinical disease assessments, unless PD was previously documented. 
• 
Radiographic disease assessments, unless PD was previously documented. 
• 
Disease and survival updates, where available 
7.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the originally scheduled 
date as possible.  Based on the investigator’s judgment, an exception can be made when 
rescheduling becomes medically unnecessary or unsafe because it is too close in time to the 
next scheduled evaluation.  In that case, the missed evaluation may be omitted. 

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7.6 
SCHEDULE OF EVENTS 
The schedule of events for Stage 1 is provided in Table 8, and the schedule of events for 
Stage 2 is provided in Table 9. 

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Table 8. Schedule of Events for Stage 1  
Observation/Investigation 
Pre-treatment evaluations  
First 
dose 
for PK 
Treatment phase - Triple Combination 
(Stage 1) 
Evaluations for each day/ 21-day cycle 
Safety 
Follow-
Up 
LTFU 
 
-28 days of 
1st dose for 
PK 
(Screening) 
-7 days of 
1st dose for 
PK 
(Screening) 
Day -7 
to 
Day -4 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
9 
Day  
10 
30 ±7 
days after 
last IMP 
dose 
Every 
8 ± 3 
Weeks 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
SAEs from consent.  AEs from first dose of SRA737 (or gemcitabine if the SRA737 dose 
for PK is omitted).  Continual Review 
X (a) 
X (b) 
Concomitant treatments 
X 
X 
Continually review 
X 
X (b) 
Radiological disease assessment (c) 
X 
 
 
End of every 6 weeks (±1 week) 
X 
X 
Tumor markers (serum or urine; if applicable) 
X 
 
 
End of every 6 weeks (±1 week) 
X 
X 
Availability of historical tumor biopsy (d) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (e) 
 
X 
 
C1 
 
 
 
 
 
X 
 
Clinical disease assessment (if applicable) 
 
X 
 
End of every 6 weeks (±1 week) 
X 
X 
Physical examination (f) 
 
Complete 
 
Symptom-directed, repeat as clinically 
indicated 
X 
 
Temperature, blood pressure and pulse rate 
 
X 
X 
X 
 
 
X 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
 
X 
 
Body surface area (BSA) (g) 
 
X 
 
X 
 
 
 
 
 
 
 
WHO performance status 
 
X 
 
X 
 
 
 
 
 
X 
 
Bloods for hematology and biochemistry (h, i) 
 
X 
X 
X 
 
 
X 
 
 
X 
 
Troponin T or I (j) 
 
X 
X 
X 
C1 
C1 
C1 
C1 
C1 
X 
 
Urine sample for urinalysis  
 
X 
 
X 
 
 
 
 
 
X 
 
Renal Function  
 
X 
 
X 
 
 
 
 
 
 
 
Electrocardiogram (ECG) (k) 
 
X 
X 
X 
C1 
C1 
C1 
C1 
C1 
X 
 
Echocardiogram (ECHO) 
 
X 
 
C2D1, then as clinically indicated 
X 
 
Gemcitabine administration 
 
 
 
X 
 
 
X 
 
 
 
 
Cisplatin administration 
 
 
 
X 
 
 
 
 
 
 
 
SRA737 administration  
 
 
X 
 
X 
X 
 
X 
X 
 
 
Tumor biopsy (l) 
 
 
 
 
C1 
C1 
 
 
 
 
 
Blood for PK (m) 
 
 
X 
Refer to laboratory manual 
 
 
Blood for PDn (m) 
 
 
X 
Refer to laboratory manual 
 
 

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a. 
Monthly follow up is required for all SAEs and for those AEs considered drug related (highly probable, probable or possible) and present at the Safety 
Follow-up visit.  Monthly follow-up will continue until the event resolves, returns to baseline, stabilizes, or the subject discontinues from study. 
b. 
SAEs assessed by the investigator as related to SRA737 and start of new anticancer therapy will also be collected. 
c. 
Radiological disease assessment:  Unless performed within previous 28 days or PD seen on previous study scan (one bone scan will be done at 
Screening only, if clinically indicated). 
d. 
Historical tumor biopsy:  If historical or pre-study biopsy material is available and P53 expression status is not known, this will be requested for 
retrospective analysis of P53 either during or after the end of the study.  
e. 
Pregnancy test:  For female patients of child bearing potential to be performed within 7 days of the first dose of SRA737 for PK  
f. 
Physical exam:  Complete physical examination to be performed at baseline. For all subsequent examinations, a symptom directed physical examination 
is to be performed on Day 1 of each cycle before gemcitabine/cisplatin or gemcitabine administration if clinically indicated. 
g. 
BSA:  Screening weight can be used to calculate BSA for Cycle 1 
h. 
Hematology and Biochemistry:  Clinical laboratory assessments should be performed on Days 1 and 8 in Stage 1 and on Days 1, 8 and 15 in Stage 2.  
Laboratory tests can be performed up to 72 h prior to the first dose of gemcitabine of each cycle. 
i. 
In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia a full blood count must be performed at least on Day 7 after the onset of the event to 
determine if a DLT has occurred.  Continue close monitoring until resolution to Grade 3 or less.   
j. 
Troponin:  Subjects should follow the same parameter (troponin T or I) assessed at baseline.  Troponin assessment should be performed within 7 days of 
the first dose of SRA737 for PK, before first dose of SRA737 for PK, before dosing on Cycle 1 Days 1, 2, 3, 8, 9, and 10, then on Day 1 of all subsequent 
cycles, and at the SFU visit.    
k. 
ECGs:  All ECGs will be conducted at Screening and then pre-dose at Day 1 of Cycles 1 and 2, and then pre-dose Day 1 at each third subsequent cycle 
and end of study.  For Stage 1: Cycle 1 Day 1 (pre-dose), Cycle 1 Days 2 and 3 (4 h post-dose), Cycle 1 Day 8 (pre-dose), Cycle 1 Days 9 and 10 (4 h 
post-dose). Then pre-dose on Day 1 of all subsequent cycles. The Cycle 1 ECG schedule should also be followed for the first cycle of intra-subject dose 
escalation. 
l. 
Tumor biopsies (Expansion cohorts only): Biopsies for PDn assessment will be taken on Cycle 1 Days 2 and 3 in Stage 1.  Biopsies will be mandatory for 
all subjects in the ‘All Solid Tumor’ expansion cohorts and optional for subjects in the NSCLC (Stage 1) cohort.  
m. PK/PDn assessments:  Refer to the Laboratory Manual for specific timings of PK and PDn sample collection. 

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Table 9. Schedule of Events for Stage 2 (Dose Escalation and Cohort Expansion) 
Observation/Investigation 
Screening evaluations – to 
be within noted window of 
first dose of SRA737 (or 
gemcitabine if the SRA737 dose 
for PK is omitted) 
First 
SRA-737 
Dose (a) 
Treatment phase - Double Combination 
(Stage 2) 
Evaluations for each day/ 28-day cycle 
Safety 
Follow-
Up 
LTFU 
 
N/A 
28 
days 
7 days 
Single 
Day  
Day -7 to  
Day -4 
D1 
D2 
D3 
D8 
D9 
D 
10 
D 
15 
D 
16 
D 
17 
30 ± 7 
days 
after last 
dose of 
IMP 
Every 
16 ± 2 
Weeks 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
SAEs from consent.  AEs from first dose of SRA737.  Continual Review 
X (b) 
X (c) 
Concomitant treatments 
 
X 
X 
Continually review 
X 
X (c) 
Radiological disease 
assessment (d) 
 
X 
 
 
End of every 8 weeks (±1 week) 
X 
X 
Tumor markers  
(serum or urine; if applicable) 
 
 
 
X 
End of every 4 weeks (±1 week) 
X 
X 
Submission/avail. of archival 
tumor tissue - tumor profiling (e) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood for ctDNA (f) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (g) 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Clinical disease assessment  
(if applicable) 
 
 
X 
 
End of every 4 weeks (±1 week) 
X 
X 
Physical examination (h) 
 
 
Complete 
 
Symptom directed, repeat as clinically indicated 
 
Temperature, BP and pulse 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
Height 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Body surface area (i) 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
WHO performance status 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Bloods for hematology and 
biochemistry (j, k) 
 
 
X 
X 
X 
 
C1 
X 
 
C1 
X 
 
 
X 
 
Troponin (l) 
 
 
 
X 
C1 
C2 
C6 
 
 
C1 
 
 
 
 
 
X 
 
Urine sample for urinalysis 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Electrocardiogram (ECG) (m) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Echocardiogram (ECHO) (n) 
 
X 
 
 
C2 
 
 
 
 
 
 
 
 
X 
 
Gemcitabine administration 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
SRA737 administration  
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 

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Observation/Investigation 
(continued) 
Screening evaluations – to 
be within noted window of 
first dose of SRA737 
First 
SRA-737 
Dose (a) 
Treatment phase - Double Combination 
(Stage 2) 
Evaluations for each day/ 28-day cycle 
Safety 
Follow-
Up 
LTFU 
 
N/A 
28 
days 
7 days 
Single 
Day  
Day -7 to  
Day -4 
D1 
D2 
D3 
D8 
D9 
D 
10 
D 
15 
D 
16 
D 
17 
30 ± 7 
days 
after last 
dose of 
IMP 
Every 
8 ± 3 
Wks 
Triplet Tumor biopsy(o) 
 
X 
 
 
 
C1 
 
 
 
 
 
 
 
 
 
Blood for PK (p) 
 
 
 
Refer to Section 7.7 and Laboratory Manual 
 
 
Blood for PDn (q) 
 
 
 
 
Refer to Section 7.7 and Laboratory Manual  
 
 
SRA737 Diary Card 
 
 
 
 
Should be reviewed at each visit 
X 
 
 
a. 
Assessments scheduled to occur for the first dose of SRA737 (given on a single day between Day -7 and Day -4) will be conducted on the first day 
of dosing unless performed within the 3 days prior or unless noted otherwise for the specific assessment.  The sponsor may eliminate or modify the 
requirements for the Day -7 to Day -4 visit once sufficient data to evaluate the single-dose PK of SRA737 have been analyzed. 
b. 
Monthly follow up is required for all SAEs and for those AEs considered drug related (highly probable, probable or possible) and present at the 
Safety Follow-up visit.  Monthly follow-up will continue until the event resolves, returns to baseline, stabilizes, or the subject discontinues from study. 
c. 
SAEs assessed by the investigator as related to SRA737, and start of new anticancer therapy will also be collected. 
d. 
Radiological disease assessment:  assessments will be performed every 8 weeks (± 1 week) and then in long-term follow-up every 16 weeks 
(± 2 weeks). Assessments will stop when PD is seen on previous study scan. 
e. 
Availability of suitable archival tumor tissue or planned biopsy for fresh tumor tissue acquisition for tumor profiling must be confirmed:  Fresh tissue is 
strongly preferred when historical material was collected more than 18 months ago.  Submission prior to or during Screening (the 28-day window 
does not apply) with confirmation of positive results is required for Cohort Expansion subjects; Archival tissue should be requisitioned for submission 
by C1D1 for Dose Escalation subjects.  See Section 7.1.1 for more information.   
f. 
Blood for exploratory ctDNA analysis will be collected from all subjects during Screening.  When prospective ctDNA tumor profiling is performed to 
determine eligibility, blood samples for tumor profiling may be collected during Screening, or prior to Screening if necessary.  
g. 
Pregnancy test:  For WOCBP, must be performed within 7 days prior to the first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is 
omitted), predose for the first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), and at SFU visit.  More frequent pregnancy 
tests may be conducted per local regulatory requirements.  Urine or blood test is acceptable.  
h. 
Physical exam:  Complete physical examination to be performed at baseline.  For all subsequent examinations, if clinically indicated, a symptom 
directed physical examination may be performed on Day 1 of each cycle before gemcitabine administration. 
i. 
BSA:  Screening weight can be used to calculate body surface area for Cycle 1. 
j. 
Hematology and Biochemistry:  Clinical laboratory (hematology and biochemistry) assessments should be performed within 7 days of the first dose 
of SRA737, at predose of first dose of SRA737 (where applicable), and on Days 1, 8 and 15 of each cycle.  In addition, clinical hematology 
laboratory assessments should also be performed at Days 3, 10, and 18 or 19 in Cycle 1 only; these samples may also be collected in subsequent 
cycles if clinically indicated due to toxicity.  Laboratory tests can be performed up to 72 hours prior to the first dose of gemcitabine of each cycle.  In 

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the case of intra-subject dose escalation, more frequent hematology laboratory assessments should be considered during the first cycle following 
escalation utilizing the same Cycle 1 assessment schedule 
k. 
In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia a full blood count must be performed at least on Day 7 after the onset of the 
event to determine if a DLT has occurred.  Continue close monitoring until resolution to Grade 3 or less.   
l. 
Troponin:  Subjects should follow the same parameter (troponin T or I) assessed at baseline.  Troponin assessment should be performed predose 
for first dose of SRA737 (where applicable), before gemcitabine dosing on Cycle 1 Days 1 and 8, on Day 1 of Cycles 2 and 6, and at the SFU visit.   
m. ECGs:  All ECGs must be conducted within 28 days of first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), at predose of 
gemcitabine Day 1 of Cycles 1 and 2, and then predose of gemcitabine Day 1 at each third subsequent cycle, the first cycle of any intra-subject dose 
escalation, and at SFU visit. 
n. 
ECHO:  ECHO must be conducted within 28 days of first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), at Cycle 2 Day 1 
(± 3 days) and repeated as clinically indicated, and at SFU visit.  The modality for this assessment should be consistent with the modality used at 
baseline.  
o. 
Triplet biopsies (3 separate core needle biopsies) will be performed in subjects with accessible tumor and who provide additional consent for this 
procedure. Biopsies will be taken in up to 1 subject, if available, per dose level in Dose Escalation, and subjects with accessible tumor and 
willingness to consent to a biopsy in Cohort Expansion. Biopsies should be obtained at the following time-points: Screening - up to 28 days prior to 
the first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted), Cycle 1 Day 2, immediately before SRA737 dosing (which should 
occur approximately 16-24 hours after the Cycle 1 Day 1 gemcitabine dose), Cycle 1 Day 2 at 4-6 hours post-SRA737 dose. Note:  Triplet biopsies 
in Dose Escalation and Dose Expansion are not mandatory.  Refer to the Laboratory Manual and protocol Sections  7.7 and 8.3 for more 
information. 
p. 
PK assessments:  Refer to the Laboratory Manual for specific timings of PK sample collection (see Section 7.7 also). 
q. 
PDn assessments:  Refer to the Laboratory Manual for more information (see Section 7.7 also). 
 

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7.7 
STAGE 2 SCHEDULE OF SECONDARY AND EXPLORATORY ASSESSMENTS 
Table 10. Schedule for Stage 2 Secondary and Exploratory Assessments 
SRA737+Gem 
Triplet 
Biopsy (PDn 
Biomarker)(a) 
PBMC  
(PDn 
Biomarker)(a) 
Comet Assay 
PDn 
SRA737 PK 
(Blood)(b) 
Within 28 days 
prior to the first 
dose of 
SRA737 
Predose 
X 
 
 
 
Day -7 to  
Day -4  
(First dose of 
SRA737 for 
PK)(b, c) 
Predose 
 
 
X (e) 
X 
1h ±15min 
 
 
 
X 
2h ±15min 
 
 
 
X 
4h ±15min 
 
 
 
X 
6h ±15min 
 
 
 
X 
8h ±15min 
 
 
 
X 
12h ±15min 
 
 
X (e) 
X (d) 
24h ±1h 
 
 
X (e) 
X 
48h ±1h 
 
 
X (e) 
X 
Cycle 1 Day 1 
Predose 
 
X 
X (e) 
X 
6h post-Gem 
 
X 
X (e) 
 
Cycle 1 Day 2 
Pre-SRA737 
X 
(16-24 h  
post-Gem) 
X 
X (e) 
 
4-6h  ±15min post-
SRA737  
X 
X 
X (e) 
 
Cycle 1 Day 3 
Predose 
 
X 
X (e) 
 
4-6h  ±15min post-
SRA737 
 
X 
X (e) 
 
Cycle 1 Day 8 
Predose 
 
 
 
X 
Cycle 1 Day 10 
Predose 
 
 
 
X 
1h ±15min 
 
 
 
X 
2h ±15min 
 
 
 
X 
4h ±15min 
 
 
 
X 
6h ±15min 
 
 
 
X 
8h ±15min 
 
 
 
X 
12h ±1h 
 
 
 
X (d) 
Cycle 1 Day 15 
Predose 
 
 
 
X 
Note:  Pharmacodynamic and PK assessments for Stage 1 can be found in the Laboratory Manual.  
(a) Triplet biopsies (3 separate core needle biopsies) will be performed in subjects with accessible tumor and who 
provide additional consent for this procedure. Biopsies will be taken in up to 1 subject, if available, per dose level in 
Dose Escalation, and subjects with accessible tumor and willingness to consent to a biopsy in Cohort Expansion. 
Biopsies should be obtained at the following time-points: Screening - up to 28 days prior to the first dose of SRA737 
(or gemcitabine if the SRA737 dose for PK is omitted), Cycle 1 Day 2, immediately before SRA737 dosing (which 

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should occur approximately 16-24 hours after the Cycle 1 Day 1 gemcitabine dose), Cycle 1 Day 2 at 4-6 hours 
post-SRA737 dose. Note:  Triplet biopsies in Dose Escalation and Dose Expansion are not mandatory.  Refer to 
the Laboratory Manual and protocol Sections 7.7 and 8.3 for more information. 
(b) The sponsor may reduce the requirement for PK sampling once sufficient data to evaluate the PK of SRA737 
have been collected and analyzed. Any modified requirements will be documented by an update to the Laboratory 
Manual.   
(c) If required to facilitate the collection of PK, subjects may remain as in-patients for at least 24 hours after their first 
dose of SRA737 between Day -7 and Day -4. 
(d) With sponsor’s approval, subjects in the Cohort Expansion may elect to not participate in the 12 hour PK draws 
during the first dose of SRA737 for PK (where SRA737 is administered on 1 day between Day -7 and -4) and at 
Cycle 1 Day 10.   
(e) Blood for Comet assay will be collected at up to 4 time points during the first dose of SRA737 for PK (where 
SRA737 is administered on 1 day between Day -7 and -4) in up to 3 subjects in the Cohort Expansion.  Blood for 
Comet assay will be collected during Dose Escalation at Cycle 1 Days 1-3 in up to 3 subjects per dose level.  
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
Pharmacokinetic and PDn assessments for Stage 1 can be found in the Laboratory Manual. 
8.1 
SRA737 PHARMACOKINETICS 
Subjects will undergo PK evaluation at several time points throughout the study (see Section 7.7 
for timing).   
Approximately 2 mL of blood will be collected from all subjects at up to 10 time points taken over 
a 48-hour time period on Day -7 to -4 (First dose of SRA737 for PK) and up to 8 time points 
taken over a 24-hour period at Cycle 1 Day 10 for Stage 2.  On Day 1 of Cycle 1 a PK sample 
will be taken prior to chemotherapy dosing.  If an alternative schedule of SRA737 is tested, the 
time points for PK assessments may need to be altered.  If this occurs, the number of PK 
assessments will not exceed 20 time points between Day 1 and Day 22 in Cycle 1, or 10 within 
a 24-hour period.  The alternative sampling schedule will be provided in the Laboratory Manual.    
The sponsor may reduce the requirement for PK sampling, including elimination of the Day -7 to 
Day -4, visit once sufficient data to evaluate the PK of SRA737 have been collected and 
analyzed. Any modified requirements will be documented by an update to the Laboratory 
Manual. 
If one of the time points detailed in the in Section 7.7 (or Laboratory Manual) is missed, a 
sample should be taken as soon as possible.   
Please see Laboratory Manual for more information on the sample collection, specific timings, 
handling, and storage. 

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8.2 
GENETIC ALTERATIONS IN TUMOR TISSUE OR CIRCULATING TUMOR DNA 
To identify genetic alternations implicated in the Chk1 pathway sensitivity including genetic 
indicators of loss of the integrity of the G1/S checkpoint and replicative stress, oncogenic 
drivers, or genetic alterations in components of the DDR and repair, archival or fresh tumor 
tissue will be collected during Screening or at Baseline.  For the Dose Escalation Phase, 
samples may be stored and tumor profiling may be performed retrospectively.  For the Cohort 
Expansion Phase, tumor profiling results must be available to determine eligibility.  Blood for 
ctDNA will be collected from all subjects during Screening for future retrospective analysis. 
Subjects enrolled prior to the implementation of Amendment v5.0 were required to submit blood 
for gemcitabine and cisplatin PK assessments and hair follicles for PDn assessments.  As of 
Amendment v5.0, these specimens were no longer collected.  The schedule of assessments for 
triplet biopsies, PBMCs, and COMET analysis has been modified as described in the 
subsequent sections below. 
8.3 
TRIPLET BIOPSIES 
Triplet biopsies (3 separate core needle biopsies) will be performed in subjects with accessible 
tumor and who provide additional consent for this procedure. Biopsies will be taken in up to 1 
subject, if available, per dose level in Dose Escalation, and subjects with accessible tumor and 
willingness to consent to a biopsy in Cohort Expansion. Biopsies should be obtained at the 
following time-points: 
− 
Screening - up to 28 days prior to the first dose of SRA737 (or gemcitabine if the 
SRA737 dose for PK is omitted) 
− 
Cycle 1 Day 2, immediately before SRA737 dosing (which should occur approximately 
16-24 hours after the Cycle 1 Day 1 gemcitabine dose) 
− 
Cycle 1 Day 2 at 4-6 hours post-SRA737 dose.   
Note:  Triplet biopsies in Dose Escalation and Dose Expansion are not mandatory.   
Inhibition of Chk1 in triplet tumor samples will be measured in fresh frozen tumor samples 
according to agreed SOPs and validated methods.  One biopsy per time point will be used for 
markers including but not limited to pSer296Chk1, pSer317Chk1, and total Chk1. 

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8.4 
PBMCS FOR EXPLORATORY BIOMARKERS ANALYSES 
Immunofluoresence and confocal microscopy will be used to measure a range of PDn 
biomarkers in PBMCs indicative of Chk1 inhibition and DNA damage.  Blood for these assays 
will be collected in Dose Escalation at Cycle 1 Days 1 to 3 from up to 3 subjects per dose level.  
See Section 7.7 for specific sample timings and the Laboratory Manual for more information on 
the sample collection, handling, and storage. 
8.5 
COMET ASSAY 
The Comet assay, a single cell gel electrophoresis assay, will be used as an exploratory 
analysis to measure DNA damage response in blood.  Blood for this assay will be collected in 
Dose Escalation at Cycle 1 Days 1 to 3 from up to 3 subjects per dose level and, in up to 3 
Cohort Expansion subjects, at the first dose of SRA737 for PK (single dose of SRA737 given 
between Day -7 and Day -4).  See Section 7.7 for specific sample timings and the Laboratory 
Manual for more information on the sample collection, handling, and storage. 
9 
ASSESSMENT OF EFFICACY 
9.1 
MEASUREMENT OF DISEASE 
Disease must be measured according to the RECIST v1.1 criteria in Appendix 2 or the most 
appropriate method for the subject’s indication.  For example, subjects with metastatic 
castration resistant prostate cancer should be followed with PSA and CTCs every 
4 weeks ± 1 week.   
9.2 
TIMING AND TYPE OF TUMOUR ASSESSMENTS 
A thorough clinical and radiological evaluation of the malignancy, as judged appropriate by the 
investigator, and consistent with the protocol, must be performed before a subject receives their 
first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted).  The same 
methods that detect evaluable lesions at baseline must be used to follow these lesions 
throughout the trial.  Imaging based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the antitumor effect of a treatment. 
All radiological assessments must be performed within 4 weeks before starting treatment with 
SRA737 on Day -7 to -4.  All clinical measurements and serum tumor markers to assess 
response must be performed within 1 week of their first dose of SRA737 (or gemcitabine if the 
SRA737 dose for PK is omitted). 

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The determination of CR or PR is required to be confirmed by a subsequent assessment at 
least 4 weeks after the original determination.  Stable disease determination requires that the 
relevant criteria be met at least once, a minimum of 6 weeks after study entry.     
Copies of any radiological assessment must be available for external independent review if 
requested by the sponsor or sponsor’s designee. 
9.2.1 
BASELINE EVALUATIONS 
These must include radiological measurements of lesions appropriate to the subject’s disease. 
This may include:  chest CT scan, liver CT scan, abdominal CT scan, magnetic resonance 
imaging (MRI), X-ray, bone scan and/or other radiological measurements as clinically indicated 
or clinical measurements as appropriate (eg, assessment of palpable lesions or measurement 
of tumor markers).  All areas of disease present must be documented (even if specific lesions 
are not going to be followed for response) and the measurements of all measurable lesions 
must be recorded clearly on the scan reports.  Any non-measurable lesions must be stated as 
being present.  For clinical measurements, documentation by color photography including a 
ruler to estimate the size of the lesion is strongly recommended, as this aids external 
independent review of responses (see Section 1.2.1 of Appendix 2) 
9.2.2 
EVALUATIONS DURING STUDY 
Tumor assessments must be repeated every 6 weeks (± 1 week) in Stage 1. In Stage 2, 
assessments will be performed every 8 weeks (± 1 week) and then in long-term follow-up every 
16 weeks (± 2 weeks). Assessments may be performed more frequently, when clinically 
indicated.  All lesions measured at baseline must be measured at every subsequent disease 
assessment, and recorded clearly on the scan reports.  All nonmeasurable lesions noted at 
baseline must be noted on the scan report as present or absent. 
All subjects who discontinued treatment for reasons other than PD must be re-evaluated at the 
time of treatment discontinuation, unless a tumor assessment was performed within the 
previous 4 weeks.  Subjects will be followed for progression until disease progression, the start 
of alternative anticancer therapy, or withdrawal from trial.   
It is the responsibility of the PI to ensure that the radiologists are aware of the requirement to 
follow-up and measure every target lesion mentioned at baseline and comment on the nontarget 
lesions in accordance with RECIST v1.1 criteria. 

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9.3 
TUMOUR RESPONSE 
All subjects who have measurable disease, receive at least one cycle of SRA737 and have a 
baseline and at least 1 postbaseline assessment of disease will be evaluable for response.  
Subjects who develop clear evidence of PD without a formal disease assessment and those 
without a formal disease assessment before study withdrawal will be considered 
non-responders.  Complete responses and PRs are required to be confirmed by a subsequent 
assessment at least 4 weeks later.  To be assigned a status of SD, follow-up measurements 
must have met the SD criteria at least once and at least 6 weeks after the initial dose of the 
SRA737 is given. 
Should rapid tumor progression occur before the completion of 3 weeks of treatment in Stage 1 
and 4 weeks of treatment in Stage 2, the subject will be classified as having early progression. 
Tumor response should be classified as “not evaluable” (NE), only when it is not possible to 
classify it under another response category, for example, when baseline and/or follow-up 
assessment is not performed or not performed appropriately.  
Expert reviewers appointed by the sponsor may undertake an independent review of the 
investigator’s assessed objective responses (CR and PR).  Any independent reviewer’s 
assessment will also be documented in the final clinical study report along with the assessment 
made by the investigator.  The eCRF will reflect the investigator’s opinion. 
9.3.1 
RECORDING OF RESPONSE IN THE ECRF 
The applicable overall response category for each visit that includes disease assessment must 
be recorded in the eCRF. 
9.3.2 
OTHER DEFINITIONS OF OUTCOME 
• 
Toxic death: 
Any death to which drug toxicity is thought to have a major contribution. 
• 
Early death: 
Death during the first 28 days of treatment. 
10 
ASSESSMENT OF SAFETY 
10.1 
ADVERSE EVENT DEFINITIONS 
10.1.1 
ADVERSE EVENT 
An AE is any untoward, undesired or unplanned medical occurrence in a subject administered 
an IMP, a comparator product or an approved drug.   

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An AE can be a sign, symptom, disease, and/or laboratory or physiological observation that may 
or may not be related to the IMP or comparator. 
An AE includes but is not limited to those in the following list. 
• 
A clinically significant worsening of a pre-existing condition.  This includes conditions that 
may resolve completely and then become abnormal again.  
• 
Any recurrence of an intermittent preexisting condition at a frequency or severity that differs 
from the subject’s historical experience. 
• 
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods.  If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should be 
reported as 2 separate AEs.  
• 
Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
• 
Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical 
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is 
associated with an already reported clinical event.  If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result (eg, decreased 
hemoglobin) should be recorded. 
• 
An AE occurring from an overdose of an IMP, whether accidental or intentional. 
• 
An AE occurring from lack of efficacy of an IMP, for example, if the investigator suspects 
that a drug batch is not efficacious or if the investigator suspects that the IMP has 
contributed to disease progression. 
• 
An AE occurring from misuse of a sponsor study drug.  
• 
An AE associated with the discontinuation of the use of a sponsor study drug. 
Note:  A preexisting condition is a clinical condition that is diagnosed before the subject receives 
the first dose of SRA737 (or gemcitabine if the SRA737 dose for PK is omitted). 
10.1.2 
SERIOUS ADVERSE EVENTS 
A SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life threatening*; 
• 
requires in subject hospitalization or prolongs existing in subject hospitalization (some 
hospitalizations are exempt from SAE reporting – eg, hospital admissions planned prior to 

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the subject entering the trial; overnight stays for planned procedures such as blood 
transfusions (Section 10.3.1);  
• 
results in persistent or significant incapacity or disability;  
• 
is a congenital anomaly or birth defect in the offspring of a subject who received the 
investigational medicinal product; 
• 
is any other medically important event**. 
*A life threatening event is defined as an event when the subject was at substantial risk 
of dying at the time of the AE, or use or continued use of the device or other medical 
product might have resulted in the death of the subject. 
**A medically important event is defined as any event that may jeopardize the subject or 
may require intervention to prevent one of the outcomes listed above.  Examples include 
allergic bronchospasm (a serious problem with breathing) requiring treatment in an 
emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions 
that do not result in hospitalization.  The development of drug dependence or drug 
abuse would also be examples of important medical events. 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome 
rather than reporting death as the SAE term.  When available the autopsy report will be 
provided to the sponsor. 
Other reportable events that must be treated as SAEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a subject or a subject’s partner 
during treatment with an IMP or occurring within 6 months of the last IMP administration, 
must be reported to the Pharmacovigilance Department in the same timelines as an SAE.  
These should be reported even if the subject is withdrawn from the trial. 
• 
Overdose with or without an AE. 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the 
conduct of the trial.  
• 
Abuse or misuse. 
• 
Medication error (any unintentional error in the dispensing or administration of an IMP).  
10.1.3 
SUSPECTED, UNEXPECTED, SERIOUS ADVERSE REACTIONS 
All AEs and SAEs will be assessed by the sponsor for seriousness, causality and expectedness.  
The study sponsor is required to expedite reports to regulatory authorities worldwide relating to 
suspected unexpected serious adverse reactions consistent with relevant legislation or 

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regulations, including the applicable US FDA Code of Federal Regulations, the European 
Commission Clinical Trials Directive (2001/20/EC, and revisions), and other country specific 
legislation or regulations. 
10.1.4 
DETERMINING ADVERSE EVENT CAUSALITY 
The relationship of an AE to the IMP is determined as follows: 
Highly probable 
1. Starts within a time related to the IMP administration and 
2. No obvious alternative medical explanation 
Probable 
3. Starts within a time related to the IMP administration and 
4. Cannot be reasonably explained by known characteristics of the subject’s 
clinical state 
Possible 
5. Starts within a time related to the IMP administration and 
6. A causal relationship between the IMP and the AE is at least a 
reasonable possibility 
Unlikely 
7. The time association or the subject’s clinical state is such that the trial 
drug is not likely to have had an association with the observed effect 
Not related 
8. The AE is definitely not associated with the IMP administered 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
 
The investigator must endeavor to obtain sufficient information to determine the causality of the 
AE (ie, IMP, other illness, progressive malignancy, etc.) and must provide his/her opinion of the 
causal relationship between each AE and IMP.  This may require instituting supplementary 
investigations of significant AEs based on their clinical judgement of the likely causative factors 
and/or include seeking a further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the 
IMP; 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding effects; 
• 
Timing of the events between administration of the IMP and the AE; 
• 
IMP blood levels and evidence, if any, of overdose; 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to 
the adverse reaction?; 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 

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10.1.5 
EXPECTEDNESS 
Assessment of expectedness for SRA737 will be made by the sponsor or sponsor designee’s 
Pharmacovigilance Department against the current version of the investigator’s Brochure. 
10.2 
EVALUATING AND RECORDING ADVERSE EVENTS 
10.2.1 
SCREENING FAILURES 
For subjects who fail screening, SAEs must be reported to the sponsor or sponsor designee’s 
Pharmacovigilance Department, from the date of consent until the date the subject is confirmed 
as ineligible. 
10.2.2 
DOCUMENTATION OF ADVERSE EVENTS 
For eligible subjects, SAE collection and monitoring will commence at the time the subject gives 
their written consent to participate in the trial, while AE collection and monitoring will commence 
at the time the subject receives their first dose of SRA737 (or gemcitabine if the SRA737 dose 
for PK is omitted). SAE and AE collection and monitoring will continue until 30 days after the last 
administration of SRA737.   
Should an investigator become aware of any drug related SAEs after this 30-day period, these 
must also be reported to the sponsor or sponsor designee within the expedited timelines in 
Section 10.3. 
10.2.3 
MONITORING AND FOLLOW-UP OF AES AND SAES 
All subjects will be monitored for AEs from the start of treatment through 30 days after the last 
dose of study therapy.  Additionally, monthly follow up is required for all SAEs and for those AEs 
considered drug related (highly probable, probable or possible) and present at the SFU visit.  
Monthly follow-up will continue until the event resolves, returns to baseline, stabilizes, or the 
subject discontinues from study. 
After a study participant’s completion or discontinuation from the study treatment, the 
investigator remains responsible to follow (through an appropriate health care option) any AEs 
that are serious or that caused the study participant to discontinue before completing the study.  
Events will be followed for outcome (resolution, with or without sequelae; stabilization of the 
event in those cases where the condition is expected to be chronic; or death).  

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The reporting period for SAEs that the investigator considers to be related to a study procedure 
begins at the time the subject signs the informed consent document.  Any SAE that occurs 
outside the time period specified above for AE monitoring (ie, through 30 days after the last 
dose of study therapy) that the investigator considers to be possibly, probably, or definitely 
related to study drug must be reported (refer to Section 10.1.2). 
Follow-up information relating to an SAE must be reported to the sponsor designee’s 
Pharmacovigilance Department within 24 hours of site staff becoming aware of the new 
information. 
The sponsor designee’s Pharmacovigilance Department will make requests for further 
information on SAEs to the trial site at regular intervals.  Requested follow up information should 
be reported to the Pharmacovigilance Department in a timely manner and as soon as possible 
after receipt of the follow up request.  For fatal or life threatening cases, follow up information 
must be reported to the sponsor designee’s Pharmacovigilance Department as soon as 
possible. 
10.3 
IMMEDIATE ADVERSE EVENT REPORTING 
All SAEs, regardless of causality, must be reported to the sponsor designee’s 
Pharmacovigilance Department in an expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided. 
The SAE report form should be faxed or e-mailed to the sponsor designee’s 
Pharmacovigilance Department within 24 hours of site staff becoming aware of the SAE. 
Primary Contact 
Secondary Contact 
Refer to your country-specific fax number 
in the Study Manual for the sponsor 
designee’s Pharmacovigilance team 
contact. 
Email:  GlobalSAE.Inbox@chiltern.com  
Refer to your country-specific contact information in the 
Study Manual for the sponsor Medical Monitor 
Email:  medicalmonitorSRA737-02@sierraoncology.com 
 
Each episode of an SAE must be recorded on a separate SAE report form.  The NCI-CTCAE 
v4.03 must be used to grade the severity of each SAE.  If new or amended information on a 
previously reported SAE becomes available, the investigator should report this to the sponsor or 
sponsor designee’s Pharmacovigilance Department on a new SAE report form.  

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If the SAE has not been reported within the specified timeframes, a reason for lateness must be 
added on the fax cover sheet when sending the SAE report form to the sponsor or sponsor 
designee’s Pharmacovigilance Department. 
Should the investigator become aware of any drug-related SAEs after the subject stops 
treatment with IMP(s), these must also be reported to the sponsor or sponsor designee’s 
Pharmacovigilance Department within the specified timelines specified above. 
If required by local regulations, SAEs must also be reported on an expedited basis to the 
EC/IRB of the study center. 
10.3.1 
EVENTS EXEMPT FROM BEING REPORTED AS SAES TO THE 
PHARMACOVIGILANCE DEPARTMENT 
Events specified in this section do not require reporting as SAEs in this trial, unless 
hospitalization is prolonged for any reason and then an SAE form must be completed.  The 
events must still be recorded in the appropriate section of the eCRF. 
Elective admissions – Elective admissions to hospital for procedures which were planned prior 
to entering the trial are not SAEs.  Hospitalization for administration of the IMP according to the 
trial protocol is also exempt from being reported as an SAE. 
10.4 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS IN 
ECRFS 
All AEs, including SAEs, must be recorded in the eCRF for eligible subjects.  All concomitant 
medications, including herbal medications and supplements must be recorded.  Any therapy 
used to treat the event must be recorded.  The eCRF will be reconciled with the safety database 
during and at the end of the trial.  Therefore, the sites should ensure the data entered on the 
SAE report form and the data entered into the eCRF are consistent.  The sponsor or sponsor’s 
designee and the investigator(s) will regularly review the safety data from both the safety and 
the clinical database. 
If known, the diagnosis of the AE or disorder should be recorded using standard medical 
terminology, rather than its individual symptoms.  The following AE information must be 
included: dates of occurrence; severity; causal relationship; action taken; and outcome.  When 
possible, the NCI-CTCAE v4.03 definitions should be used to assess the severity of an AE. 

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10.5 
URGENT SAFETY MEASURES 
The sponsor/sponsor’s designee or investigator may take appropriate urgent safety measures 
(USMs) in order to protect the subject of a clinical trial against any immediate hazard to their 
health or safety.  This includes procedures taken to protect subjects from pandemics or 
infections that pose serious risk to human health.  
USMs may be taken without prior authorization from the competent authority. 
The Medicines and Healthcare products Regulations Agency (MHRA), the Research Ethics 
Committee (REC), and/or other appropriate Regulatory Authorities and Ethics Committees 
(EC)/Institutional Review Boards (IRB) must be notified within 3 days of such measures being 
taken. 
Should the site initiate a USM, the investigator must inform the sponsor or sponsor’s designee 
immediately either by: 
Primary Contact 
Secondary Contact 
Refer to your country-specific fax 
number in the Study Manual for the 
sponsor designee’s 
Pharmacovigilance team contact. 
Email:   
GlobalSAE.Inbox@chiltern.com 
Refer to your country-specific contact information in the 
Study Manual for the sponsor Medical Monitor 
Email:  medicalmonitorSRA737-02@sierraoncology.com 
Phone:  1-604-558-6575 
 
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The sponsor or sponsor’s designee will then notify the applicable regulatory authority(ies) 
(eg, MHRA) and the applicable RECs within the required timeframes (eg, 3 days of USM 
initiation in the UK). 
10.6 
PREGNANCY REPORTING 
Female subjects who become pregnant during the trial or treatment period, must have study 
treatment stopped immediately. 

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The investigator must make every effort to try and ensure that a clinical trial subject or a partner 
of a clinical trial subject does not become pregnant during the trial or for 6 months afterwards.  
This should be done as part of the consent process by explaining clearly to the subject the 
potential dangers of becoming pregnant and also providing each subject with information about 
appropriate medically approved contraception.  Two forms of medically approved contraception 
must be used as described in Appendix 4. 
It should be explained to the subject that if his partner is pregnant or breast feeding when he is 
enrolled on the trial, the subject should use barrier method contraception as described in 
Appendix 4 to prevent the unborn baby or the baby being exposed to the SRA737.  
However, if a subject or a partner of a subject does become pregnant, the reporting procedures 
below must be followed. 
Any pregnancy occurring in a subject or a subject’s partner during treatment with an IMP or 
occurring within 6 months of last IMP administration must be reported to the sponsor or sponsor 
designee’s Pharmacovigilance Department within 24 hours of the site staff becoming aware of it 
using a Pregnancy Notification Report (provided in the Investigator Trial File [ITF]).   
It is the investigator’s responsibility to obtain consent for follow-up from the subject or subject’s 
partner.  The sponsor or sponsor designee’s Pharmacovigilance Department will follow up all 
pregnancies for the pregnancy outcome via the investigator, using a Pregnancy Follow-up 
Report. 
The investigator must ensure that all subjects are aware at the start of a clinical trial of the 
importance of reporting all pregnancies (in themselves and their partners) that occur whilst 
being treated with the IMP and occurring up to 6 months after the last IMP administration.  The 
investigator should offer counseling to the subject and/or the partner, and discuss the risks of 
continuing with the pregnancy and the possible effects on the fetus.  Monitoring of the subject 
and the baby should continue until the conclusion of the pregnancy, if the subject or subject’s 
partner has consented to this. 
11 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
As this is an open label, first-in-human study, data trends will be reviewed in real time.  There 
will also be 2 planned interim reviews on the accumulating data.  These are not formal statistical 
interims and the reviews are conducted in part for subject safety.  There will be no adjustment to 

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significance levels for these planned reviews of the accumulating data during the trial, at the 
following time points:  
• 
At the end of  cohort expansion  
• 
At the completion of subject follow-up for the last subject enrolled at the end of the dose 
escalation 
The final analysis will be conducted after one of the following conditions is met: 
• 
The trial is terminated early. 
• 
The end of trial as defined in Section 12.5 has been reached.  
Additional analysis may be conducted for regulatory, publication, or decision making purposes. 
11.1 
ANALYSIS POPULATIONS 
11.1.1 
SAFETY EVALUABLE POPULATION 
All enrolled subjects who receive at least 1 dose of SRA737 will be evaluable for safety. 
11.1.2 
RESPONSE EVALUABLE POPULATION 
All enrolled subjects who have measurable disease, receive at least 75% or 83% of SRA737 in 
1 cycle (Stages 1 and 2, respectively), and have a baseline assessment of disease plus at least 
1 post-baseline disease assessment will be evaluable for response.  All subjects who will be 
enrolled into the Cohort Expansion will be evaluable for response if they have measurable 
disease, receive at least 1 cycle of study medication as defined above, have a baseline 
assessment of disease plus at least 1 post-baseline disease assessment and are confirmed as 
having met the genetic selection eligibility requirements. 
In addition, subjects who have measurable disease and received at least 83% of SRA737 in 
1 cycle but developed PD, intolerable toxicity, or death prior to the post-baseline assessment 
will also be considered evaluable and will be classified as nonresponders. 
11.1.3 
PHARMACOKINETIC EVALUABLE POPULATION 
All subjects who receive at least 1 dose of SRA737 and provided at least 1 evaluable PK 
concentration will be included in the PK analysis.  Concentrations will be eligible for inclusion 
into PK analyses if the subject receives all doses and does not vomit within 4 hours postdose 
prior to the relevant PK sampling day(s). 

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11.1.4 
PHARMACODYNAMIC EVALUABLE POPULATION 
All enrolled subjects who receive at least 1 dose of SRA737 and have evaluable data for each 
specific PDn assessment will be evaluable for PDn. 
11.2 
STATISTICAL ANALYSIS 
11.2.1 
PRESENTATION OF DATA 
Data will be presented in a descriptive fashion.  Variables will be analyzed to determine whether 
the criteria for the trial conduct are met.  This will include a description of subjects who did not 
meet all the eligibility criteria, an assessment of protocol deviations, IMP accountability and 
other data that impact on the general conduct of the trial. 
Baseline characteristics will be summarized for all enrolled subjects.   
Treatment administration will be described for all cycles.  Dose administration, dose 
modifications or delays and the duration of therapy will be described. 
11.2.2 
SAFETY 
Safety data will be collected from the date of written consent.  Safety variables will be 
summarized by descriptive statistics.  Laboratory variables will be described using the 
NCI-CTCAE v4.03.  The MTD for the SRA737 and gemcitabine tested, if reached, and the 
RP2D and schedule will be described. 
Treatment-emergent adverse events (also referred to as AEs) will be reported for each dose 
level and coded using a current version of the MedDRA thesaurus, presented as tables of 
frequency of AEs by body system and by worse severity grade observed.  Additional tables will 
be prepared to summarize incidence of AEs reported as related and unrelated events. 
11.2.3 
EFFICACY ANALYSES 
The analysis of all efficacy endpoints will be based on the Response Evaluable Population.   
Descriptive analyses of the distribution of objective response rate (ORR), duration of response 
(DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), 
time to progression (TTP) per Response Evaluation Criteria in Solid Tumors, version 1.1 
(RECIST v1.1), and OS will be prepared.   

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Objective response rate, defined as the proportion of evaluable subjects with a best overall 
response of PR or CR per RECIST v1.1, will be summarized using binomial proportions and 
confidence intervals computed by the method of Wilson.  The distribution of DOR, in a subset of 
subjects responding will be summarized using Tukey’s 5 number summary, including the 
minimum, mean, median, maximum, and standard deviation.  Time to response will be 
summarized using Tukey’s 5 number summary.  
The ORR and DCR will be summarized for the Response Evaluable Population and for 
important subgroups including, but not limited to, genetically-defined subjects selected by the 
NGS techniques, either retrospectively or prospectively, subjects enrolled into each of the 
indication-specific expansion cohorts, and subjects enrolled to Stage 1 or Stage 2.  Additional 
subgroups of interest may also be identified, and the ORR will be estimated, as described in the 
Statistical Analysis Plan.  Responses will be defined using the RECIST v1.1, and will also be 
summarized as best absolute change from baseline.  
Duration of response is defined as the time from first evidence of PR or better to disease 
progression or death.  Duration of response will be right-censored for subjects who at least 
achieve a PR based on the censoring conventions defined for PFS in the Statistical Analysis 
Plan.  Analysis of DOR will be performed using the Kaplan-Meier method.  Medians and other 
quartiles for DOR will be estimated in addition to the corresponding 2-sided 95% confidence 
intervals. 
All other efficacy variables listed below will be further defined in the statistical analysis plan.   
Although an analysis of OS is not a planned endpoint for the purposes of efficacy evaluation, 
survival information will be captured as death is also a safety variable.  Statistical analysis of OS 
will include data from all subjects, and data from subjects alive at the end of the study will be 
included in the Kaplan Meier Analysis as a censored observation with censoring at the last 
available visit where survival status was ascertained.   
Progression-free survival will include data from all subjects including subjects who did not 
progress and were alive at the end of the study.  Censoring will be defined using the algorithm 
below and included in the Kaplan Meier analysis. 

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Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessments 
Cycle 1 Day 1 
Censored 
Progression documented 
between scheduled visits 
Earliest of: 
• 
Date of radiological assessment showing 
new lesion (if progression is based on new 
lesion); or 
• 
Date of last radiological assessment of 
measured lesions (if progression is based 
on increase in sum of measured lesions) 
Progressed 
No progression 
Date of last radiological assessment of 
measured lesions 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment of 
measured lesions 
Censored 
Treatment discontinuation for 
toxicity or other reason 
Date of last radiological assessment of 
measured lesions 
Censored 
New anticancer treatment 
started 
Date of last radiological assessment of 
measured lesions 
Censored 
Death before first PD 
assessment 
Date of death 
Progressed  
Death between adequate 
assessment visits 
Date of death 
Progressed 
Death or progression after more 
than 1 missed visit 
Date of last radiological assessment of 
measured lesions 
Censored 
 
The statistical analysis of OS and PFS will be prepared using the Kaplan Meier estimator, and 
variance estimated using the Greenwood Estimator. 
Binomial proportions will be summarized with a confidence interval estimated by the method of 
Wilson.  The evaluation of binomial proportions, for example from ORR may use confidence 
intervals for binomial proportions computed by the method of Wilson. 
11.2.4 
PHARMACOKINETICS 
Pharmacokinetic parameters will be determined using non-compartmental method(s).  
Pharmacokinetic parameters including but not limited to Cmin, Cmax, Tmax, AUCinf, AUCtau, t½, total 
body clearance, and apparent volume of distribution will be estimated and reported, as 
appropriate.  Pharmacokinetic data generated from this study may be used in conjunction with 
PK data from other clinical studies in future meta-analyses for population PK assessment and 
will be reported separately. 

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11.2.5 
PHARMACODYNAMICS 
11.2.5.1 
Tumor Profiling 
Archival and/or fresh tumor biopsy samples and blood samples for ctDNA will be obtained at 
screening or baseline and analyzed using NGS to characterize the mutational status of a pre-
specified panel of genes.  The proportion of subjects with evaluable tissue and blood based 
assays will be described.  The frequency of each genetic alteration will be characterized.  The 
proportion of subjects with mutations within each of the categories of genetic alterations 1) 
activating mutations or amplification of growth promoting oncogenes; 2) loss-of-function 
mutations or deletions in tumor suppressor pathways controlling the G1/S checkpoint; 3) defects 
in DDR signaling and DNA repair genes; 4) gain of function mutations of replication stress 
genes) will be characterized.  The association between the presence and type of genetic 
alteration and clinical outcome (response) will be explored. 
11.2.5.2 
Triplet Tumor Biopsies  
The tumor biopsy lysates will be analyzed using ELISAs including but not limited to 
pS296 Chk1, pS317 Chk1, and total Chk1.  The PDn parameters to be determined are 
absorbance, extrapolated concentrations, data normalized as a percentage of the Screening 
(Stage 2) and Cycle 1 Day 2 (Stage 2) biopsies and phosphorylated biomarker levels 
normalized to total biomarker levels.  
11.2.5.3 
PBMCs 
The fixed PBMCs will be analyzed using immunofluorescence and confocal microscopy in order 
of priority (which may be altered as data emerges) including but not limited to:  pS296 Chk1, 
pS317 Chk1, pS345 Chk1, total Chk1, gamma H2AX, and RAD51.  The PDn parameters to be 
determined for the Chk1 biomarkers are nuclear fluorescence intensity per cell and mean 
fluorescent intensity.  The PDn parameter to be determined for the gamma H2AX biomarker is 
percentage of cells with over 5 foci.  For all biomarkers the data will also be normalized as a 
percentage of Day1 predose.   
11.2.5.4 
Comet Assay 
The Comet assay, a single cell gel electrophoresis assay, will be used as an exploratory assay 
to measure DNA damage response in blood.  A separate statistical analysis plan may be 
prepared for the analysis of DNA damage in blood. 

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11.2.5.5 
Additional PDn Assays 
Subjects enrolled prior to the implementation of Amendment v5.0 were required to submit blood 
and hair follicles for the purposes of exploratory PDn assessments.  The following assessments 
will be performed: 
• 
Samples for cell death markers will be taken from subjects in expanded cohorts in the dose 
escalation phase and the  cohort expansion phase, i.e., will not be taken from subjects in the 
early dose escalation single subject cohorts. M30 and M65 ELISA assays will be used to 
measure markers of cell death in plasma according to agreed SOPs and validated methods.   
• 
Immunofluoresence and confocal microscopy will be used to measure the PDn biomarker 
gamma H2AX in hair follicles, which is indicative of DNA damage.  
A separate statistical analysis plan may be prepared for PDn assay analyses. 
11.3 
SAMPLE SIZE 
This study will enroll approximately 140 subjects in total including 10 subjects in Stage 1, 
approximately 30-40 subjects during Stage 2 Dose Escalation, and another approximately 90 
subjects in Stage 2 Cohort Expansion (up to 8 subjects in the original expansion cohort plus 
approximately 20 prospectively-selected genetically-defined subjects in each of 4 indication-
specific expansion cohorts added with Amendment v6.0).  The sample size for dose escalation 
is based on assumptions for allometric scaling and the estimated number of dose levels 
required to establish MTD.  For the cohort expansion, the sample size of 20 subjects enrolled in 
each indication-specific expansion cohort was chosen such that 0 of 20 responses observed 
excludes an ORR of 16% in the 95% confidence interval (CI).   
12 
ADMINISTRATION 
This trial is conducted under the appropriate clinical trial authorization and approval from the 
relevant REC(s), Regulatory Authorities, and ECs/IRBs will be obtained before the start of this 
trial.  This trial is sponsored and monitored by Sierra Oncology, Inc. and its designee.  
Applicable regulatory requirements are described in this section. 
12.1 
PROTOCOL DEVIATIONS AND AMENDMENTS 
The protocol should be adhered to throughout the conduct of the study, if a situation arises 
where the conduct of the study may not be in line with the protocol, then site should contact the 
sponsor or sponsor’s designee to discuss this. 

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Amendments to the protocol may only be made with the approval of the sponsor.  A protocol 
amendment may be subject to review by the assigned REC(s), Regulatory Authorities 
(eg, MHRA), and ECs/IRBs Committees.  Written documentation of the approval must be 
received before the amendment can be implemented and incorporated into the protocol if 
necessary. 
12.2 
SERIOUS BREACH OF GCP 
A serious breach is a breach which is likely to effect to a significant degree: the safety or 
physical or mental integrity of the subjects of the trial, or the scientific value of the trial. 
In order that the sponsor can fulfil their obligations in terms of reporting serious breaches of 
GCP to the Regulatory Authorities within 7 calendar days of identification, site staff must inform 
the sponsor of any unplanned deviations to the trial protocol (or GCP principles) as soon as 
possible after the deviation occurs to allow prompt evaluation by the sponsor. 
12.3 
OBTAINING WRITTEN INFORMED CONSENT 
Written informed consent must be obtained from the subject before any protocol-specific 
procedures are carried out. 
The subject must be given adequate time to think about their commitment to the study.  If new 
information has been issued, subjects must be informed of this and re-consented if appropriate. 
Only the site staff with delegated responsibility by the PI, and who have signed the Delegation 
Log, are permitted to obtain informed consent from subjects and sign the consent form.  All 
signatures must be obtained before the occurrence of any medical intervention required by the 
protocol (ICH GCP 4.8.8).  The date of the signatures of both the subject and the individual 
obtaining informed consent should be the same. 
The delegated site staff member must inform the subject about the background to, and present 
knowledge of the normal management of their disease and SRA737 and must also ensure that 
the subject is aware of the following points: 
• 
That SRA737 is new and that the exact degree of activity is at present unknown, but that 
treating him/her will contribute to further knowledge. 
• 
The known toxicity of SRA737 and the possibility of experiencing side effects. 

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• 
The potential dangers of becoming pregnant (or the subject’s partner becoming pregnant) 
and he/she has been given information about appropriate medically approved contraception 
(refer to Appendix 4). 
• 
That he/she may refuse treatment either before or at any time during the trial and that 
refusal to participate will involve no penalty or loss of benefits to which they are otherwise 
entitled. 
• 
Who to contact for answers to pertinent questions about the research and their rights, and 
also who to contact in the event of a research-related injury. 
A copy of the signed informed consent document (ICD) must be given to the subject to keep 
and the original ICD, must be filed in the ITF (unless otherwise agreed that the original 
document will be filed in the medical records and a copy kept in the ITF). 
12.4 
COMPLETION OF THE ELECTRONIC CASE REPORT FORM 
Electronic CRFs approved by the sponsor will be used to collect the data.  The investigator is 
responsible for ensuring the accuracy, completeness, clarity and timeliness of the data reported 
in the eCRFs. 
Only the investigator and those personnel who have signed the Delegation Log provided by the 
sponsor or sponsor’s designee and have been authorized by the investigator should enter or 
change data in the eCRFs.  Authorized users will be included on a user list in order to be 
provided access to the eCRF.  All protocol required investigations must be reported in the 
eCRF.  The investigators must retain all original reports, traces and images from these 
investigations for future reference.   
The collection and processing of personal data from the subjects enrolled in this clinical trial will 
be limited to those data that are necessary to investigate the efficacy, safety, quality and 
usefulness of the study drug used in this trial.  The data must be collected and processed with 
adequate precautions to ensure subject confidentiality and compliance with applicable data 
privacy protection according to the applicable regulations.  The data collected will comply with 
applicable local regulations on the protection of individuals with regard to the processing of 
personal data. 
Data will be entered directly into electronic screens by authorized site personnel.  Amendments 
to eCRF data will be made directly to the system and the system audit trail will retain details of 
the original value(s), who made the change, a date and time, and a reason for the change. 

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Once an eCRF form has been entered by the site personnel, the data are cleaned using manual 
and automated checks.  Queries will be issued electronically to the site.  Authorized personnel 
must answer the queries by making relevant amendments to data and/or providing a response.  
Answered queries will be closed or reissued as appropriate. 
Once the subject is ‘off study’ and the eCRF has been fully completed, the investigator must 
provide an electronic signature to authorize the complete subject casebook. 
At the end of the trial all eCRFs are retained and archived by the sponsor and a portable 
document format copy provided to the investigator who is responsible for archiving at site. 
12.5 
END OF STUDY 
The ‘end of trial’ is defined as the date when the last subject has completed the SFU visit or the 
final long-term follow-up visit (whichever is the latter). 
It is the responsibility of the sponsor to inform the Medicines and Healthcare Products 
Regulatory Agency (MHRA), the Research Ethics Committee (REC), and other appropriate 
Regulatory Authorities and ECs/IRBs within 90 days of the ‘end of the trial’ that the trial has 
closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the 
sponsor, the sponsor or sponsor’s designee will notify the MHRA, the REC and other 
appropriate Regulatory Authorities and ECs/IRBs within 15 days of the decision and a detailed, 
written explanation for the termination/halt will be given. 
Recruitment will cease when any of the following occur: 
• 
The drug is considered too toxic to continue treatment before the required number of 
subjects have been recruited.   
• 
The stated number of subjects to be recruited has been reached. 
• 
The stated objectives of the trial are achieved. 
Regardless of the reason for termination, all data available for subjects at the time of 
discontinuation of follow up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.   
In terminating the trial, the sponsor and the investigators must ensure that adequate 
consideration is given to the protection of the subject’s interest. 

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12.6 
TRIAL PERFORMANCE, MONITORING, AUDITING AND INSPECTION 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and 
the organizational preparations made with the trial center.  The sponsor or sponsor’s designee 
must be informed immediately of any change in the personnel involved in the conduct of the 
trial. 
During the trial, the CRA will be responsible for monitoring data quality in accordance with 
sponsor or sponsor designee’s standard operating procedures.   
Before the study start, the investigator will be advised of the anticipated frequency of the 
monitoring visits.  The investigator will receive reasonable notification before each monitoring 
visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check PK and PDn samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
At the end of the trial all unused SRA737 supplies must be destroyed at site (only once 
authorized to do so by the CRA) or if authorized by the sponsor or sponsor’s designee returned 
to the supplier. 
It is the responsibility of the sponsor to notify the REC of the ‘end of the trial’ (See definition in 
Section 12.5).  Principal investigators are responsible for notifying their local ECs/IRBs, as 
appropriate. 
During the course of the trial, the sponsor or sponsor’s designee, may conduct an on-site audit. 
Principal Investigators conducting this trial accept the potential for inspection by the MHRA or 
other Regulatory Authorities. 
12.7 
SOURCE DOCUMENT VERIFICATION 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data.  
Therefore, it is the investigator’s responsibility to ensure that both he/she and his/her study team 

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records all relevant data in the medical records.  The investigator must allow the CRA direct 
access to relevant source documentation for verification of data entered into the eCRF, taking 
into account data protection regulations.  Entries in the eCRF will be compared with subjects’ 
medical records and the verification will be recorded in the eCRF. 
Some source data may exist only electronically and be entered, or loaded directly into the 
eCRF.   
12.8 
RECORD RETENTION 
During the clinical trial and after trial closure the investigator must maintain adequate and 
accurate records to enable both the conduct of a clinical trial and the quality of the data 
produced to be evaluated and verified.  These essential documents (as detailed in Chapter V of 
Volume 10 (Clinical Trials) of The Rules Governing Medicinal Products in the European Union 
based upon Section 8 of the ICH GCP Guidelines), including source documents such as scans, 
trial related documents and copies of the eCRFs, associated audit trail and SAE report forms, 
shall show whether the investigator has complied with the principles and guidelines of GCP. 
All essential documents required to be held by the investigator must be stored in such a way 
that ensures that they are readily available, upon request, to the Regulatory Agency or sponsor, 
for the minimum period required by national legislation or for longer if needed by the sponsor.  
Records must not be destroyed without prior written approval from the sponsor. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
12.9 
ETHICAL CONSIDERATIONS 
Before starting the trial, the protocol and subject ICD must go through the Sierra Oncology 
review process and receive the favorable opinion/approval of the assigned REC/ECs/IRBs. 
It is the PI’s responsibility to update subjects (or their authorized representatives, if applicable) 
whenever new information (in nature or severity) becomes available that might affect the 
subject’s willingness to continue in the trial.  The PI must ensure this is documented in the 
subject’s medical notes and the subject is re-consented. 

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The sponsor and CI/PI must ensure that the trial is carried out in accordance with the GCP 
principles and requirements of applicable ICH GCP and local regulations. 
12.10 
PUBLICATION POLICY AND PRESS RELEASES 
Sierra Oncology, Inc. (Sierra Oncology) is committed to the publication and widespread 
dissemination of the results of this study.  
This study represents a joint effort between Sierra Oncology and the investigators, and as such, 
the parties agree that the recommendation of any party concerning manuscripts or texts shall be 
taken into consideration in the preparation of final scientific documents for publication or 
presentation.  
All proposed publications and presentations by the investigators or their personnel and 
associates resulting from or relating to this study must be submitted to Sierra Oncology for 
review before submission for publication or presentation.  If the proposed publication or 
presentation contains patentable subject matter, which, at Sierra Oncology’s sole discretion, 
warrants intellectual property protection, Sierra Oncology may delay any publication or 
presentation for the purpose of pursuing such protection. 

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13 
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14 
APPENDICES 
Appendix 1.  WHO Performance Scale 
Activity Performance Description 
Score 
Fully active, able to carry out all normal activity without restriction. 
0 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, for example, light 
housework, office work. 
1 
Ambulatory and capable of all self-care, but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.  
2 
Capable of only limited self-care.  Confined to bed or chair more 
than 50% of waking hours.  
3 
Completely disabled. Cannot carry out any self-care.  Totally 
confined to bed or chair. 
4 
 
 
 
 

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APPENDIX 2:  ASSESSMENT OF DISEASE RESPONSE 
Assessment of disease response in this study should be performed according to the RECIST 
criteria specified below. 
New response evaluation criteria in solid tumours (RECIST criteria):   
Revised RECIST guideline (version 1.1) 
E.A. Eisenhauer et al. (2009) European Journal of Cancer 45: 228-247 
Note that this is an abridged version of the RECIST criteria.  Please refer to the above article for 
detailed appendices and if in doubt. 
Measurability of tumour at baseline 
1.1. 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
1.1.1. Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 
10mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on 
imaging guidance). 
• 
10mm calliper measurement by clinical exam (lesions which cannot be accurately measured 
with callipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.   
1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph nodes 
with 10 to <15mm short axis) as well as truly non-measurable lesions.  Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 

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masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable.  
1.2. Specifications by methods of measurements 
1.2.1. Measurement of lesions 
All measurements should be recorded in metric notation, using callipers if clinically assessed.  
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 

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Method of assessment 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and ≥10mm 
diameter as assessed using callipers (e.g. skin nodules).  For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray:  
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung.  
CT and MRI:  
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).  More details 
concerning the use of both CT and MRI for assessment of objective tumour response evaluation 
are provided in the publication from Eisenhauer et al.  
Ultrasound:  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 

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review at a later date and, because they are operator dependent, it cannot be guaranteed that 
the same technique and measurements will be taken from one assessment to the next 
(described in greater detail in Appendix II).  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy and laparoscopy: 
The utilisation of these techniques for objective tumour evaluation is not advised.  However, 
they can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection 
is an endpoint. 
Tumour markers:  
Tumour markers alone cannot be used to assess objective tumour response.  If markers are 
initially above the upper normal limit, however, they must normalise for a subject to be 
considered in complete response.   
Cytology and histology:  
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumour types such as germ cell tumours, where known 
residual benign tumours can remain).  When effusions are known to be a potential adverse 
effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumour has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and progressive disease. 
2. Tumour response evaluation 
2.1 Assessment of overall tumour burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumour burden at baseline and use this as a comparator for subsequent measurements.  
Measurable disease is defined by the presence of at least one measurable lesion (as detailed 
above in Section 1).   

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2.2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where subjects have only one or two organ sites involved a maximum of two 
and four lesions respectively will be recorded).  For evidence to support the selection of only five 
target lesions, see analyses on a large prospective database in the article by Bogaerts et al.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected.  An example in Fig. 3 of the 
publication by Eisenhauer et al. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumour.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumour.  Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagital or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm 
are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterise any objective tumour 
regression in the measurable dimension of the disease.  

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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
2.3.1. Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note: the appearance of one or more new lesions is 
also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2. Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10 mm on study.  This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of <10 mm.  Case report forms or 
other data collection methods may therefore be designed to have target nodal lesions recorded 
in a separate section where, in order to qualify for CR, each node must achieve a short axis 

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<10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions. 
Target lesions that become ‘too small to measure’ 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm).  
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’.  When this occurs it is important 
that a value be recorded on the case report form.  If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm.  If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well).  
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error.  To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane 
between them may be maintained that would aid in obtaining maximal diameter measurements 
of each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest 
diameter for the ‘coalesced lesion’. 
2.3.3. Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 

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Complete Response (CR): Disappearance of all non-target lesions and normalisation of tumour 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumour 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions.  (Note: the appearance of one or more new lesions is also considered 
progression). 
2.3.4. Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumour burden has increased sufficiently to 
merit discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to quality for unequivocal progression status.  The designation of 
overall progression solely on the basis of change in non-target disease in the face of SD or PR 
of target disease will therefore be extremely rare. 
When the subject has only non-measurable disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease.  The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an 
increase in non-measurable disease burden.  Because worsening in non-target disease cannot 
be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can 
be applied when assessing subjects for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: i.e. an 
increase in tumour burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase diameter in a measurable lesion).  Examples include an increase 
in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localised to 

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widespread, or may be described in protocols as ‘sufficient to require a change in therapy’.  If 
‘unequivocal progression’ is seen, the subject should be considered to have had overall PD at 
that point.  While it would be ideal to have objective criteria to apply to non-measurable disease, 
the very nature of that disease makes it impossible to do so; therefore the increase must be 
substantial. 
New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumour (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the subject’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases.  The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease).  New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: 

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• 
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. 
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  A ‘positive’ FDG-PET scan lesion means one which is 
FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
• 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD. 
2.4. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment. Should a response not be documented until after the end of therapy 
in this trial, post-treatment assessments may be considered in the determination of best overall 
response as long as no alternative anti-cancer therapy has been given.  The subject’s best 
overall response assignment will depend on the findings of both target and non-target disease 
and will also take into consideration the appearance of new lesions.   
2.4.1. Time point response 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for subjects 
who have measurable disease at baseline.   
When subjects have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
2.4.2. Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD. For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the subject will have 
achieved PD status, regardless of the contribution of the missing lesion. 

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2.4.3. Best overall response: all time points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in this trial (in which confirmation of complete or partial response 
IS NOT required):  
Best response in these trials is defined as the best response across all time points (for example, 
a subject who has SD at first assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR).  When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline.  If the minimum time is not 
met when SD is otherwise the best time point response, the subject’s best response depends 
on the subsequent assessments.  For example, a subject who has SD at first assessment, PD 
at second and does not meet minimum duration for SD, will have a best response of PD.  The 
same subject lost to follow-up after the first SD assessment would be considered inevaluable.  A 
‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
Table 1 – Time point response: subjects with target (+/–non-target) disease 
Target lesions  
Non-target lesions  
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD  
No 
NE 
PD 
Any 
Yes or No 
PD 
Any  
PD  
Yes or No 
PD 
Any  
Any  
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD 
= progressive disease, and NE = inevaluable.  
 

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Table 2 – Time point response: subjects with non-target disease only 
Non-target lesions  
New lesions  
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD(a) NE 
Not all evaluated 
No 
PD 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = 
inevaluable.  
(a) ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can 
be measured is not advised. 
 
2.4.4. Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans.  This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in size of the nodes.  As noted earlier, this means that subjects 
with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease as shown in 
Tables 1 to 3. 
Conditions that define ‘EP, early death and inevaluability’ are study specific and should be 
clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner similar 

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to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.   
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 
2.6.2. Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
2.6.3. Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). 

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APPENDIX 3.  NEW YORK HEART ASSOCIATION (NYHA) SCALE 
Class I  
subjects with cardiac disease but without resulting limitation of physical 
activity; ordinary physical activity does not cause undue dyspnoea (or 
fatigue, palpitation or anginal pain) 
Class II  
subjects with cardiac disease resulting in slight limitation of physical activity; 
they are comfortable at rest; ordinary physical activity results in dyspnoea (or 
fatigue, palpitation or anginal pain) 
Class III  
subjects with cardiac disease resulting in marked limitations of physical 
activity; they are comfortable at rest; less than ordinary physical activity 
causes dyspnoea (or fatigue, palpitation or anginal pain) 
Class IV  
subjects with cardiac disease resulting in inability to carry out physical 
activity without discomfort; symptoms of dyspnoea (or of angina) may be 
present even at rest; if any physical activity is undertaken, discomfort is 
increased. 

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APPENDIX 4.  CONTRACEPTIVE GUIDANCE FOR WOMEN OF CHILDBEARING 
POTENTIAL (WOCBP) AND MALE PARTNER OF WOCBP 
The risks of treatment with SRA737 during pregnancy, given in combination with gemcitabine 
plus cisplatin or gemcitabine alone, have not been evaluated.  Please refer to the latest version 
of the Investigator’s Brochure for SRA737 as well as to the regional prescribing information for 
Gemcitabine and Cisplatin for additional information.  
Women of Childbearing Potential 
This protocol defines a women of childbearing potential (WOCBP) as a sexually mature woman 
who:   
• 
Has not undergone a hysterectomy or bilateral oophorectomy, or  
• 
Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule 
out childbearing potential) for at least 24 consecutive months (ie, has had menses at any 
time in the preceding 24 consecutive months). 
Contraceptive Requirements for Females 
In order to be eligible for the clinical trial, WOCBP planning to participate must agree to use 2 
forms of contraception (one reliable form plus a barrier method) effective from the date of the 
first administration of SRA737 (ie, at least 7 days prior for hormonal methods) throughout the 
trial and for 6 months afterwards.  The investigator should counsel subjects on appropriate 
methods for avoiding pregnancy during the study.  These include the following: 
• 
Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, 
implants) and condom; 
• 
Intra-uterine device (IUD) or intrauterine system (IUS) and condom; 
• 
Diaphragms with spermicidal gel and condom 
The following highly effective methods (failure rate <1% per year), are also acceptable as single 
methods:  
• 
Vasectomy**  
• 
Tubal sterilization* 
Abstinence is only considered an acceptable method of contraception if it is a pre-existing part 
of a subject’s lifestyle.  Symptom-thermal methods (basal body temperature, cervical mucous, 
or calendar/rhythm) or withdrawal are not considered adequate forms of contraception for the 
purposes of this study. 

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* Tubal sterilization via the Essure procedure is not considered a reliable form of 
contraception unless tubal blockage is verified by hysterosalpingogram (HSP) 
approximately 3 months after microinsertion.  Prior to verification, another contraception 
method described above should be used. 
** Vasectomised partner is also considered a highly effective birth control method 
provided that the partner is the sole sexual partner of the WOCBP trial participant and 
that the vasectomised partner has received medical confirmation of the surgical success.  
Prior to verification, another contraception method described above should be used. 
Contraceptive Requirements for Male Subjects with Female Partners of Childbearing 
Potential 
All male study participants must agree to consistently and correctly use a condom plus 
spermicidal gel from the date of the first administration of SRA737 throughout the trial and for 6 
months after the last dose of study drug.  If their female partner is a WOCBP (as defined 
above), additionally, male subjects must be willing to ensure that their partner uses 1 of the 
methods of birth control listed above effective from the date of the first administration of SRA737 
(ie, at least 7 days prior to the first dose for hormonal methods) throughout the trial and for 6 
months after the last dose of study drug. Male subjects with pregnant or lactating partners must 
be advised to use condom plus spermicidal gel to prevent exposure of the fetus or neonate. 
Male subjects must agree to refrain from sperm donation from the first administration of study 
drug for at least 6 months after the last dose of study drug. 
Procedures to be Followed in the Event of Pregnancy 
Subjects will be instructed to notify the investigator if they, or the partners of male subjects 
become pregnant at any time during the study, or if they become pregnant within 6 months] of 
the last dose of study drug.  Subjects who become pregnant or who suspect that they are 
pregnant must report the information to the investigator.  Subjects whose partner has become 
pregnant or suspects she is pregnant must report the information to the investigator.  All 
pregnancies (subjects and their partners) should be followed until resolution if possible. 
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 10.6. 

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APPENDIX 5.  QT PROLONGING DRUGS AND DRUGS METABOLIZED BY CYP1A2 
List of known QTc prolongation drugs from www.crediblemeds.com.  Reprinted on 16 November 
2016. 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anticancer 
Astemizole 
(Removed from 
Market) 
Hismanal 
Antihistamine 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bepridil (Removed 
from Market) 
Vascor 
Antianginal 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / Antiemetic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Cisapride (Removed 
from Market) 
Propulsid 
GI stimulant 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Cocaine 
Cocaine 
Local anesthetic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Domperidone (Only 
on Non US Market) 
Motilium, Motillium, Motinorm Costi, 
Nomit 
Antinausea 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic / Antiemetic 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, 
Ery-Tab, Eryc Ranbaxy, Erypar, 
Eryped, Erythrocin Stearate Filmtab, 
Erythrocot, E-Base, Erythroped, 
Ilosone,  MY-E, Pediamycin, Zineryt, 
Abboticin, Abboticin-ES, Erycin, 
PCE Dispertab, Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E 
(India), Exodus (Brazil), Esto 
(Israel), Seroplex, Elicea, Lexamil, 
Lexam, Entact (Greece), Losita 
(Bangladesh), Reposil (Chile), 
Animaxen (Colombia), Esitalo 
(Australia), Lexamil (South Africa) 
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine 
Antiarrhythmic 

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Generic Name 
Brand Names (Partial List) 
Drug Class 
Fluconazole 
Diflucan, Trican 
Antifungal 
Gatifloxacin 
(Removed from 
Market) 
Tequin 
Antibiotic 
Grepafloxacin 
(Removed from 
Market) 
Raxar 
Antibiotic 
Halofantrine 
Halfan 
Antimalarial 
Haloperidol 
Haldol (US & UK), Aloperidin, 
Bioperidolo, Brotopon, Dozic, 
Duraperidol (Germany), Einalon S, 
Eukystol, Halosten, Keselan, Linton, 
Peluces, Serenace, Serenase, 
Sigaperidol 
Antipsychotic 
Ibogaine (Only on 
Non US Market) 
None 
Psychedelic 
Ibutilide 
Corvert 
Antiarrhythmic 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Levomepromazine 
(Only on Non US 
Market) 
Nosinan, Nozinan, Levoprome 
Antipsychotic 
Levomethadyl 
acetate (Removed 
from Market) 
Orlaam 
Opioid agonist 
Levosulpiride (Only 
on Non US Market) 
Lesuride,  Levazeo,  Enliva (with 
rabeprazole) 
Antipsychotic 
Mesoridazine 
(Removed from 
Market) 
Serentil 
Antipsychotic 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon 
Opioid agonist 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, 
Ondisolv, Setronax 
Antiemetic 
Oxaliplatin 
Eloxatin 
Antineoplastic Agent 
Papaverine HCl 
(Intra-coronary) 
none 
Vasodilator, Coronary 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Probucol (Removed 
from Market) 
Lorelco 
Antilipemic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Propofol 
Diprivan,  Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora 
Antiarrhythmic 
Roxithromycin (Only 
on Non US Market) 
Rulide, Xthrocin, Roxl-150, Roxo, 
Surlid, Rulide, Biaxsig, Roxar, 
Antibiotic 

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Generic Name 
Brand Names (Partial List) 
Drug Class 
Roximycinv, Roxomycin, Rulid, 
Tirabicin, Coroxin 
Sevoflurane 
Ulane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Sparfloxacin 
(Removed from 
Market) 
Zagam 
Antibiotic 
Sulpiride (Only on 
Non US Market) 
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor 
Antipsychotic, atypical 
Sultopride (Only on 
Non US Market) 
Barnetil,  Barnotil,  Topral 
Antipsychotic, atypical 
Terfenadine 
(Removed from 
Market) 
Seldane 
Antihistamine 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anticancer 
 
List of drugs known to be metabolized by CYP1A2 from 
http://medicine.iupui.edu/CLINPHARM/ddis/main-table.  Reprinted on 01 September 2017. 
Generic Name 
Brand Name (Partial List) 
amitriptyline 
Elavil 
caffeine 
 
clomipramine 
Anafranil 
clozapine 
Clozaril 
cyclobenzaprine 
Flexeril 
duloxetine 
Cymbalta 
estradiol 
 
fluvoxamine 
 
haloperidol 
Haldol 
imipramine N-DeMe 
Tofranil 
mexiletine 
 
nabumetone 
Relafen, Relifex, Gambaran 
naproxen 
Aleve, Naprosyn 
olanzapine 
Zyprexa 
ondansetron 
Zofran 
phenacetin→acetaminophen→NAPQI 
Tylenol, Paracetamol 
propranolol 
Inderal 
riluzole 
Rilutek, Teglutik 
ropivacaine 
Naropin 

Sierra Oncology, Inc. 
Clinical Study Protocol No. SRA737-02 
SRA737 
Page 156 of 157 
SRA737-02 Protocol Amendment Final Version 7.0 (03-Aug-2018) 
CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
Generic Name 
Brand Name (Partial List) 
tacrine 
Cognex 
theophylline 
 
tizanidine 
Zanaflex, Sirdalud, Relentus 
triamterene 
Dyrenium, Maxzide, Dyazide 
verapamil 
Calan, Covera-HS 
(R)warfarin 
Coumadin 
zileuton 
Zyflo 
zolmitriptan 
 
 
 
 

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Clinical Study Protocol No. SRA737-02 
SRA737 
Page 157 of 157 
SRA737-02 Protocol Amendment Final Version 7.0 (03-Aug-2018) 
CONFIDENTIAL 
EudraCT Number:  2015-004467-36 
APPENDIX 6.  GENETIC PREDICTORS OF SRA737 SENSITIVITY 
Subjects must have predicted sensitivity to Chk1 inhibition for enrollment into the Cohort 
Expansion Phase. Factors including genetic profiling of tumor tissue or ctDNA, HPV status 
(including very high prevalence of HPV positivity in some tumor types), and BRCA1 and BRCA2 
gene status may considered for evaluation of Chk1 sensitivity.  
Evaluation of genetic profiles will identify gene mutations documented or predicted to enhance 
sensitivity to Chk1 inhibition/loss. These genes of interest are grouped into four main classes, 
consistent with the Hallmarks of Cancer (Hanahan 2011).  Note, this list is not exhaustive as 
scientific discoveries and technology continue to evolve. 
Tumor Suppressor 
 
DNA Damage Repair 
 
Replicative Stress 
 
Oncogenic Driver 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
Amplification or gain of function mutations are desired for this gene  
2. 
Loss of function mutations are desired for this gene 
 
Other genetic predictors can be added to this list, include mutations meeting  any of the 
following criteria: 
• A new gene/mutation that has been identified and published in at least 1 peer reviewed 
article documenting its relationship or sensitivity to genetic alterations with a Chk1 or ATR 
mutation. 
• Data from PDX studies performed by the sponsor or its collaborator demonstrating evidence 
of genetic sensitivity. 
• Data of similar quality that has been reviewed by the sponsor but is not yet published or 
conducted by the sponsor or their collaborator. 
• Detection of microsatellite instability in a tumor sample may increase the probability of 
detecting a germline mutation in a DNA mismatch repair gene.  Five mononucleotide repeat 
markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) are used to determine 
microsatellite instability status. 
Genetic predictors may also be removed from this list as new information on the relationship or 
sensitivity of genetic alterations in genes included in the list becomes available or the 
technology employed in genomic profiling evolves. The Laboratory Manual will be updated if 
and when genes are added to or removed from this list.