Conditions: Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL)
Keywords: Replication stress Advanced solid tumors CCNE1 TP53 BRCA1 BRCA2 MYC RAD50 Fanconi anemia Cell cycle Metastatic Colorectal Cancer Platinum-Resistant or Intolerant High Grade Serious Ovarian Cancer Advanced Non-Small Cell Lung Cancer Metastatic Castration-Resistant Prostate Cancer Head and Neck Squamous Cell Carcinoma Squamous Cell Carcinoma of the Anus Phase 1 Phase 2 Dose escalation Chk1 inhibitor Checkpoint kinase 1 Synthetic lethality Next-Generation Sequencing Genetic biomarkers
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 107
Healthy volunteers: no

Brief summary:
The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

Detailed description:
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability, leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic RS.

This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality.

This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion.

In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified.

In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types:

* castration-resistant prostate cancer (mCRPC);
* high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;
* HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect);
* non-small cell lung cancer (NSCLC);
* head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and
* colorectal cancer (mCRC).

To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories:

* Oncogenic drivers such as CCNE1 or MYC, etc.
* Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability.
* Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility.
* Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes.

Tumor genetics will be prospectively determined using Next-Generation Sequencing.

Arms:
arm 1: None

Interventions: intervention 1: SRA737
Intervention descriptions: intervention 1: SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

Protocol document:
Prot_000.pdf: 
Sierra Oncology, Inc. 
Clinical Study Protocol No. SRA737-01 
SRA737 
Page 1 of 138 
 
SRA737-01 Protocol Amendment Final Version 8.0 (10 Jan 2018) 
CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
A PHASE 1/2 TRIAL OF SRA737 (A CHK1 INHIBITOR) ADMINISTERED ORALLY IN 
SUBJECTS WITH ADVANCED CANCER 
 
Sponsor protocol 
number: 
SRA737-01 
EudraCT number: 
201500448686 
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 
Tel: 734-233-3966 
Confidentiality 
Statement 
This document contains information that is confidential and 
proprietary to Sierra Oncology, Inc. (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 SRA737-01, the International Conference on 
Harmonisation (ICH), Guideline for Good Clinical Practice 
(GCP), and the applicable country and regional (local) 
regulatory requirements. 
 


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Page 2 of 138 
 
SRA737-01 Protocol Amendment Final Version 8.0 (10 Jan 2018) 
CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
VERSION HISTORY 
Version No. 
Date of issue 
Reason for update 
1.0 
25-January-2016 
Initial version submitted for MHRA/REC approval  
2.0 
02-March-2016 
Addition of QTc exclusion criteria and amendments to 
contraceptive advice (made at the request of the 
MHRA prior to approval) 
 
 
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, SRA737 (formerly known as 
CCT245737).  In addition, the study is being 
amended to assess preliminary efficacy in all subjects 
including 40 additional biomarker-selected and 
indication-specific subjects with tumors anticipated to 
be sensitive to inhibition of Chk1. Another new 
objective is to assess the relationship between drug 
exposure and any effects on the QT interval.  
Procedures are being revised to ensure appropriate 
subject selection, in accordance with the new and 
retained study objectives.   
5.0 
10-February-2017 
Protocol Amendment Version 5.0 clarifies the 
frequency of bone scans for subjects with prostate 
cancer.  In addition, a clarification was provided for 
the MSI testing criteria and ECG data collection. 
6.0 
18-May-2017 
Protocol Amendment Version 6.0 removes the 
maximum number of prior regimens criteria for 
subjects participating in the Cohort Expansion Phase 
and circulating tumor cells requirement for metastatic 
castration-resistant prostate cancer subjects.  In 
addition, the eligibility criteria for ovarian cancer 
subjects have been clarified. 


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SRA737 
Page 3 of 138 
 
SRA737-01 Protocol Amendment Final Version 8.0 (10 Jan 2018) 
CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
Version No. 
Date of issue 
Reason for update 
7.0 
14-Sep-2017 
Protocol Amendment Version 7.0 increases the size 
of each indication-specific cohort in the Cohort 
Expansion Phase from 8 to 20. The cohort enrolling 
subjects with squamous cell carcinoma of the head 
and neck was amended to also include squamous 
cell carcinoma of the anus. 
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.  
8.0 
10-Jan-2018 
A specific expansion cohort of approximately 20 
subjects with high-grade serous ovarian cancer 
(HGSOC) with CCNE1 gene amplification was added 
to the study.  This is in addition to the expansion 
cohort of subjects with HGSOC with other eligible 
genetic profiles. 


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Page 4 of 138 
 
SRA737-01 Protocol Amendment Final Version 8.0 (10 Jan 2018) 
CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
TABLE OF CONTENTS 
Page 
1 
PROTOCOL SYNOPSIS ......................................................................................................... 13 
2 
INTRODUCTION ..................................................................................................................... 24 
 
Background .................................................................................................. 24 
 
Rationale for Choice of Tumor Types in the Expansion Cohorts ................... 27 
2.2.1 
Metastatic Colorectal Cancer ......................................................... 27 
2.2.2 
Ovarian Cancer ............................................................................. 29 
2.2.3 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) .......... 31 
2.2.4 
Non-Small Cell Lung Cancer.......................................................... 31 
2.2.5 
Head and Neck Squamous Cell Carcinoma (HNSCC) and 
Squamous Cell carcinoma of the Anus (SCCA) ............................. 33 
 
Investigational Medicinal Product:  SRA737 ................................................. 35 
2.3.1 
Mechanism of Action of SRA737 ................................................... 35 
2.3.2 
Non Clinical Pharmacology ............................................................ 36 
2.3.3 
In Vitro Admet and Nonclinical Pharmacokinetics .......................... 39 
2.3.4 
In Vivo Pharmacokinetics ............................................................... 41 
2.3.5 
Safety Pharmacology ..................................................................... 42 
2.3.6 
Toxicology ..................................................................................... 43 
2.3.7 
Rationale for the Selection of the Starting Dose and Schedule ...... 47 
 
Clinical Experience ....................................................................................... 47 
 
Rationale for the Proposed Trial ................................................................... 48 
 
Benefit-Risk Assessment ............................................................................. 49 
3 
TRIAL DESIGN ....................................................................................................................... 50 
 
Clinical trial objectives and endpoints ........................................................... 50 
3.1.1 
Primary objectives and endpoints .................................................. 50 
3.1.2 
Secondary objectives and endpoints.............................................. 51 
3.1.3 
Exploratory objectives and endpoints ............................................. 51 
 
Design of the clinical trial .............................................................................. 51 
 
Dose escalation Phase................................................................................. 55 
3.3.1 
Cohort Review Process ................................................................. 55 
3.3.2 
Dose Escalation Decision Rules .................................................... 56 
 
Definition of Dose Limiting Toxicity ............................................................... 57 
 
Definition of Maximum Tolerated Dose and Recommended Phase 2 
Dose and Schedule ...................................................................................... 58 


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Cohort Expansion Phase .............................................................................. 58 
 
Intra-Subject Dose Escalations .................................................................... 59 
 
Subject Evaluability ...................................................................................... 59 
3.8.1 
DLT Evaluable ............................................................................... 59 
3.8.2 
Replacement of subjects ................................................................ 59 
4 
SUBJECT SELECTION AND ENROLLMENT ....................................................................... 59 
 
Number of Subjects ...................................................................................... 60 
 
Subject Selection criteria .............................................................................. 60 
4.2.1 
Inclusion criteria ............................................................................. 60 
4.2.2 
Exclusion criteria............................................................................ 62 
5 
DOSAGE AND TREATMENT ADMINISTRATION ................................................................. 64 
 
Starting Dose and Regimen ......................................................................... 64 
 
Alternative Dosing Regimen ......................................................................... 64 
 
Duration of treatment ................................................................................... 65 
 
Dose modifications ....................................................................................... 65 
5.4.1 
Dose reductions or delays ............................................................. 65 
 
Supportive Care, Concomitant Medications, and Study Restrictions ............ 66 
5.5.1 
Optional and Allowed Concomitant Medications ............................ 66 
5.5.2 
Excluded Concomitant Medications ............................................... 67 
 
Discontinuation From Treatment .................................................................. 68 
 
Discontinuation From the Study ................................................................... 68 
6 
PHARMACEUTICAL INFORMATION .................................................................................... 69 
 
SRA737 ....................................................................................................... 69 
 
Storage Conditions for SRA737 ................................................................... 69 
 
Dispensing ................................................................................................... 70 
 
SRA737 Administration ................................................................................ 70 
 
SRA737 Accountability ................................................................................. 70 
7 
INVESTIGATIONS SCHEDULE ............................................................................................. 71 
 
Pre-enrollment Evaluations .......................................................................... 71 
7.1.1 
Screening Evaluations: Pre-Screeing and Within 28 Days Prior 
to Administration of SRA737 .......................................................... 71 
7.1.2 
Screening Evaluations:  Within 7 Days Prior to Administration 
of the First Dose of SRA737 .......................................................... 74 
 
Evaluations during the trial ........................................................................... 74 
7.2.1 
First Dose for PK (Day -7 to Day -4) Schedule ............................... 74 


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7.2.2 
Standard Evaluations for Each Cycle ............................................. 76 
 
Safety Follow-up (SFU) Visit ........................................................................ 79 
 
Long-term Follow-up .................................................................................... 80 
 
Missed Evaluations ...................................................................................... 80 
 
Schedule of Events ...................................................................................... 81 
 
Schedule of Secondary and Exploratory Assessments................................. 84 
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS................................. 85 
 
Pharmacokinetics ......................................................................................... 85 
 
Pharmacodynamics ...................................................................................... 85 
8.2.1 
Tumor Profiling .............................................................................. 85 
8.2.2 
Exploratory Analyses of ctDNA ...................................................... 86 
8.2.3 
Additional Exploratory Analyses ..................................................... 86 
8.2.4 
Additional Pharmacodynamic Assays ............................................ 86 
9 
ASSESSMENT OF EFFICACY ............................................................................................... 86 
 
Measurement of Disease ............................................................................. 86 
 
Timing and Type of Tumor Assessments ..................................................... 87 
9.2.1 
Baseline Evaluations ..................................................................... 87 
9.2.2 
Evaluations During and After the End of Treatment ....................... 88 
 
Tumor Response .......................................................................................... 88 
9.3.1 
Recording of Response in the eCRF.............................................. 89 
9.3.2 
Other Definitions of Outcome ......................................................... 89 
10 
ASSESSMENT OF SAFETY ................................................................................................... 89 
 
Adverse Event Definitions ............................................................................ 89 
10.1.1 
Adverse Event ............................................................................... 89 
10.1.2 
Serious adverse events ................................................................. 90 
10.1.3 
Suspected Unexpected Serious Adverse Reactions ...................... 91 
10.1.4 
Determining adverse event causality ............................................. 91 
10.1.5 
Expectedness ................................................................................ 93 
 
Evaluating and Recording Adverse Events ................................................... 93 
10.2.1 
Screening Failures ......................................................................... 93 
10.2.2 
Documentation of Adverse Events ................................................. 93 
10.2.3 
Monitoring and Follow-up of AEs and SAEs ................................... 93 
 
Immediate Adverse Event Reporting ............................................................ 94 
10.3.1 
Events exempt from being reported as SAEs to the 
Pharmacovigilance Department ..................................................... 95 


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CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
 
Recording of Adverse Events and Serious Adverse Events in eCRFs .......... 95 
 
Urgent safety measures ............................................................................... 96 
 
Pregnancy Reporting ................................................................................... 96 
11 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................................ 97 
 
Analysis Populations .................................................................................... 98 
11.1.1 
Safety Evaluable Populaton ........................................................... 98 
11.1.2 
Response Evaluable Populaton ..................................................... 98 
11.1.3 
Pharmacokinetics Evaluable Populaton ......................................... 98 
11.1.4 
Pharmacokinetics/Corrected QT Interval Evaluable Populaton ...... 98 
11.1.5 
Pharmacodynamics Evaluable Populaton ...................................... 99 
 
Statistical Analyses ...................................................................................... 99 
11.2.1 
Presentation of Data ...................................................................... 99 
11.2.2 
Safety ............................................................................................ 99 
11.2.3 
Efficacy Analyses ........................................................................... 99 
11.2.4 
PK/QTC ....................................................................................... 101 
11.2.5 
Pharmacodynamics ..................................................................... 102 
 
Sample Size ............................................................................................... 103 
12 
STUDY ADMINISTRATION .................................................................................................. 103 
 
Protocol Deviations and Amendments ........................................................ 103 
 
Serious Breach of Good Clinical Practice (GCP) ........................................ 104 
 
Obtaining Written Informed Consent .......................................................... 104 
 
Completion of the Electronic Case Report Form......................................... 105 
 
End of Study .............................................................................................. 106 
 
Trial Performance, Monitoring, Auditing and Inspection.............................. 106 
 
Source Document Verification .................................................................... 107 
 
Record Retention ....................................................................................... 108 
 
Ethical Considerations................................................................................ 108 
 Publication Policy and Press Releases ...................................................... 109 
13 
REFERENCES ...................................................................................................................... 110 
14 
APPENDICES ....................................................................................................................... 115 
APPENDIX 1.  WHO PERFORMANCE SCALE ................................................................................ 115 
APPENDIX 2.  ASSESSMENT OF DISEASE RESPONSE .............................................................. 116 
APPENDIX 3.  NEW YORK HEART ASSOCIATION (NYHA) SCALE ............................................. 129 
APPENDIX 4.  CONTRACEPTIVE GUIDANCE FOR WOMEN OF CHILDBEARING 
POTENTIAL (WOCBP) AND MALE PARTNERS OF WOCBP ........................................... 130 


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CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
APPENDIX 5.  LIST OF QT PROLONGATION DRUGS AND DRUG METABOLIZED BY 
CYP1A2 ................................................................................................................................. 133 
APPENDIX 6 GENETIC PREDICTORS OF SRA737 SENSITIVITY ................................................. 137 
APPENDIX 7 PROSTATE CANCER CLINICAL TRIALS WORKING GROUP (PCWG) AND 
EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (ESMO) GUIDANCE ....................... 138 
 
List of Tables 
Table 1.  Non-clinical pharmacokinetics of SRA737 ............................................................ 41 
Table 2.  Dose Delay and Discontinuation Guidelines ......................................................... 66 
 
 
List of Figures 
Figure 1.  Schematic of key roles of Chk1 in the DNA damage response ............................ 25 
Figure 2.  SRA737 (formerly CCT245737; 150 mg/kg/day PO) inhibits  the growth of 
the MOLM 13 model of AML. ............................................................................. 37 
Figure 3.  SRA737 (formerly CCT245737; 150 mg/kg PO) inhibits the growth of N MYC 
driven neuroblastoma in a genetically engineered mouse model ....................... 37 
Figure 4.  Antitumor efficacy of SRA737 (formerly CCT245737) in the MDA MB 231 
orthotopic triple negative breast cancer xenograft model. .................................. 38 
Figure 5.  Tumor growth inhibition with SRA737 in the OVCAR-3 tumor-bearing mouse 
model. ................................................................................................................ 39 
Figure 6 
Study Design ..................................................................................................... 54 
 
 
 
 
 
 
 


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CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
A 
AE 
adverse event 
 
AML 
acute myeloid leukemia 
 
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 
C 
CBC 
Complete blood count (full blood count) 
Chk1 or 2 
Checkpoint kinase 1 or 2 
 
CI 
confidence interval  
 
Cmax 
maximum observed plasma concentration 
 
Cmin 
minimum observed plasma concentration 
 
CR 
complete response 
 
CRA 
Clinical Research Associate 
 
CT 
computerized tomography 
 
CTC 
circulating tumor cells 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
ctDNA 
circulating tumor DNA 
 
CYP 
Cytochrome P450 
D 
Day 
cycle day 
 
DCR 
disease control rate 
 
DDR 
DNA damage response 
 
DLT 
dose limiting toxicity 
 
DNA 
deoxyribonucleic acid 
 
DOR 
duration of response 
E 
EC 
ethics committee 
ECG 
Electrocardiogram 
 
ECHO 
Echocardiogram 
 
eCRF 
electronic case report form 
F 
5-FU 
5-fluorouracil 
 
FDG 
Fluorodeoxyglucose 
G 
GCP 
Good Clinical Practice 
 
GI 
GIT 
Gastrointestinal 
Gastrointestinal Tract 
 
GLP 
Good Laboratory Practice 
H 
h  
Hour 
 
HGSOC 
High-grade serous ovarian cancer 
 
HNSCC 
Head and Neck Squamous Cell Carcinoma 


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CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
I 
IC50 
half maximal inhibitory concentration 
 
ICD 
informed consent document 
 
ICH  
International Conference on Harmonisation  
 
IMP 
investigational medicinal product 
 
IRB 
Institutional Review Board 
 
ITF 
Investigator Trial File 
 
IV 
Intravenous 
L 
LHRH 
luteinizing hormone releasing hormone 
 
LV 
Leucovorin 
M 
mCRPC 
metastatic castration-resistant prostate cancer 
 
min 
minute(s) 
 
MHRA 
Medicines and Healthcare products Regulations Agency  
 
MRI 
magnetic resonance imaging 
 
MSI 
microsatellite instability 
 
MTD 
maximum tolerated dose 
N 
NCI 
National Cancer Institute 
 
NE 
not evaluable 
 
NGS 
Next generation sequencing 
 
NHL 
non-Hodgkin lymphoma 
 
NSCLC 
non-small cell lung cancer 
 
NYHA 
New York Heart Association 
O 
ORR 
overall response rate 
 
OS 
overall survival 
P 
PBMC 
peripheral blood mononuclear cells 
 
PCWG 
Prostate Cancer Clinical Trials Working Group 
 
PD 
progressive disease 
 
PDn 
Pharmacodynamics 
 
PDX 
Patient-derived xenograft 
 
PET 
positron emission tomography 
 
PFS 
progression-free survival 
 
PI 
principal investigator 
 
PK 
Pharmacokinetics 
 
PO 
by mouth/orally 
 
PPI 
proton pump inhibitors  
 
PR 
partial response 
 
PSA 
prostate-specific antigen 
Q 
QT, QTc 
QT interval, corrected QT interval 
 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 


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Page 11 of 138 
 
SRA737-01 Protocol Amendment Final Version 8.0 (10 Jan 2018) 
CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
R 
REC 
Research Ethics Committee 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
 
RP2D 
recommended Phase 2 dose 
S 
SAE 
serious adverse event 
 
SCCA 
squamous cell carcinoma of the anus 
 
SD 
stable disease 
 
SFU 
safety follow-up 
 
Sierra Oncology 
Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.) 
 
SRA737 (investigational 
medicinal product) 
Previously known as CCT245737 
T 
T1/2 
terminal elimination half-life 
 
TCGA 
The Cancer Genome Atlas 
 
Tmax 
time to reach Cmax 
U 
ULN 
upper limit of normal 
 
USM 
urgent safety measure 
W 
WHO 
World Health Organization 
 
WOCBP 
Women of Childbearing Potential  
 


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CONFIDENTIAL 
EudraCT number: 2015-004486-86 
 
PROTOCOL ACCEPTANCE PAGE 
 
Title 
A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) Administered 
Orally in Subjects with Advanced Cancer 
Protocol Number 
SRA737-01  
Version (Date) 
Protocol Amendment Version 8.0 (10 Jan 2018) 
 
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 
A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in 
Subjects with Advanced Cancer 
Short Title of Study 
A Phase 1/2 Trial of SRA737 in Subjects with Advanced Cancer 
Study objective(s):  
 
Primary Objective:   
• To establish the safety profile of SRA737  
• To determine the maximum tolerated dose (MTD) with 1 or more 
schedules of administration of SRA737 
• To propose a recommended Phase 2 dose (RP2D) and schedule of 
SRA737  
• 
To evaluate the preliminary efficacy of SRA737 including efficacy 
in prospectively-selected genetically-defined subjects enrolled into 
indication-specific expansion cohorts 
Secondary Objectives: 
• To characterize the pharmacokinetic (PK) profile of SRA737 
• To assess the relationship between response and the presence of 
selected genetic alterations as detected in tumor tissue and/or 
circulating tumor deoxyribonucleic acid (ctDNA)  
Exploratory Objectives: 
• To investigate the pharmacodynamics (PDn) of SRA737 in tumor 
tissue  
• To investigate the PDn of SRA737 in surrogate tissue such as 
blood or peripheral blood mononuclear cell (PBMCs)   
• To explore possible predictors of response 
• To explore the relationship between exposure (PK) and QT/QTc, 
other electrocardiogram (ECG) parameters and cardiovascular 
safety findings 
Study design: 
This is a multicenter, first-in-human, Phase 1/2, open-label, dose-
escalation and dose-expansion trial in subjects with advanced solid 
tumors or non-Hodgkin lymphoma (NHL).  The trial will consist of 
2 stages. 
Stage 1:  A Dose Escalation Phase  
It is expected that between 30 and 50 subjects with solid tumors or NHL 
will be enrolled in the Dose Escalation phase of the study.  Intensive PK 
and ECG monitoring for QTc assessments will be collected from all 
enrolled subjects, beginning with sampling before and after a single dose 
of SRA737 given on one day between Day -7 and Day -4.  Tumor tissue 
(archival or fresh) and blood will be collected for retrospective biomarker 
analyses.  Cohorts consisting initially of a single subject will receive 
escalating doses of SRA737, starting in Cohort 1 with 20 mg/day 
administered orally on a continuous daily dosing schedule in 28-day 
cycles.  The dose will be escalated until the MTD has been identified, 
unless determined otherwise by the Sponsor in consultation with the 
Chief Investigator, for example, if an alternative schedule is pursued 
instead.   


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Study design 
(cont’d): 
Once a SRA737-related, Grade 2 toxicity is observed in a dose 
escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 
subjects, and subsequent dose level cohorts will follow a rolling 6 design 
(see Section 3.3 for additional details).  Dose escalation with an 
alternative schedule may begin at any time and may either run either in 
parallel or instead of continued escalations in the continuous schedule.  
The final number of subjects enrolled into the trial is dependent on the 
number of dose levels explored in the Dose Escalation Phase. Patients 
who are not evaluable for assessment of dose limiting toxicity (DLT) may 
be replaced.   
Stage 2:  A Cohort Expansion Phase   
The Cohort Expansion Phase consists of 6 indication-specific expansion 
cohorts of approximately 20 prospectively-selected genetically-defined 
subjects each (namely, subjects with previously treated metastatic 
colorectal cancer [CRC], high grade serous ovarian cancer [HGSOC] 
without CCNE1 gene amplification, HGSOC with CCNE1 gene 
amplification (or alternative genetic alteration with similar functional 
effect), metastatic castration-resistant prostate cancer [mCRPC], 
advanced non-small cell lung cancer [NSCLC], and squamous cell 
carcinoma of the head and neck [HNSCC] or squamous cell carcinoma of 
the anus [SCCA]).  This allows for a preliminary exploration of the 
efficacy of SRA737.  
The goal of the expansion cohorts is to assess SRA737 across multiple 
tumor types in subjects who have a range of genomic profiles of interest 
as described in inclusion criterion 9. The Sponsor may choose to refine or 
select particular genomic profile requirements in each (or all) Expansion 
Cohort(s) 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 choose to select for alternative genomic profiles in 
the event profile(s) not associated with tumor responses are over-
represented in subjects already enrolled. 
Intensive PK and ECG monitoring for QTc assessments will be collected 
until the Sponsor determines sufficient data have been collected and 
analyzed across the study as a whole.  Tissue (archival or fresh) and 
blood will be collected for prospective genetic analysis to determine 
eligibility.  See Section 7.1.1 for more details.  
Prospective screening of subjects within the selected indications to 
determine eligibility based on tumor genetics will begin prior to the 
completion of dose escalation. Eligibility will be determined by the 
Sponsor’s review of genetic abnormalities detected in genes in the 
categories listed in inclusion criterion 9. Enrollment to Dose Escalation 
and Expansion Cohorts may occur in parallel.    
A subject that qualifies for the Cohort Expansion Phase will be enrolled 
into a Dose Escalation Cohort whenever possible.  Any such subject will 
be considered to have enrolled in both phases simultaneously.  Only 
when a dose escalation enrollment slot is not available for an eligible 
genetically-defined subject, that subject may be enrolled to an expansion 
cohort and treated with SRA737 at the highest dose level previously 
determined to be safe.  Intra-subject dose escalation is allowed for these, 
and for all, study subjects.   
Number 
ofinvestigational 
sites: 
This is a multicenter study. 


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Planned number of 
subjects: 
It is estimated that up to 50 subjects will be enrolled into the Dose 
Escalation Phase of the study.  Six cohorts of approximately 20 subjects 
each (i.e. a total of approximately 120 subjects) will be enrolled into the 
Cohort Expansion Phase; the final number of subjects enrolled into the 
trial will depend on the number of dose levels, the number of subjects 
who participate in both the Dose Escalation and Cohort Expansion 
phases, and potentially alternative dose schedules explored. 
Sample size 
justification: 
The sample size for dose escalation is based on assumptions from 
allometric scaling and the number of dose levels required to establish the 
MTD.  Six indication-specific expansion cohorts of approximately 20 
prospectively-selected genetically-defined subjects each will permit 
confirmation that the 95% confidence intervals around an observed 
objective response rate (ORR) in each cohort is ± 16%.    
Study population: 
Dose Escalation Phase:  Subjects with solid tumors or NHL. 
Cohort Expansion Phase:  Prospectively-selected genetically-defined 
subjects with metastatic CRC, HGSOC without CCNE1 gene 
amplification, HGSOC with CCNE1 gene amplification, mCRPC, 
advanced NSCLC, or HNSCC/SCCA. 
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 is 
20 mg daily.   
Treatment 
regimen(s): 
 
SRA737 will be administered orally, daily of each 28-day cycle for 
subjects receiving the continuous dosing schedule.  Alternate dosing 
schedules may also be explored.  Subjects may continue to receive 
treatment as long as none of the treatment discontinuation criteria are 
met (Section 5.6).  Intra-subject dose escalation(s) will be permitted. 
Inclusion criteria: 
Dose Escalation Phase and Cohort Expansion Phase  
1. Written (signed and dated) informed consent and be capable of 
cooperating with treatment and follow up.  
2a. For subjects in the Dose Escalation Phase:  any locally advanced or 
metastatic, histologically or cytologically proven solid tumor or NHL, 
relapsed after or progressing despite conventional treatment and for 
which no other conventional therapy is considered appropriate by 
the investigator or has been declined by the subject.   
2b. For subjects in the Cohort Expansion Phase: any locally advanced 
or metastatic, histologically or cytologically proven malignancy of the 
types specified in inclusion criterion 10, for which no other 
conventional therapy is considered appropriate by the investigator or 
has been declined by the subject.   
3. Life expectancy of at least 12 weeks. 
4. World Health Organization (WHO) performance status of 0–1 
(Appendix 1). 
 
 
 


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Inclusion criteria 
(cont’d): 
5. Hematological and biochemical indices within the ranges shown 
below, measured within one week prior to the subject receiving their 
first dose of investigational medicinal product (IMP).  
Laboratory Test 
Lower acceptable limit 
Hemoglobin (Hb) 
≥ 90 g/L  
Absolute neutrophil count 
≥ 1.5 x 109/L  
Platelet count 
≥ 100 x 109/L 
Bilirubin  
≤ 1.5 x upper limit of normal (ULN) 
unless due to Gilbert’s syndrome in 
which case up to 3 × ULN is 
permissible  
Alanine aminotransferase 
and/or aspartate 
aminotransferase (and Alkaline 
Phosphatase  
≤ 2.5 x ULN unless raised due to 
tumor in which case up to 5 x ULN 
is permissible  
Serum Creatinine 
≤ 1.5 x ULN 
6. Subject has attained the age of 18 years 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 
details. 


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Inclusion criteria 
(cont’d): 
Cohort Expansion Phase 
8. Subjects must have measurable disease per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST v1.1), or for mCRPC, 
evaluable disease per any of the following: 
a. Measurable disease per RECIST v1.1;  
b. Increasing prostate specific antigen (PSA, see Prostate Cancer 
Clinical trials Working Group [PCWG] Guidelines – Appendix 7); 
or  
c. circulating tumor cell (CTC) count of 5 or more cells per 7.5ml of 
blood.   
9. Subjects must have tumor tissue or ctDNA evidence that their tumor 
harbors a combination of mutations which are expected to confer 
sensitivity to Chk1 inhibition. Eligibility will be determined by the 
Sponsor’s review of genetic abnormalities detected in genes in the 
following categories, as listed in Appendix 6:  
a. Key tumor suppressor genes regulating G1 cell cycle 
progression/arrest such as RB1, TP53, etc. For patients with 
HNSCC or SCCA, positive HPV status is also considered for 
eligibility. 
b. The DNA damage response pathway including ATM, BRCA1, 
and BRCA2. For patients with CRC, mismatch repair genetic 
alterations and/or high microsatellite instability are also 
considered for eligibility. 
c. Genetic indicators of replicative stress such as gain of 
function/amplification of Chk1 or ATR or other related gene. 
d. Oncogenic drivers such as MYC, KRAS, etc. 
e. CCNE1 gene amplification (or alternative genetic alteration with 
similar functional effect) is required for the CCNE1 gene 
amplification-specific HGSOC cohort.  


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Inclusion criteria 
(Cont’d): 
10. Subjects must meet one of the following criteria (a-e): 
a. Metastatic CRC 
• Histologically and/or cytologically confirmed CRC  
• Must have received at least 1 prior regimen for 
advanced/metastatic disease 
b. HGSOC 
• Histologically confirmed high grade serous ovarian, 
fallopian tube or primary peritoneal cancer  
• Recurrent platinum-intolerant subjects, or those with 
platinum-resistant disease, defined as radiological 
evidence of disease progression within 6 months of the last 
receipt of platinum-based chemotherapy.  Patients with 
platinum refractory disease (as defined by the European 
Society for Medical oncology [ESMO] Guidelines – 
Appendix 7) are not eligible. 
c. Advanced NSCLC 
• Locally advanced and recurrent or metastatic, histologically 
confirmed NSCLC  
• Must have received at least 1 prior regimen for 
advanced/metastatic disease  
d. mCPRC  
• Histologically or cytologically confirmed adenocarcinoma of 
the prostate that has progressed after androgen 
deprivation therapy  
e. NHSCC or SCCA 
• Histologically confirmed HNSCC from any primary site, or 
SCCA 
• For HNSCC: locally advanced disease (ie, persistent or 
progressive disease following curative-intent radiation, and 
not a candidate for surgical salvage due to incurability or 
morbidity), or metastatic disease 
• For SCCA: locally advanced disease or metastatic disease 
for which no curative intent therapy is available 
• Must have received at least 1 prior regimen for 
advanced/metastatic disease 
 


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Exclusion criteria: 
1. Have received the following prior or current anticancer therapy: 
a. Radiotherapy within the last 6 weeks (except for symptom 
control and where the lesions will not be used as measurable 
disease) 
b. Endocrine therapy during the previous 4 weeks except for 
luteinizing hormone releasing hormone (LHRH) agonists for 
prostate cancer  
c. Chemotherapy during the previous 4 weeks 
d. Immunotherapy during the previous 6 weeks  
e. Nitrosoureas or Mitomycin C during the previous 6 weeks 
f. 
Other IMPs during the 4 weeks before treatment  
g. Any prior treatment with a Chk1 inhibitor, or prior treatment with 
an ATR inhibitor within 6 months prior to receiving SRA737. 
2. Other malignancy within the past 2 years with the exception of 
adequately treated tumors that are associated with an expected 
5 year disease-free survival of approximately 95% or better. 
3. 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 or Sponsor’s designee monitor should not exclude 
the subject.  
4a.  For subjects in the Dose Escalation Phase that are not to be 
included in the Expansion Cohort, new or progressing brain 
metastases.  Subjects with brain metastases that have been 
radiologically stable over an 8-week period may be included.   
4b.  For subjects in the Cohort Expansion Phase, present or prior brain 
metastases.   
5. Women of childbearing potential (WOCBP) or women who are 
already pregnant or lactating. However, those patients who have a 
negative serum or urine pregnancy test before enrollment and agree 
to use two forms of contraception as per Appendix 4 or agree to 
sexual abstinence, effective from the first administration of SRA737, 
throughout the trial and for six months afterwards are considered 
eligible.  
6. Male subjects with partners of childbearing potential (unless they 
agree to take measures not to father children by using a barrier 
method of contraception as per Appendix 4 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. 
7. Major surgery from which the subject has not yet recovered. 
8. At high medical risk because of nonmalignant systemic disease 
including active uncontrolled infection.   
9. Known to be serologically positive for hepatitis B, hepatitis C or 
human immunodeficiency virus (HIV). 


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Exclusion criteria 
(cont’d): 
10. 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.  
11. Prior bone marrow transplant or extensive radiotherapy to greater 
than 25% of bone marrow within 8 weeks.  
12. Peanut allergy.  Refer to Section 6 for additional details.   
13. QTcF > 450 msec in adult males and > 470 msec in adult females. 
14. 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).   
15. Not able to swallow capsules without chewing or crushing. 
16. 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 or Sponsor’s designee would be 
acceptable. 
17. 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: consent will be 
obtained; availability of suitable archival tissue or planned biopsy of 
accessible tissue will be confirmed or submitted for tumor profiling, and 
MSI or HPV status will be determined if required (MSI for subjects with 
CRC and other subjects if clinically relevant; HPV for subjects with 
HNSCC or SCCA). Within 28 days prior to the first dose of SRA737, the 
following will be performed/obtained: demographic information, medical 
history, and concomitant treatment will be recorded; cardiac assessments 
(echocardiogram [ECHO] and electrocardiogram [ECG]), and radiological 
disease assessments will be performed; blood will be collected for CTCs 
(mCRPC subjects only), and ctDNA for tumor profiling; optional tumor 
biopsy for additional pharmacodynamic analysis; and collection of serious 
adverse events (SAEs) will be initiated.  Within 7 days prior to the first 
dose of SRA737, the following assessments will be completed:  SAEs 
and concomitant medications, WHO performance status, pregnancy test 
(WOCBP), and laboratory assessment of blood (hematology and 
biochemistry).   
Intensive PK collection will begin with a single dose administered 
between Day -7 to Day -4.  The Sponsor may reduce the requirement for 
PK sampling, including modification or elimination of the Day -7 to Day -4 
visit once sufficient data to evaluate the single-dose PK of SRA737 have 
been collected and analyzed.  Also, central ECG assessments described 
below may be reduced in frequency or eliminated by the Sponsor once 
sufficient data have been collected and analyzed. If any of these occur, 
the modified requirements will be documented by an update to the 
appropriate study documents.  At the single-dose PK run-in on the Day -7 
to Day -4 visit (where applicable), subjects may remain as in-patients for 
at least 24 hours after their first dose of SRA737 to facilitate collection of 
study required assessments.   


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Overview of 
assessments 
(cont’d): 
Temperature, height, weight, pulse rate, seated BP, replicate ECG, 
pregnancy test (WOCBP), urinalysis, and blood for hematology, 
biochemistry, troponin I or T, ctDNA for exploratory analyses, serum 
tumor markers, CTCs (mCRPC subjects only), additional exploratory 
analyses (mutational burden), and PK will be obtained predose.  
Additional blood will be collected postdose for up to 48 hours for PK.  
For Dose Escalation subjects; archival tumor tissue should be 
requisitioned by Cycle 1 Day 1.  Adverse events will be collected starting 
at the administration of SRA737.  If an optional tumor biopsy was taken 
at baseline for additional pharmacodynamic analysis, a second biopsy 
should be collected at one timepoint 2 to 8h after dosing from Cycle 1 
Day 15 through Cycle 1 Day 22 (inclusive). 
Continuous daily dosing (or an alternative schedule dosing) will begin on 
Day 1 with the following procedures occurring at regular intervals.   
• 
AE and concomitant medication collection on an ongoing basis 
• 
Symptom-directed physical exam, if medically indicated, Day 1 of 
each cycle 
• 
Radiological assessment every 8 weeks after Day 1  
• 
Subjects with bone metastases being followed by bone scans will 
have scans every 8–9 weeks for the first 6 months and then 
every 16 weeks thereafter.   
• 
Clinical disease assessment, serum tumor markers (if applicable) 
and CTCs (for mCRPC subjects only), every 4 weeks after Day 1  
• 
Vital signs and WHO Performance Status, Day 1 of each cycle 
• 
Laboratory assessment of blood (hematology, biochemistry, 
troponin I or T) and urine (urinalysis):  see Section 7.2.2 for 
detailed schedule  
• 
ECHO on Cycle 2 Day 1 
• 
ECG (locally- and centrally-read):  see Section 7.2.2 for detailed 
schedule  
• 
Blood collection for PK, ctDNA for exploratory analysis, and 
additional exploratory analyses (mutational burden):  see Section 
7.2.2 for detailed schedule 
• 
Compliance:  review of diary card 
Hematology assessments to be repeated weekly for the cycle following 
an intra-subject dose escalation, where applicable. 
Subjects who discontinue treatment will complete the Safety Follow-up 
visit 30 days (± 7 days) after the last dose.  Assessments required at the 
visit include AE and concomitant medication collection, vital signs, 
weight, WHO performance status, ECG, ECHO, radiological and clinical 
disease assessment (as clinically relevant), urinalysis, and laboratory 
assessment of blood for hematology, biochemistry, pregnancy (WOCBP), 
troponin I or T, ctDNA for exploratory analysis, CTCs (for mCRPC 
subjects only), serum tumor marker (if applicable), and additional 
exploratory analyses (mutational burden).   
 


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Overview of 
assessments 
(cont’d): 
Subjects without progressive disease (PD) at the time of SRA737 
discontinuation will continue in Long-term Follow-up to undergo disease 
evaluations every 16 weeks (± 2 weeks) and have the following collected:  
radiological and clinical disease assessments, SAEs assessed as related 
to SRA737 by the investigator, first subsequent anticancer therapy, and 
blood for serum tumor markers (if applicable) and CTCs (for mCRPC 
subjects only) 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 
variables: 
All subjects receiving at least 75% of planned doses of SRA737 within 
Cycle 1 and those subjects receiving less than these planned doses of 
SRA737 due to dose-limiting toxicities (DLTs) will be evaluable for dose 
review decisions. 
Efficacy variables: 
All subjects who have measurable disease, receive at least 75% of 
1 cycle of study medication and have a baseline assessment of disease 
plus at least 1 post-baseline assessment of disease will be evaluable for 
response.  All subjects enrolled into one of the 6 indication-specific 
expansion cohorts will be evaluable for response if they have 
measurable, prospectively-selected genetically-defined tumors as 
specified in Section 4, received at least 75% of 1 cycle of study 
medication, have a baseline assessment of disease and at least 1 post-
baseline disease assessment.  In addition, subjects who have 
measurable disease and received at least 75% of 1 cycle of study 
medication but develop PD, intolerable toxicity, or death prior to the post-
baseline assessment will also be considered evaluable and will be 
classified as nonresponders. 
Safety variables: 
All subjects who receive at least one dose of SRA737 will be evaluable 
for safety. 
Other: 
Pharmacokinetics:  All subjects who receive at least 1 dose of SRA737 
and provide 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 the full dose and does not vomit within 
4-hours postdose. 
PK/QTc:  All enrolled subjects who receive at least 1 dose of SRA737 
and for whom adequate QTc and ECG data are available will be 
evaluable for PK/QTc analyses.   
Pharmacodynamics:  All enrolled subjects who receive at least 1 dose of 
SRA737 who 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.  
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.  


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Statistical methods 
and analyses 
(cont’d): 
The analysis of all efficacy endpoints will be based on the Response 
Evaluable Population and will be evaluated using RECIST v1.1 criteria, or 
for subjects with NHL, the revised International Working Group (IWG) 
criteria (Cheson 2007), or for subjects with mCRPC, using a composite 
response rate defined as any one of the following (Scher 2016):  A) 
Response based on RECIST v1.1; B) PSA decrease of ≥ 50%; or C) 
CTC count conversion.  Absolute values for PSA and CTCs will be 
recorded at baseline and response will be analyzed based on percentage 
of change.   
The ORR will be summarized using binomial proportions and confidence 
intervals computed by the method of Wilson. Duration of response (DOR) 
is defined as the interval from the first documentation of objective 
response (of partial response or complete response) to the earlier of the 
first documentation of PD or death from any cause.  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.  Other efficacy variables will be further 
defined in the statistical analysis plan.   
The PK parameters will be determined using non-compartmental 
method(s).  Parameters, such as AUCinf, AUCtau, Cmin, Cmax, Tmax, t½, will 
be estimated and reported, as appropriate.   
Pharmacodynamic parameters utilizing blood and tumor 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 
 
BACKGROUND 
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, replication stress and 
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 anti-tumor 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).  
The DDR to double strand breaks, is predominately mediated through the PI3K-related 
kinase family member, ATM kinase, whereas, the DDR to single strand breaks, stalled 
replication forks and DNA cross links are mediated mainly through 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, as 
shown in Figure 1,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).  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). Chk1 inhibitors (along with inhibitors of the upstream kinase ATR) are 
now in early phase trials both as monotherapies and in combination (see Section 2.4). 


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Figure 1.  Schematic of key roles of Chk1 in the DNA damage response  
 
 
Source:  Curtin 2012. 
 
Mutations or genetic alterations in several classes of genes results in the development and 
maintenance of genomic instability, contributing to DNA damage and tumorigenesis 
(Hanahan 2011).  These classes include activating mutations or amplification of growth 
promoting oncogenes such as MYC, CCNE1 and KRAS (Negrini 2010), loss-of-function 
mutations or deletions in p53 and Rb tumor suppressor pathways controlling the G1/S 
checkpoint and defects in DDR signaling and DNA repair genes (eg, ATM, BRCA1). 
While genomic instability of tumors provides a selective growth advantage by enabling 
adaptation, resistance and survival, these same tumor cells are dependent on remaining 
DDR factors and intact cell cycle checkpoints to sustain viability. An exciting therapeutic 
strategy is to deliberately target these remaining DDR pathways in genomically unstable 
tumor cells, leading to irreparable levels of DNA damage, mitotic catastrophe and 
subsequent tumor cell death.  By targeting these remaining DDR components in the 


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presence of pre-existing deficits in cell cycle/DDR genes, one can achieve synthetic lethality 
in this highly sensitive genetic background.  This approach has been validated by the recent 
clinical success of single agent PARP inhibitor therapy in ovarian, breast and prostate 
cancer patients harboring mutations in BRCA1 and BRCA2 (Underhill 2011).  
The central role of Chk1 in DDR network signaling, including control of both S and G2/M cell 
cycle checkpoints, stabilization of replication forks, and aspects of homologous 
recombination repair, provides several avenues for achieving synthetic lethality in specific 
tumors.  Synthetic lethality occurs when intrinsic alterations in one or more genes are 
coupled to targeted therapeutic inhibition of a second gene leading to cell death.   
Against a variety of altered genetic backgrounds, Chk1 inhibition has demonstrated 
synthetic lethality as a single agent.  As a widely recognized replication stress driving 
oncogene, MYC is frequently amplified in a range of tumors and has been strongly 
implicated in contributing to replication stress and potently enhancing sensitivity to Chk1 
inhibitors (Gaillard 2015). Moreover, SRA737 (formerly known as CCT245737) and its 
analogues demonstrate robust single agent activity in tumor models with MYC or MYCN 
overexpression (Cole 2011; Derenzini 2015).   
Activating mutations in RAS isoforms occur frequently in pancreatic, non-small cell lung 
cancer (NSCLC), colorectal, and other cancers and these mutations contribute to replication 
stress and genomic instability (Negrini 2010; Gaillard 2015).  The ATR/Chk1 pathway 
suppresses replication stress in RAS-transformed cells and the Chk1 inhibitor, AZ7762, 
induces robust single-agent cytotoxicity in these cells (Zhang 2016).  SRA737 potentiates 
chemotherapy-induced cytotoxicity in vivo in a lung cancer model harboring a KRAS 
activating mutation in the context of a p53 deficiency (Walton 2016).  Correspondingly, ATR 
(and Chk1 to lesser extent) is amplified in certain tumors, particularly in high-grade serous 
ovarian cancer (HGSOC), squamous non-small cell lung cancer (NSCLC) and head and 
neck squamous cell cancer (HNSCC) and may increase sensitivity to Chk1 inhibition.  
Defective G1/S DNA damage checkpoints, arising through inactivation of the p53 and Rb 
pathways, result in synthetic lethality in the context of Chk1 inhibition. 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). Triple-negative breast 


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cancer and ovarian cancer cell lines with p53-deficiency display enhanced sensitivity to 
Chk1 inhibitors (Ma 2012).  Moreover, a subject with metastatic urothelial cancer harboring a 
RAD50 mutation (ATM deficiency) achieved a complete and durable response following 
treatment with a Chk1 inhibitor (AZD7762) and irinotecan (Al-Ahmadie 2014). 
Lastly, genomic defects in components of the DNA repair machinery are implicated in both 
germline and somatic cancers and also contribute to genomic instability (Negrini 2010).  
Interestingly, similar to what is observed with PARP inhibitors, Chk1 phosphorylates BRCA2 
and inhibitors are synthetically lethal in cell lines deficient in BRCA2 (Chen 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).  
Collectively, these findings support the likelihood that tumors with genomic instability as a 
consequence of genetic alterations described above will display enhanced sensitivity to 
Chk1 inhibition, both as a single agent and in combination with DNA damaging agents or 
other DDR inhibitors. 
 
RATIONALE FOR CHOICE OF TUMOR TYPES IN THE EXPANSION COHORTS 
Preclinical xenograft data confirms the activity of SRA737 as a single-agent in diverse 
genetically-aberrant tumor settings including models of pediatric neuroblastoma, acute 
myeloid leukemia (AML), double-hit lymphoma and triple negative breast cancer.  A number 
of genetic alterations are thought to predict sensitivity to SRA737 therapy including (i) 
activating mutations or amplification of growth promoting oncogenes; (ii) loss-of-function 
mutations or deletions in tumor suppressor pathways controlling the G1/S checkpoint; (iii) 
defects in DDR signaling and DNA repair genes; and (iv) gain of function mutations of 
replication stress genes.  Tumor indications of high unmet medical need with high 
prevalence of these genetic aberrations include metastatic colorectal, ovarian, prostate, 
head and neck, and non-small cell lung cancer.  
2.2.1 
METASTATIC COLORECTAL CANCER 
Colorectal cancer (CRC) is the third most common cancer worldwide, with 1,360,000 new 
cases diagnosed in 2012 and 693,000 deaths worldwide (Ferlay 2013).   


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Approximately 25% of patients present with metastatic disease at diagnosis and about 50% 
of patients with CRC will eventually develop metastases.  
Until the last two decades, 5-fluorouracil (5-FU) with leucovorin (LV) remained the standard 
therapy in advanced CRC.  The current approach to treating metastatic CRC (mCRC) favors 
the use of combination cytotoxic therapy including 5-FU, LV, and irinotecan (FOLFIRI); 
5-FU, LV, and oxaliplatin (FOLFOX); capecitabine and oxaliplatin (XELOX); or 5-FU, LV, 
oxaliplatin, and irinotecan (FOLFOXIRI) in the first-line setting.  
The treatment of mCRC has been further refined with the development of monoclonal 
antibodies that target the vascular endothelial growth factor (VEGF; bevacizumab) and 
epidermal growth factor receptor (EGFR; cetuximab and panitumumab) that have afforded 
improved outcomes in mCRC in the first-line and second-line setting (Gong 2016).  Newest 
advances for previously treated patients include regorafenib, trifluridine-tipiracil and tipiracil. 
For example, regorafenib, an orally available multikinase inhibitor, prolonged median overall 
survival (OS) by 1.4 months compared with placebo (OS 6.4 months vs 5.0 months), hazard 
ratio (HR) = 0.77 [95% CI 0.64, 0.94]) (Grothey 2013). 
Despite these recent advances, CRC remains an area of high unmet need where in late-
stage disease, median OS remains less than 12 months.  
Deficient mismatch repair (dMMR) of DNA is one of the genetic pathways that is involved in 
the development of CRC.  DNA mismatch repair (MMR) is known to cause microsatellite 
instability (MSI).  Hereditary non-polyposis colon cancer, the most common form of 
hereditary colon cancer, is a syndrome of deficient DNA MMR, but dMMR is also present in 
10–20% of patients with sporadic CRC (Koopman 2009).  Colorectal cancers with high 
frequency microsatellite instability (MSI-H) generally have a better prognosis and are more 
likely to respond to immunotherapy.  To date, more than 300 different predisposing MMR 
gene mutations are known across 5 or possibly 6 human MMR genes, mainly affecting the 
MMR genes MLH1, MSH2, and MSH6.   Universal screening in newly diagnosed CRC is 
recommended by many experts (Wang 2016).   
Activating mutations or amplification of known oncogenic drivers such as MYC and KRAS 
are frequent in colorectal cancer at rates of 20% for MYC and 30-50% for KRAS. Aberrant 
activation of these oncogenic drivers have been strongly linked to sensitivity to Chk1 
inhibition (Dietlein 2015, Gilad 2010).   


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Genetic mutations in CRC, in particular mutations of KRAS, p53, or in MMR genes allow for 
replication errors or instability in repeat DNA sequences in the cellular pathways of interest, 
which makes this indication an ideal therapeutic target for a Chk1 inhibitor, such as 
SRA737. 
2.2.2 
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 based on response greater than 6 
months following, within 6 months following, or during platinum-based chemotherapy, 
respectively. 
Patients with platinum-resistant disease have a poor prognosis with a short expected 
median 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 3–4 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 


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population and have shown compound toxicity.  Accordingly, sequential single-agent 
therapy is currently the recommended 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 high-grade serous ovarian cancer (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).  A 
specific expansion cohort of subjects with HGSOC and an eligible genetic profile including 
CCNE1 amplification, in addition to a separate expansion cohort of subjects with HGSOC 
with other eligible genetic profiles, will be enrolled in this study of SRA737.  


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2.2.3 
METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) 
Prostate cancer is the fourth most common cancer worldwide, with 1,112,000 new cases 
diagnosed in 2012 and 307,000 deaths worldwide (Ferlay 2013).    
In metastatic castration-resistant prostate cancer (mCRPC), patients have developed 
resistance to standard androgen deprivation therapies.  There are several recent therapies 
that have demonstrated improved OS for patients with mCRPC including agents that target 
the androgen receptor pathway such as abiraterone acetate and enzalutamide, as well as 
cabazitaxel, a dendritic cell vaccine, Sipuleucel-T, and bone-targeted radiopharmaceutical 
treatment, radium Ra 223 dichloride (Beer 2014, Parker 2015, Ryan 2013, Tannock 2004).  
Abiraterone acetate and enzalutamide have become common first-line therapies for mCRPC 
because of their tolerability and efficacy in the pre-chemotherapy setting.  Following 
androgen receptor-targeted therapy, systemic chemotherapy with docetaxel plus prednisone 
is also an available therapy, but it appears to be less effective in the post-abiraterone or 
enzalutamide setting, with median progression-free survival (PFS) of approximately 
4.5 months (Suzman 2014) and carries with it toxicities of Grade 3 or Grade 4 neutropenia, 
sensory neuropathy, stomatitis, diarrhea and fatigue (Tannock 2004).  
There is therefore a great need to develop novel therapeutic strategies to treat mCRPC, but 
also to develop biomarker strategies to stratify patients for optimal therapy.  Key tumor 
suppressor proteins such as TP53 and RB1 were found to be mutated in 51 and 27% of 
over 50 patient samples, respectively.  MYC, an oncogenic driver linked to Chk1 sensitivity 
was mutated in 20% of patient samples.  BRCA2 was also found to be altered in roughly 
12% of patient samples (Grasso 2012).  Analysis of another cohort of 150 mCRPC patients 
revealed that approximately 90% of cases harbor actionable mutations, including 
aberrations in DNA repair genes such as BRCA1, BRCA2, and ATM in 19.3% of subjects 
(Geethakumari 2016).  Genetic mutations in prostate cancer and the resulting alterations in 
the cellular pathways of interest, make this indication an ideal therapeutic target for a Chk1 
inhibitor, such as SRA737. 
2.2.4 
NON-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).  The predominant form of lung cancer 
is NSCLC which accounts for 70 to 80% of all lung cancers.  NSCLC is further stratified into 


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squamous and adenocarcinoma subtypes.  Unfortunately, a majority of patients with lung 
cancer are diagnosed with inoperable disease and they are treated with palliative 
chemotherapy.   
The ESMO guidelines for the management of advanced/metastatic disease, suggest that 
treatment should take into account a range of factors including histology, molecular 
pathology, age, performance status (PS) and co-morbidities.  Systemic therapy should be 
offered to all Stage 4 patients with PS 0–2 (Reck 2014).  
For the vast majority of patients with advanced or metastatic disease (40–50% of all patients 
at time of diagnosis), platinum-based chemotherapy is associated with a median survival of 
about 10–11 months.  Advances have been made with the introduction of targeted therapies 
in small subsets of patients with NSCLC with EGFR mutations (Maemondo 2010) and 
anaplastic lymphoma kinase (ALK) rearrangements (Solomon 2014) who are treated with 
EGFR and ALK inhibitors respectively.  The use of newer cytotoxic agents such as 
pemetrexed, the introduction of maintenance therapy, and most recently, the use of immune 
therapies such as antagonist antibodies to programmed death receptor 1 (PD-1) and 
programmed death ligand 1 (PD-L1) led to further improvement of OS.  Nonetheless, even 
with these therapies, the majority of patients with NSCLC do not attain prolonged disease 
control (Dempke 2016). 
Despite recent advances, finding new treatments for previously treated patients remains an 
area of unmet medical need.  The Cancer Genome Atlas Project characterized over 175 
lung squamous cell carcinoma patient samples for genetic signatures.  The major tumor 
suppressor genes, TP53 and CDKN2A, were found to be altered in 94% and 44% of patient 
samples, respectively.  Additionally, roughly 16% of patients had gain of function mutations 
in key oncogenic drivers (MYC, KRAS, CCNE1).  ATR was amplified in 18-19% of patient 
samples, and BRCA1 and BRCA2 were found to be mutated in roughly 6% of patients 
(TCGA 2012).  Samples from patents with adenocarcinoma of the lung show generally lower 
but not insignificant rates of these mutations:  TP53 47%; CDKN2A 24%; MYC 10%, KRAS 
30-35%; ATR 5-6%, BRCA1 3%, and BRCA2 6% (TCGA 2014).  Genetic mutations in 
NSCLC and the resulting alterations in the cellular pathways of interest, makes this 
indication an ideal therapeutic target for a Chk1 inhibitor, such as SRA737. 


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2.2.5 
HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AND 
SQUAMOUS CELL CARCINOMA OF THE ANUS (SCCA) 
Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer 
worldwide, with approximately 550,000 new cases diagnosed in 2008 and 300,000 deaths 
worldwide (Jemal 2011).  
The classification of sites in tumors of the oral cavity, oropharynx, pharynx, and 
hypopharynx varies in the literature.  More than 90% of these tumors of the mucosal lining 
are classified as squamous cell carcinoma developed from premalignant lesions such as 
leukoplakia and erythroleukoplakia (Lambert 2011).  Ninety percent of cancers that are 
known collectively as head and neck cancers are usually of squamous histology.   
The prognosis of patients with recurrent or metastatic HNSCC is generally poor.  The 
majority of HNSCC patients present with locally advanced disease for which multimodality 
therapeutic approach is employed.  Despite advances in multimodality treatment, the 5-year 
progression-free survival rate of patients with HPV-negative locally advanced HNSCC does 
not exceed 40%–50% (Economopoulou 2016). The median OS for recurrent or metastatic 
HNSCC remains less than 1 year despite modern chemotherapy and targeted agents.   
As per ESMO guidelines, options for fit patients with recurrent or metastatic HNSCC should 
include the combination of cetuximab with cisplatin or carboplatin plus 5-fluorouracil 
(Gregoire 2010).  The recommendation to include cetuximab in combination with 
chemotherapy for patients with recurrent or metastatic disease is based on the results of the 
EXTREME study (Vermorken 2008) comparing cetuximab with chemotherapy (cisplatin or 
carboplatin and 5-FU) or chemotherapy alone.  Patients receiving cetuximab with 
chemotherapy lived an average of 10.1 months, compared with 7.4 months for those 
receiving chemotherapy only (p = 0.04).  
In patients for which polychemotherapy tolerability is anticipated to be poor, mono-
chemotherapy such as weekly methotrexate or taxanes should be used.  Cetuximab alone 
has a favorable toxicity profile with activity that is comparable to methotrexate alone 
(Gregoire 2010). 
Recent therapeutic advances include nivolumab and pembrolizumab, PD-1 inhibitors which 
have shown clinically significant activity in patients who progressed on or after platinum-
based regimens. In a pivotal Phase 3 trial of nivolumab versus standard, single-agent 


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systemic therapy (methotrexate, docetaxel, or cetuximab), the median OS was 7.5 months 
(95% CI, 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the 
group that received standard therapy. Overall survival was significantly longer with 
nivolumab than with standard therapy (HR for death, 0.70; 97.73% CI, 0.51 to 0.96; 
p = 0.01) (Ferris 2016).  
Given the poor prognosis for most patients with recurrent or metastatic HNSCC and limited 
treatment options, novel approaches are needed.  When over 250 clinical samples were 
profiled by The Cancer Genome Atlas Project for Head and Neck Squamous cell 
carcinomas, it was found that 50% of the samples had loss of function for the tumor 
suppressors TP53 and CDKN2A.  Additional mutations of interest were amplification of MYC 
(13%) and sporadic loss of key proteins within the DDR pathway (BRCA1, BRCA2, ATM 2-
4%) (TCGA 2015).  Genetic mutations in HNSCC and the resulting alterations in the cellular 
pathways of interest, makes this indication an ideal therapeutic target for a Chk1 inhibitor, 
such as SRA737. 
In contrast to HNSCC, squamous cell carcinoma of the anus (SCCA) is rare. New cases of 
anal cancer in the USA were estimated at 8200 for 2017 (Siegel 2017) and 1300 new cases 
of SCCA were diagnosed in the UK in 2014 (Cancer Research UK 2017). Squamous cell 
carcinoma is the most common pathology for cancers of the anus and the incidence is 
increasing worldwide; estimated to have risen by 5.9% per year between 1992 and 2000 in 
the USA (Kang 2007). More than 90% of SCCA cases are associated with HPV infection 
and the high prevalence of HPV infection is implicated in the increase in SCCA (Nelson 
2013, Julie 2016). 
Therapy with a combination of cisplatin and 5FU is the standard for metastatic disease 
(NCCN guidelines 2017). Active investigation into improved therapies is ongoing. However, 
currently the 5-year OS rates for subjects with advanced disease are below 20% and there 
is an unmet need for effective therapies with active investigation into improved therapies 
ongoing (Julie 2016).  
A Phase 1b expansion cohort study with the Chk1 inhibitor prexasertib included a subset of 
24 patients with advanced SCCA (Martinez 2017). In this subset, the disease control rate 
based on RECIST Criteria v1.1 (ie, Complete Response [CR] + Partial Response [PR] + 
Stable Disease [SD]) was 75% (18/24) including one CR and 4 PRs. Next generation 


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sequencing of pretreatment tumor tissue identified genetic alterations corresponding to three 
pathways (cell cycle, DDR and PI3K) that were notably associated with favorable response. 
Known or likely loss-of-function mutations in FBXW7 and PARK2, two genes involved in 
Cyclin E1 proteolysis, were found in patients with a favorable response. Mutations and/or 
germline variants in multiple DDR genes (BRCA1, BRCA2, MRE11A and ATR) but not in 
FANC pathway genes were also found in patients with a treatment benefit. In addition, 
PIK3CA mutations were observed at a higher frequency in patients with SCCA who 
exhibited a treatment benefit. These clinical and genomic profile findings support the 
hypothesis that oncogene-induced replication stress in the context of attenuated DDR may 
sensitize patients to Chk1 inhibitor monotherapy and provide a rationale for treating SCCA 
patients with SRA737 monotherapy. 
 
INVESTIGATIONAL MEDICINAL PRODUCT:  SRA737 
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1.  
The agent was developed through collaboration between The Institute of Cancer Research 
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 combination therapy in subjects with solid tumors 
(NCT02797977).   
For additional information concerning SRA737, refer to the Investigator’s Brochure. 
2.3.1 
MECHANISM OF ACTION OF SRA737 
SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Chk1, a serine-
threonine kinase enzyme that acts as a central regulator of the DDR network.  In cancer 
cells, replication stress induced by oncogenes (eg, MYC and RAS oncogenes) combined 
with loss of function in tumor suppressors (eg, p53 and ATM tumor suppressor genes) 
results in persistent DNA damage and genomic instability.  Chk1 has an important role in the 
S phase checkpoint where it stabilizes and preserves replication fork complexes following 
replication stress, preventing catastrophic replication fork collapse.  Targeted inhibition of 
the remaining components of the DDR network such as by SRA737 may be synthetically 
lethal to cancer cells and have utility as a monotherapy in a range of tumor indications.  
Preclinical studies have demonstrated that SRA737 is a potent inhibitor of Chk1 which 


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abrogates etoposide-induced G2/M cell cycle checkpoint arrest in HT-29 colon cancer cells 
at nanomolar concentrations.   
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 have 
also confirmed the selectivity of SRA737 across the broader kinome.  
As previously mentioned, Chk1 inhibitors may exhibit single agent activity in defined tumor 
genetic backgrounds exhibiting high levels of replication stress including those with 
activating mutations in genes such as MYC or KRAS, loss-of-function mutations in tumor 
suppressor genes such as TP53 or ATM, or defects in other DNA repair genes.  This 
concept has been verified using siRNA knockdown of Chk1 and several Chk1 inhibitors in 
tumor types including AML, cMyc driven lymphomas, N-Myc regulated neuroblastomas and 
various solid tumors (Cavelier 2009, Ferrao 2012, Murga 2011, Cole 2011, Brooks 2013, 
Davies 2011, Hoglund 2011).  Tumor cells deficient in homologous recombination and 
Fanconi anemia pathway genes were shown to be hypersensitive to Chk1 inhibition 
(Krajewska 2014, Chen 2009).  Enhanced sensitivity to Chk1 inhibition may also be linked to 
loss-of-function in ATM or genes in the ATM DDR pathway such as RAD50 
(Al-Ahmadie 2014).  Inactivation of ATM and CHK2 is associated with tumor growth, in 
contrast, amplification and activation of ATR and CHEK1 is correlated with increased 
tumorigenesis (Manic 2015).  In the context of monotherapy, prolonged inhibition of Chk1 is 
expected to be required rather than transient inhibition after genotoxic induced DNA 
damage.  Accordingly, SRA737 is being investigated as a monotherapy for use in tumors 
exhibiting a high degree of replicative stress using a continuous daily schedule. 
The single agent activity of SRA737 has been investigated in a number of murine xenograft 
models harboring genetic alterations likely to sensitize tumor cells to Chk1 inhibition, as 
follows: 
The activity of SRA737 was assessed in the MOLM13 xenograft model of AML.  Daily 
administration of SRA737 (150 mg/kg orally [PO] for 11 days) led to tumor regression and 
an approximate tripling of murine PFS compared to control animals (Figure 2).   


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Figure 2.  SRA737 (formerly CCT245737; 150 mg/kg/day PO) inhibits  
the growth of the MOLM 13 model of AML.   
 
A) Tumor growth over the course of the study 
B) Kaplan Meier survival analysis 
 
The activity of SRA737 was also assessed in a spontaneous, genetically-engineered murine 
model of N-Myc-driven neuroblastoma (Cole 2011).  Administration of the compound at 
150 mg/kg PO for 7 days resulted in significant reduction in tumor burden (Figure 3A).  
Magnetic resonance imaging (MRI) of a single tumor before and after treatment with 
SRA737, confirmed these findings with an 85% reduction in tumor volume (Figure 3B). 
Figure 3.  SRA737 (formerly CCT245737; 150 mg/kg PO) inhibits the growth of N MYC 
driven neuroblastoma in a genetically engineered mouse model  
 
(A)Tumor growth   
(B) Tumor volume imaged by MRI pre and post treatment 
with SRA737 (150 mg/kg PO) in a single mouse  
Similar findings were also noted in an Eu-Myc model of lymphoma where a significant 
reduction in tumor mass in the inguinal, brachial, mesenteric and cervical lymph nodes was 
observed (data not shown). 


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SRA737 has also shown activity as a single agent in an orthotopic solid tumor model (triple 
negative breast cancer MDA-MB-231).  Significant antitumor activity of SRA737 (150 mg/kg 
PO for 3 cycles of 5 days) was noted during the extended dosing period as shown in 
Figure 4.   
Figure 4.  Antitumor efficacy of SRA737 (formerly CCT245737) in the MDA MB 231 
orthotopic triple negative breast cancer xenograft model.   
 
A) mean tumor volume  
 
 
B) mouse body weight 
 
The anti-tumor activity of SRA737 monotherapy was evaluated in the OVCAR-3 xenograft 
model of HGSOC.  This tumor cell line was derived from a platinum insensitive patient and 
harbors an amplification of CCNE1 (encoding cyclin E) and mutation in TP53 (encoding 
p53), two genomic alterations reported to contribute to Chk1 inhibitor sensitivity.  Treatment 
of OVCAR-3 tumor-bearing mice with SRA737 (100 mg/kg for 3 cycles in a 5 days on, 
2 days off schedule) was well tolerated as demonstrated by minimal body weight loss and 
resulted in tumor growth inhibition.  On Day 46, a significant tumor growth inhibition of 60% 
relative to vehicle treated mice was observed (P<0.0001), as shown in) Figure 5. 
A
B


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Figure 5.  Tumor growth inhibition with SRA737 in the OVCAR-3 tumor-bearing 
mouse model.   
Note: Average tumor volume and body weight change (+/- SEM) with n=10 per treatment group. 
In summary, SRA737 has demonstrated significant antitumor activity (including some tumor 
stasis and minor regression) in a variety of murine xenograft studies.  Analysis of various 
DDR markers confirmed this activity was directly related to SRA737’s mechanism of action.  
Initial pharmacokinetics/pharmacodynamics (PK/PDn) assessment suggests that sustained 
circulating plasma concentrations above 100 nM are required to significantly inhibit Chk1 
autophosphorylation for a 24-hour period. 
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 and induction 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. 
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. 
2 0
2 5
3 0
3 5
4 0
4 5
5 0
0
5 0 0
1 0 0 0
1 5 0 0
T im e  (d a y s )
T u m o r V o lu m e  (m m
3)
V e h ic le
S R A 7 3 7  (1 0 0  m p k )
S R A 7 3 7
R A 7 3 7
2 0
2 5
3 0
3 5
4 0
4 5
5 0
-1 0
-5
0
5
1 0
T im e  (d a y s )
B o d y  W t C h a n g e  (% )
fro m  B a s e lin e


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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 
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 (CYP) 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). 
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 quantitative reverse transcription PCR.  
Minimal, concentration-dependent increases in CYP1A2 mRNA levels (up to 7-fold 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.   
Partial agonism of the 5HT2B receptor was the only finding of note, although an absence of 
particularly potent nor complete agonist activity (EC50 = 2.1 µM; 46% maximal effect of 
serotonin) likely renders this observation of limited toxicological significance in the intended 
subject population. 
 
 


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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-glycoprotein, 
and that favorable absorption following oral administration to humans is likely. 
2.3.4 
IN VIVO PHARMACOKINETICS 
The pharmacokinetics (PK) of SRA737 have been determined in the mouse, rat, dog and 
monkey following oral and intravenous administration (Table 1). Very favorable absolute oral 
bioavailability (%F) was noted, particularly in the mouse (105%), dog (86%) 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 (≈ 3-5 h).  Further studies in mice confirmed dose linearity in pertinent 
pharmacokinetic parameters over the range of 50 to 300 mg/kg orally administered. 
Table 1.  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 
- 
PO (10 mg/kg) 
2.9 
0.61 
3.94 
105 
Rat 
IV (5 mg/kg) 
1.0 
- 
1.38 
- 
PO (10 mg/kg) 
4.6 
0.19 
1.17 
42 
Dog 
IV (1 mg/kg) 
2.8 
- 
0.20 
- 
PO (10 mg/kg) 
3.5 
0.13 
0.85 
86 
 
Monkey 
 
IV (1 mg/kg) 
5.3 
- 
1.52 
- 
PO (2 mg/kg) 
5.0 
0.50 
2.73 
90 
PO (10 mg/kg) 
5.1 
2.64 
15.8 
104 
%F = absolute oral bioavailability; AUC(0-t) = exposure; Cmax = maximum observed plasma 
concentration; IV = intravenously; PO = orally; t1/2 = terminal elimination half-life. 
 


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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 and 4.2 µM [2.4 and 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) in an isolated rabbit Purkinje fiber model 
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 anaesthetized 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-clinical 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 oral 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-related changes were noted.  Significant maximal plasma exposure (Cmax) of 
approximately 0.6 µg/mL and 2.3 µg/mL in male and female animals, respectively, at the 


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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), because of the sporadic natures 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 ECG 
waveform or intervals. Mean circulating plasma levels at the approximate time ECGs were 
recorded (≈ 4 h 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, cardiovascular safety assessments are included in the ongoing 
Phase 1/2 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’s Brochure. 
2.3.6.1 
28-Day Mouse Study 
The toxicity and population toxicokinetics 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 75mg/kg/day (≈ 30, 120, or 215mg/m2/day). 
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, atrophy of the femoral and 
sternal marrow, decreased thymic weight, and a concordant increase in splenic weight likely 


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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 tract in this 28-day study.  It should be noted that apoptosis of cells in the 
gastrointestinal tract (GIT) 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 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 Maximum Tolerated Dose (MTD) in this study was 75 mg/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 toxicokinetics of 
SRA737 when administered in combination with intravenous gemcitabine and cisplatin on 
an intermittent schedule over 18 days.  Male and female animals were administered 
SRA737 orally 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 white blood cell 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 total exposure (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 toxicokinetics of SRA737 following 
daily oral 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 
(namely 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, GIT and lung, or septicemia was noted in the premature decedent 
animals.   
A decrease in red blood cell 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. 


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Decreased white blood cell counts were also observed at 40 and 75 mg/kg 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. 
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 µg/mL to 0.6 µg/mL and total 
exposure (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 (≈ 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 


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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 were noted.  These findings were 
reversible on cessation of drug administration. 
Toxicological findings in the monkey, the most appropriate non-rodent toxicity species, 
indicated SRA737 had the potential to cause findings similar to those observed in mouse 
and minipig although at much higher doses. 
Toxicological findings in the GIT 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 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. 
2.3.7 
RATIONALE FOR THE SELECTION OF THE STARTING DOSE AND 
SCHEDULE 
The murine toxicity studies indicated a SRA737 MTD of 75 mg/kg/day (≈ 225 mg/m2/day) as 
a single-agent.  The International Conference on Harmonisation (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 (HED) of 22.5 mg/m2/day (0.61 mg/kg/day) 
equating to an absolute dose of 36mg (for a 60 kg patient) could be utilized.  For the further 
assurance of patient safety, a lower starting dosing of 20 mg was selected.    
Using similar allometric scaling, pharmacologically-active concentrations of SRA737 may 
occur at clinical doses of approximately 80 mg to 160 mg.  Based on the nonclinical toxicity 
studies, the most likely target organs for SRA737 toxicity are the bone marrow and GIT.   
 
CLINICAL EXPERIENCE  
SRA737 had not been administered to humans prior to the initiation of this 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.  


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LY2606368, an unselective Chk1/Chk2 inhibitor administered by intravenous infusion is 
currently the most advanced second-generation agent.  This compound was the subject of 7 
Phase 1 and 2 clinical studies both as monotherapy and in combination with various 
chemotherapeutic agents and radiotherapy as this current SRA737 study was activated.  
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.  Data from this study had not 
been reported at the time of activation of this current SRA737 study. 
The proposed trial design for SRA737 as a monotherapy is consistent with several previous 
studies of Chk1 inhibitors.  Based on the limited existing clinical data from second-
generation clinical programs, myelosuppression may be anticipated to occur in the clinical 
trial of SRA737 as a monotherapy.  
Further information on SRA737 is available in the current version of the Investigator’s 
Brochure. 
 
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, 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 define the RP2D for 
SRA737, while also evaluating which patients are most likely to benefit from treatment. 
Specific cohort expansion indications have been selected as being most likely to represent 
potential areas for SRA737 monotherapy efficacy, and the diagnostic test will be explored as 
a means to identify patients with greatest likelihood of benefit from treatment. 


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Benefit-Risk Assessment   
SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Chk1, a central 
regulator of the DDR network. In cancer cells, replication stress induced by oncogenes (eg, 
MYC and RAS oncogenes) combined with loss of function in tumor suppressors (eg, TP53) 
results in persistent DNA damage and genomic instability, a trigger of the DDR network. 
Targeted inhibition of the remaining components of the DDR network such as Chk1 by 
SRA737 may be synthetically lethal to cancer cells and thus may have utility as a 
monotherapy in a range of tumor indications particularly in tumors with high rates of 
replication stress and genomic instability.   
A body of experimental data supports the exploration of SRA737 as a single agent 
particularly in a molecularly-defined population. This first-in-human dose escalation study 
will be enriched in dose expansion cohorts with prospectively-selected genetically-defined 
subjects in tumor types that are known to have a high prevalence of genomic aberrations 
hypothesized to sensitize the tumor to Chk1 inhibition. Prospective selection of patients 
most likely to derive benefit from SRA737 will provide data to support the selection of 
specific indications and inform refinement of patient selection strategies in further clinical 
development. The indications for the expansion cohorts have been selected 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.   
Recent non-clinical toxicology data generated in the monkey, the most representative 
species for toxicity assessment of SRA737, indicate favorable tolerability at daily oral doses 
of 20 mg/kg, where mean Cmax and AUC values reached 3.2 µg/mL (≈ 8 µM) and 24 µg.h/mL 
(≈ 65 µM.h), respectively.   In contrast, clinical Cmax and AUC values of 1.1 µg/mL and 
9 µg.h/mL were observed in the 600mg clinical dosing cohort (n=1), indicating a favorable 
exposure safety margin with considerable opportunity for ongoing dose escalation during the 
clinical study. 
The likely target organs for SRA737 toxicity are the bone marrow and the GIT, both of which 
will be closely monitored in the ongoing study. Although no significant nonclinical cardiac 
liabilities have been observed in the benchmark non-rodent toxicity studies, cardiovascular 
safety assessments are included in this Phase 1/2 clinical study as a precaution. The 
rationale for the starting dose and schedule of SRA737, based initially on preclinical data, is 
provided in Section 2.3.7. 


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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 (AEs, Section 5.4). 
Based on the non-clinical and clinical information currently available, the balance between 
anticipated efficacy/benefits and the potential safety risks for SRA737 remains highly 
favorable.   
3 
TRIAL DESIGN 
 
CLINICAL TRIAL OBJECTIVES AND ENDPOINTS 
3.1.1 
PRIMARY OBJECTIVES AND ENDPOINTS 
Primary objectives 
Endpoints 
To establish the safety profile of SRA737 
Safety parameters (referencing National Cancer 
Institute – Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] v4.03) including: 
incidence, seriousness, severity and causality of 
each AE to SRA737, 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 with 1 or more 
schedules of administration of SRA737 
The highest dose at which ≤ 33% of subjects have a 
dose limiting toxicity (DLT) in a cohort of up to 
6 subjects 
To propose a recommended Phase 2 dose 
and schedule of SRA737  
 
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  
To evaluate the preliminary efficacy of 
SRA737 including efficacy in 
prospectively-selected genetically-defined 
subjects enrolled into indication-specific 
expansion cohorts 
Objective response rate (ORR)  
Disease control rate (DCR) 
Time to response (TTR)  
Duration of response (DOR)  
Progression-free survival (PFS) 
Time to progression (TTP) 
Overall survival (OS) 
 


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3.1.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives 
Endpoints 
To characterize the pharmacokinetic 
profile of SRA737 
Plasma concentration-time profile based on PK 
parameters including, but not limited to: AUCinf, 
AUCtau, Cmax, Cmin, Tmax, and t1/2 
To assess the relationship between 
response and the presence of selected 
genetic alterations detected in tumor tissue 
and/or circulating tumor deoxyribonucleic 
acid (ctDNA)   
 
ORR and gene alterations in tumor tissue or ctDNA 
at baseline as measured by next generation 
sequencing (NGS)  
 
3.1.3 
EXPLORATORY OBJECTIVES AND ENDPOINTS 
Exploratory objectives 
Endpoints 
To investigate the pharmacodynamics of 
SRA737 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 pharmacodynamics of 
SRA737 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: pS317 Chk1, pS345 Chk1, total Chk1, 
gammaH2AX and RAD51 
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 explore the relationship between 
exposure (PK) and QT/QTc, other 
electrocardiogram (ECG) parameters and 
cardiovascular safety findings 
Association of QT, QTc, blood pressure (BP), 
heart rate, other ECG intervals with time-matched 
PK concentrations. Profile of QTc over the dosing 
interval 
 
 
DESIGN OF THE CLINICAL TRIAL 
This is a multicenter, first-in-human, Phase 1/2, open-label, dose-escalation trial in subjects 
with advanced solid tumors or non-Hodgkin lymphoma (NHL), with cohort-expansion phase 
in 6 indication-specific expansion cohorts (Figure 6).  The trial will consist of 2 stages: 
• 
Stage 1:  A Dose Escalation Phase.  
It is expected that between 30 and 50 subjects with solid tumors or NHL will be 
enrolled in the Dose Escalation Phase of the study.   
Intensive PK and ECG monitoring for QTc assessments will be collected from all 
enrolled subjects, beginning with sampling before and after a single dose of SRA737 
given on one day between Day -7 and Day -4.  Tissue (archival or fresh) and blood 
will be collected for retrospective biomarker analyses.  


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Cohorts consisting initially of a single subject will receive escalating doses of 
SRA737, starting in Cohort 1 with 20 mg/day administered orally on a continuous 
daily dosing schedule in 28-day cycles.  The dose will be escalated until the MTD 
has been identified, unless determined otherwise by the Sponsor in consultation with 
the Chief Investigator, for example, if an alternative schedule is pursued instead.   
Once a SRA737-related, Grade 2 toxicity is observed in a dose escalation cohort 
during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose 
level cohorts will follow a rolling 6 design.  See Section 3.3 for additional details.   
Dose escalation with an alternative schedule may begin at any time and may either 
run in parallel or instead of continued escalations in the continuous schedule.  
The final number of subjects enrolled into the trial is dependent on the number of 
dose levels explored in the Dose Escalation Phase.  
• 
Stage 2:  A Cohort Expansion Phase.   
Approximately 120 subjects will be enrolled into the Cohort Expansion Phase which 
consists of 6 indication-specific expansion cohorts of approximately 20 prospectively-
selected genetically-defined subjects each (namely, subjects with previously treated 
metastatic CRC, HGSOC without CCNE1 gene amplification, HGSOC with CCNE1 
gene amplification (or alternative genetic alteration with similar functional effect), 
mCRPC, advanced NSCLC, and HNSCC/SCC).  This allows for a preliminary 
exploration of the efficacy of SRA737. 
Intensive PK and ECG monitoring for QTc assessments will be performed for 
subjects in the Cohort Expansion Phase. However, the Sponsor may reduce or 
modify the requirements for PK sampling, including elimination or modification of the 
Day -7 to Day -4 visit, once sufficient data to evaluate the PK of SRA737 have been 
collected and analyzed. If this occurs, the modified requirements will be documented 
by an update to the appropriate study documents. 
Tissue (archival or fresh) and blood will be collected for prospective genetic analyses 
to determine eligibility.  See Section 7 for more details. 
Prospective determination of tumor genetics to determine eligibility of subjects within 
the selected indications may begin prior to the completion of dose escalation.  
Enrollment to the Dose Escalation and Expansion Cohorts may occur in parallel.  A 
subject that qualifies for the Cohort Expansion Phase will be enrolled into an 
Escalation Cohort whenever possible.  Any such subject will be considered to have 
enrolled in both phases simultaneously.  Only when a dose escalation enrollment slot 
is not available for an eligible prospectively-selected genetically-defined subject, that 
subject may be enrolled to an expansion cohort and treated with SRA737 at the 
highest dose level previously determined to be safe.  Intra-subject dose escalation is 
allowed for these, and for all, study subjects when a higher dose level has been 
determined to be safe in a cohort of Dose Escalation subjects.  
Enrollment into the Expansion Cohorts requires that each subject’s tumor has 
evidence of a combination of mutations which are expected to confer sensitivity to 


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Chk1 inhibition. Eligibility will be determined by the Sponsor's review of genetic 
abnormalities listed in Appendix 6.  


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Figure 6 Study Design  
 
DLT= dose-limiting toxicity, NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, TBD = to be determined, 
MTD = maximum tolerated dose 


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DOSE ESCALATION PHASE 
The Dose Escalation Phase will begin with an accelerated titration design which allows for 
single subject cohorts and 100% dose escalation increments if the previous dose level is 
determined to be safe by the cohort review process.  The dose of SRA737 will be doubled in 
subsequent cohorts until a subject in any cohort experiences a SRA737-related or probably 
related National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Grade 2 or greater toxicity during Cycle 1; cohorts will then be expanded to 3 to 6 
subjects following a rolling 6 design for that and subsequent cohorts.  In the absence of a 
DLT, the dose of SRA737 will be escalated in less than 100% (typically 25–75%) 
increments.  The extent of the dose increase will be informed by the Cohort Review 
Committee.   
Once the first subject in each rolling 6 cohort has completed an observation period of 7 days 
of continuous dosing (Days 1–7 inclusive), or a similar duration of observation on an 
alternative schedule, subsequent subjects may start treatment unless the Sponsor 
determines that safety findings in the first subject in that cohort warrants other action.  With 
the exception of the single subject cohorts, a minimum of three evaluable subjects must 
have completed one cycle in order to decide to escalate the SRA737 dose.  The minimum 
possible time between dose escalation cohorts is therefore 5 weeks.   
Subjects who receive less than 75% of their planned doses in Cycle 1 for reasons other than 
SRA737-related toxicity will not be evaluable for assessment of DLT for dose review 
decisions and may be replaced in the cohort.  Safety information for these subjects will, 
however, be considered to guide the extent of the dose increase.  
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, and principal 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 the 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 


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as a minimum the chief investigator 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.  DLTs 
will be the primary consideration for the purposes of dose escalation decisions; however, 
should cumulative toxicity become apparent this will also be taken into consideration. 
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;  
• 
Whether subjects receiving subsequent cycles of SRA737 at lower dose levels could 
be allowed to proceed with intra-subject dose escalation.    
3.3.2 
DOSE ESCALATION DECISION RULES 
The dose level of SRA737 will be assigned according to the number of subjects already 
enrolled at the current dose level, the number of DLTs (and any other drug-related AEs) 
observed at the current dose level and the number of subjects enrolled who are at risk of 
developing a DLT.  When sufficient data, as determined during the Cohort Review Meeting, 
are available to assess these in the rolling 6 cohorts, the subsequent SRA737 dose level will 
be assigned according to the following: 
• 
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 can 
be considered. 
• 
If the data are available from 3 subjects who have been treated in a cohort and one 
DLT has been observed at that dose level, then the cohort will be expanded to up to 
6 subjects. 
• 
If two DLTs have been observed at any dose level, dose escalation will stop and this 
dose will be defined as the maximum administered dose for that schedule.  
o The dose will be de-escalated and the previous dose level will be expanded 
to up to 6 subjects.  If the previous dose level already included a cohort of 
6 subjects, then this could be identified as the MTD unless it is decided that 
an intermediate dose level would be tested.  
o An intermediate dose level between the previous and current dose level may 
be explored following full discussion between the Sponsor and Chief 
Investigator.   
• 
The maximum administered dose could also equal the MTD in the event that dose 
escalation is stopped before 2 DLTs are observed at a given dose level, due to the 
expectation that higher dose levels would be too toxic to administer to subjects. 


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DEFINITION OF DOSE LIMITING TOXICITY 
The DLT window is defined from the first Day -7 to Day -4 dose until the end of Cycle 1 (up 
to 35 days). 
A DLT is defined as any highly probably or probably SRA737-related 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 per 
Cohort Review discussion: 
o Alopecia of any grade 
o Grade 3 or 4 nausea or vomiting in subjects that have not received optimal 
treatment with anti-emetics 
o Grade 3 or 4 diarrhea in subjects that have not received optimal treatment 
with anti-diarrheal medication 
o Transient, asymptomatic Grade 3 biochemical abnormalities if agreed by the 
Medical Monitor and the Chief Investigator 
o Grade 3 fatigue, unless there is an increase by at least 2 grades from 
baseline (classed as the grade prior to first dose) 
• 
Inability to receive 75% of planned dose in the first cycle during the DLT window due 
to drug-related toxicity  
DLTs 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 delegate 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. 


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DEFINITION OF MAXIMUM TOLERATED DOSE AND RECOMMENDED 
PHASE 2 DOSE AND SCHEDULE 
If 2 out of up to 6 subjects at the same dose level experience a DLT, as defined above, the 
MTD will be determined as a lower dose level for that schedule. 
The RP2D and schedule 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 for the selected schedule.  
 
COHORT EXPANSION PHASE 
Prospectively-selected genetically-defined subjects will be enrolled in 6 indication-specific 
expansion cohorts to establish the safety profile and preliminary efficacy of SRA737.  Each 
expansion cohort will enroll approximately 20 subjects from the following indications: 
metastatic CRC, HGSOC without CCNE1 gene amplification, HGSOC with CCNE1 gene 
amplification, mCRPC, advanced NSCLC, or HNSCC/SCCA. 
Screening for expansion cohorts will be initiated prior to the completion of dose escalation 
and determination of MTD or RP2D.  If a slot is not available in the Dose Escalation Cohort, 
eligible prospectively-selected genetically-defined subjects will be enrolled in the Expansion 
Cohort 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.   
The goal of the expansion cohorts is to assess SRA737 across multiple tumor types in 
subjects who have a range of genomic profiles of interest as described in inclusion 
criterion 9. The sponsor may choose to refine or select particular genomic profile 
requirements in each (or all) Expansion Cohort(s) 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 choose to 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 


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sufficient numbers of genetic variants within an indication are studied (for example BRCAm 
and BRCAwt). 
 
INTRA-SUBJECT DOSE ESCALATIONS 
Once a higher dose level has been determined to be safe in a cohort of Dose Escalation 
subjects, subjects who have not experienced ≥ Grade 2 SRA737-related toxicity at the dose 
at which they are currently being treated, in the most recent prior cycle, are able to escalate 
to the next higher dose level for that schedule once the sponsor approves the escalation.  
Only one dose level increase can be undertaken each cycle.  
This intra-subject escalation will be to a dose level already evaluated at a Cohort Review 
Meeting and found to be acceptable from a safety perspective.  If the subject(s) then goes 
on to experience an event meeting the definition of DLT, this information will be taken into 
account for future dose escalation decisions.  
 
SUBJECT EVALUABILITY 
3.8.1 
DLT EVALUABLE 
All subjects receiving at least 75% of planned doses of SRA737 within Cycle 1 and those 
subjects receiving less than these planned doses of SRA737 due to DLT will be considered 
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 less than 75% of planned doses of SRA737 during the DLT period for reasons other 
than drug-related toxicity.  
In the Cohort Expansion Phase, subjects who are not response-evaluable may be replaced 
in order to achieve 20 response-evaluable prospectively-selected genetically-defined 
subjects per 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 system by site staff and be allocated a subject number by the electronic data 
capture system.  Once the investigator or designated representative has confirmed the 
eligibility of the subject, the site must submit a completed eligibility checklist, and receive 


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confirmation of eligibility for a dose escalation cohort, an indication-specific cohort 
expansion, or both, and confirmation of the assigned dose level from the Sponsor or 
Sponsor’s designee before the subject may be enrolled. 
 
NUMBER OF SUBJECTS 
The study will enroll up to 170 subjects including an estimated 30–50 subjects during dose 
escalation and 6 expansion cohorts, each consisting of approximately 20 subjects. The final 
number of subjects enrolled into the trial will depend on the number of dose levels, the 
number of subjects who participate in both the Dose Escalation and Cohort Expansion 
phases, and potentially alternative dose schedules explored.     
 
SUBJECT SELECTION CRITERIA 
The subject must fulfil the eligibility criteria (listed in Sections 4.2.1 and Section 4.2.2). 
4.2.1 
INCLUSION CRITERIA 
Dose Escalation Phase and Cohort Expansion Phase  
1. Written (signed and dated) informed consent and capable of co-operating with 
treatment and follow up.  
2a.  For subjects in the Dose Escalation Phase:  any locally advanced or metastatic, 
histologically or cytologically proven solid tumor or NHL, that is relapsed after or 
progressing despite conventional treatment for which no conventional therapy is 
considered appropriate by the investigator or is declined by the subject.   
2b. For subjects in the Cohort Expansion Phase:  locally advanced or metastatic, 
histologically or cytologically proven malignancy of the types specified in inclusion 
criterion 10, for which no other conventional therapy is considered appropriate by the 
investigator or has been 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 one week prior to the subject receiving their first dose of investigational 
medicinal product (IMP).  


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Laboratory Test 
Lower acceptable limit 
Hemoglobin (Hb) 
≥ 90 g/L  
Absolute neutrophil count  
≥ 1.5 x 109/L  
Platelet count 
≥ 100 x 109/L 
Bilirubin  
≤ 1.5 x upper limit of normal (ULN) unless due to 
Gilbert’s syndrome in which case up to 3 × ULN 
is permissible  
Alanine aminotransferase and/or 
aspartate aminotransferase and 
Alkaline Phosphatase  
≤ 2.5 x ULN unless raised due to tumor in which 
case up to 5 x ULN is permissible  
Serum Creatinine 
≤ 1.5 x ULN 
 
6. Attained the age of 18 years 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 details. 
Cohort Expansion Phase  
8. Subjects must have measurable disease (per Response Evaluation Criteria in Solid 
Tumors, version 1.1 [RECIST v1.1]) or, for mCRPC, evaluable disease per any of the 
following: 
a. Measurable disease per RECIST v1.1;  
b. Increasing prostate specific antigen (PSA, see PCWG – Appendix 7); or  
c. Circulating tumor cell (CTC) count of 5 or more cells per 7.5ml of blood. 
9. Subjects must have tumor tissue or ctDNA evidence that their tumor harbors a 
combination of mutations which are expected to confer sensitivity to Chk1 inhibition. 
Eligibility will be determined by the Sponsor's review of genetic abnormalities 
detected in genes in the following categories, as listed in Appendix 6:  
a. Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as 
RB1, TP53, etc. For patients with NHSCC or SCCA, positive HPV status is also 
considered for eligibility. 
b. The DDR pathway including ATM, BRCA1, and BRCA2. For patients with CRC, 
MMR genetic alterations and/or high microsatellite instability are also considered 
for eligibility. 
c. Genetic indicators of replicative stress such as gain of function/amplification of 
Chk1 or ATR or other related gene.  
d. Oncogenic drivers such as MYC, KRAS, etc. 
e. CCNE1 gene amplification (or alternative genetic alteration with similar functional 
effect) is required for the CCNE1 gene amplification-specific HGSOC cohort. 
10. Subjects must meet one of the following criteria (a-e): 


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a. Metastatic CRC, defined by the following: 
o Histologically and/or cytologically confirmed CRC, and  
o Must have received at least 1 prior regimen for advanced/metastatic 
disease 
b. HGSOC, defined by the following: 
o Histologically confirmed high-grade serous ovarian, fallopian tube or 
primary peritoneal cancer, and  
o Recurrent platinum-intolerant subjects, or those with platinum-resistant 
disease, defined as radiological evidence of disease progression within 
6 months of the last receipt of platinum-based chemotherapy.  Patients 
with platinum refractory disease (ESMO – Appendix 7) are not eligible 
c. Advanced NSCLC, defined by the following: 
o Locally advanced and recurrent or metastatic, histologically confirmed 
NSCLC, and   
o Must have received at least 1 prior regimen for advanced/metastatic 
disease 
d. mCRPC, defined by the following: 
o Histologically or cytologically confirmed adenocarcinoma of the prostate 
that has progressed after androgen deprivation therapy  
e. HNSCC or SCCA, defined by the following: 
o Histologically confirmed HNSCC from any primary site, or SCCA: 
 
For HNSCC: locally advanced disease (ie, persistent or progressive 
disease following curative-intent radiation, and not a candidate for 
surgical salvage due to incurability or morbidity), or metastatic disease 
 
For SCCA: locally advanced disease or metastatic disease for which 
no curative intent therapy is available 
o Must have received at least 1 prior regimen for advanced/metastatic 
disease 
4.2.2 
EXCLUSION CRITERIA 
1. Have received the following prior or current anticancer therapy: 
a. Radiotherapy within the last 6 weeks (except for symptom control and where 
the lesions will not be used as measurable disease)  
b. Endocrine therapy during the previous 4 weeks except for luteinizing hormone 
releasing hormone (LHRH) agonists for prostate cancer  


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c. Chemotherapy during the previous 4 weeks  
d. Immunotherapy during the previous 6 weeks  
e. Nitrosoureas or Mitomycin C during the previous 6 weeks  
f. Other IMPs during the 4 weeks before treatment  
g. Any prior treatment with a Chk1 inhibitor, or prior treatment with an ATR 
inhibitor within 6 months prior to receiving SRA737. 
2. Other malignancy within the past 2 years with the exception of adequately treated 
tumors that are associated with an expected 5-year disease-free survival 
of approximately 95% or better. 
3. 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 or sponsor’s designee should not exclude the 
subject.  
4a. For subjects in the Dose Escalation Phase that are not to be included in an 
Expansion Cohort: new or progressing brain metastases.  Subjects with brain 
metastases that have been radiologically stable over an 8-week period may be 
included in this phase.   
4b. For subjects in the Cohort Expansion Phase: present or prior brain metastases.   
5. Women of childbearing potential (WOCBP) or women who are already pregnant or 
lactating. However, those patients who have a negative serum or urine pregnancy 
test before enrollment and agree to use two forms of contraception as per Appendix 
4 or agree to sexual abstinence, effective from the first administration of SRA737, 
throughout the trial and for six months afterwards are considered eligible.  
6. Male subjects with partners of childbearing potential (unless they agree to take 
measures not to father children by using a barrier method of contraception as per 
Appendix 4 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. 
7. Major surgery from which the subject has not yet recovered. 
8. At high medical risk because of non-malignant systemic disease including active 
uncontrolled infection.   
9. Known to be serologically positive for hepatitis B, hepatitis C or human 
immunodeficiency virus (HIV). 
10. 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 


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ischemia within the past 6 months, or prior history of cardiac arrhythmia requiring 
treatment.   
11. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone 
marrow within 8 weeks.  
12. Peanut allergy.  Refer to Section 6 for additional details.   
13. QTcF > 450 msec in adult males and > 470 msec in adult females. 
14. 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).   
15. Not able to swallow capsules without chewing or crushing.  
16. 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 or Sponsor’s designee would be acceptable. 
17. 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 
 
STARTING DOSE AND REGIMEN 
SRA737 will be administered orally on a continuous daily schedule.  The starting dose for 
Cohort 1 is 20 mg per day.  Each cycle of continuous treatment will last 28 days, and 
subjects may continue as long as none of the treatment discontinuation criteria (see 
Section 5.6) are met.  
 
ALTERNATIVE DOSING REGIMEN 
Consideration may be given to alternative dosing schedules at any time during the study, 
following discussion between the Sponsor and investigators.  It may be more likely that an 
alternative schedule will be needed if the Cmin at the MTD of SRA737 is less than 100 nM 
(the concentration below which sustained Chk1 inhibition is not anticipated), and/or if safety 
and tolerability data, PK and/or PDn data (eg, time to onset and time to recovery of 
myelosuppression) indicate that an alternative dosing schedule would be more suitable.  
Alternative schedules may include, but are not limited to, the following examples: 5 days of 
dosing followed by 2 days of non-dosing each week; 1 week of daily dosing followed by 1, 2, 
or 3 weeks of non-dosing; 2 or 3 weeks of daily dosing followed by 1, or 2 weeks of non-


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dosing; or twice daily dosing.  Alternative dosing schedule cohorts may be recruited in 
parallel to or instead of the continuous schedule cohorts.   
The initial starting dose for an alternate schedule will depend on the safety, tolerability and 
PK results from the previous schedule cohorts.  If an alternative schedule is to be tested 
after an MTD has been identified with the previous schedule, the starting total weekly dose 
for the new schedule will not exceed the total weekly dose at the MTD for the previous 
schedules.  If an MTD has not been identified with the previous schedule, a dose escalation 
step may occur; however, the dose escalation may not exceed 50% based on the total 
weekly dose.    
 
DURATION OF TREATMENT 
Treatment should continue until disease progression unless the subject meets one of the 
other treatment discontinuation criteria outlined in Section 5.6.   
 
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 should be made conservatively, using the 
guidelines for the most severe AEs and the worst scenario of the recommended dose 
reduction(s).  Once the dose has been reduced, it should not be re-escalated. 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 OR DELAYS 
Guidelines for dose delays due to AEs are provided in Table 2. 


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Table 2.  Dose Delay and Discontinuation Guidelines 
Event 
Recommended Action 
Grade 3 neutropenia or 
Grade 3 
thrombocytopenia 
• 
Recommend twice weekly monitoring of blood tests if the subject 
is to continue dosing. 
Grade 4 neutropenia or 
thrombocytopenia 
or 
Any non-hematologic 
≥ Grade 3 SRA737-
related toxicity* 
• 
Consider dose interruption  
• 
If toxicities have not resolved to ≤ Grade 1 or ≤ 1 grade worse 
than baseline with a dose interruption, continue to delay 
treatment for up to 4 weeks.  If no recovery after 4-week delay, 
discontinue treatment.   
• 
If toxicities have resolved to ≤ Grade 1 or ≤ 1 grade worse 
than baseline, treatment may be reinitiated.   
Consider resumption of treatment at the next lowest dose 
level for the schedule under investigation or at a reduced 
dose at an alternative, intermittent schedule.  
*Exceptions may include nausea, vomiting or diarrhea lasting < 48 hours, asymptomatic 
biochemical abnormalities lasting < 5 days, Grade 3 fatigue (unless there was an increase in 
severity of > 2 grades from baseline), or other event agreed with the Sponsor or Sponsor’s 
designee. 
 
 
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  
Subjects should not be administered G-CSF prophylactically but may be administered as 
medically indicated. 
5.5.1.2 
Palliative Radiotherapy 
Palliative radiotherapy may be given concomitantly for the control of bone pain or other 
symptoms.  Irradiated lesions will not be evaluable for response.   
5.5.1.3 
Contraception Usage 
To be eligible for this study, WOCBP (as defined per Appendix 4) and male subjects with 
partners of childbearing potential must use 2 forms of contraception or agree to sexual 


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abstinence effective from the first administration of SRA737 through the trial and for 6 
months afterwards.  See Appendix 4 for more information.  
5.5.1.4 
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 
summary list of applicable drugs for this study is provided in Appendix 5. 
5.5.1.5 
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. PPIs should therefore be avoided if possible and used with 
caution if necessary. 
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. Subjects 
requiring anticoagulation should change from warfarin to low molecular weight heparin while 
they are on study.   
5.5.2 
EXCLUDED CONCOMITANT MEDICATIONS 
Subjects must not receive other anti-cancer therapy or investigational drugs while on the 
trial, with the exception of LHRH agonist therapy for the treatment of prostate cancer. 


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DISCONTINUATION FROM TREATMENT 
Subjects can decline to continue receiving SRA737 but continue participation in the study.  If 
this occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from SRA737 and must discuss with the subject options for continuation of 
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: 
• 
Evidence of disease progression 
• 
Unacceptable toxicity 
• 
Noncompliance with study procedures 
• 
Withdrawal by the investigator for clinical reasons not related to SRA737 
• 
Treatment with prohibited concomitant medications 
• 
Intercurrent illness that interferes with study assessments 
• 
Pregnancy of a subject during the study  
• 
Commencement 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.  
 
DISCONTINUATION FROM THE 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 days ± 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 


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should be performed before withdrawal from the study whenever possible.  All 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 for the following reasons: 
• 
Withdrawal of consent 
• 
Death or loss to follow-up 
• 
Sponsor’s decision to terminate the study 
6 
PHARMACEUTICAL INFORMATION 
 
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, 25, 50, 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 (#12; see Section 4.2.2) is required because 
the current manufacturing facility of the SRA737 cannot guarantee that 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 manufactured at the initial 
facility is depleted and no longer available for subject dosing.  Refer to the SRA737 
Pharmacy Manual for more information. 
 
 
 
STORAGE CONDITIONS FOR SRA737 
SRA737 must be stored according to the label (refrigerated at 2°C–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). 


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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.  
 
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 5.5.1.5.  Should a 
subject miss a scheduled dose due to an error, then the dose may be taken up to 6 hours 
after the scheduled dosing time.  After this time the subject should wait until the next 
scheduled time before taking the dose.  On clinic days, subjects must be counseled not to 
take their meds, but instead to bring their meds into clinic so that nursing staff may direct 
dosing to ensure the correct PK collections are made.  Should a subject vomit the 
administered dose, the subject should not re-take the dose and should wait until their next 
scheduled dose. 
 
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.  


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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. 
 
PRE-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.  
Please also refer to the tabulated Schedule of Events in Section 7.6. 
7.1.1 
SCREENING EVALUATIONS: PRE-SCREEING AND WITHIN 28 DAYS PRIOR 
TO ADMINISTRATION OF SRA737  
Repeat dosing will begin on Day 1, but subjects will also receive a single dose between 
Day -7 and Day -4 for the purpose of PK analysis until the sponsor determines sufficient 
data to evaluate the PK of SRA737 have been collected and analyzed. If this occurs, the 
modified requirements will be documented by an update to the Laboratory Manual.   
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. 
The following will be performed/obtained as part of Pre-Screening (no time restriction): 
• 
Written informed consent (as detailed in Section 12.3)   
• 
Determination of HPV status either from the subject’s medical records, or 
assessment by local laboratory (subjects with HNSCC or SCCA only). 
• 
Submission of, or confirmation of availability of, suitable archival tumor tissue or 
fresh tumor tissue (such as with fine needle aspirate) for tumor profiling.  
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.  


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If the subject is enrolled, archival tissue should be requisitioned for 
submission by Cycle 1 Day 1.   
o For subjects being considered for enrollment to the Cohort Expansion Phase, 
determination of tumor genetics (as confirmed by a validated method 
performed in a Central Laboratory selected by the sponsor) and MSI status 
(required for CRC subjects and other subjects if clinically relevant), will be 
used to determine eligibility for the Cohort Expansion Phase.  Archival or 
fresh tumor tissue should be submitted for prospective testing at the Central 
Laboratory as early as possible. 
o When archival material was collected more than 18 months ago, the ability to 
collect fresh tumor tissue should be discussed with the sponsor. 
o Suitable archival tumor tissue is defined as ≥ 40 µm tissue, of which a 
minimum of 20% is of malignant origin, on at least 10 and up to 20 unstained 
slides or in an FFPE block, plus one original (not recut) H&E slide.   
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.  
For CRC patients, this could include MSI (high status).  In cases where the 
data are approved as sufficient to support enrollment, archival or fresh tumor 
tissue must still be submitted for retrospective testing by the Central 
Laboratory after study entry, as noted in Section 7.2.1.   
 


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The following must be performed/obtained within 28 days before the subject receives 
their first dose of SRA737:   
• 
Demographic details 
• 
Medical history including current diagnosis, prior treatment, concomitant 
conditions/diseases, previous cancers (if appropriate), baseline signs and symptoms, 
and concomitant treatment  
• 
Radiological disease assessments appropriate to the subject’s disease must be 
performed.  These may include, but are not limited to: radiological measurements 
(chest computerized tomography [CT] scan of the liver, abdomen or pelvis, MRI, 
x-ray; and/or a bone scan).  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. 
• 
Echocardiogram (ECHO)  
• 
ECG (locally-read) 
o QTcF is to be calculated according to the following formula: 
Fridericia’s formula: QT / (RR)0.33 
[Observed QT interval divided by cube root of RR interval] 
• 
Laboratory tests (blood samples): 
o CTCs for mCRPC subjects only (Performed via CellSearch CTC Test) 
• 
ctDNA for tumor profiling:  If prospective tumor profiling by ctDNA at a Central 
Laboratory is available, then the blood sample will be obtained within 28 days prior to 
the first dose. If retrospective analysis will be performed, the sample may be 
obtained prior to the first dose between Day -7 and Day -4 dosing day. (See 
Laboratory Manual for details) 
• 
Optional tumor biopsy material for exploratory PD assays (See Section 8.2.4) should 
optimally be collected within 7 days prior to the first dose of SRA737, but may be 
done at same time as biopsy for eligibility during Screening. 
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).  


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7.1.2 
SCREENING EVALUATIONS:  WITHIN 7 DAYS PRIOR TO ADMINISTRATION 
OF THE FIRST DOSE OF SRA737 
The following must be performed within the 7 days before the subject receives the first 
dose of SRA737 either between Day -7 to Day -4 or on Day 1, as applicable: 
• 
Assessment of any SAEs experienced since signing of the consent and concomitant 
medications 
• 
WHO performance status 
• 
Complete physical examination including clinical disease measurements, as clinically 
relevant (ie, subjects with clinically assessable disease)   
• 
Clinical disease evaluations 
• 
Laboratory tests (blood/urine samples):   
o Hematology:  complete blood count (CBC) with differential count  
o Biochemistry:  sodium, potassium, chloride, magnesium, adjusted calcium, 
phosphate, urea, creatinine, total protein, albumin, direct and indirect 
bilirubin, LDH, alkaline phosphatase, alanine aminotransferase and/ or 
aspartate aminotransferase, non-fasting glucose 
o Pregnancy testing (WOCBP only):  serum or urine test is acceptable   
• 
Optional tumor biopsy material for exploratory PD assays (See Section 8.2.4) should 
optimally be collected within 7 days prior to the first dose of SRA737, but may be 
done at the same time as biopsy for eligibility during Screening. 
• 
Enrollment of the subject on the study only once the investigator has confirmed 
eligibility and the Sponsor approves (see Section 4 for further eligibility details). 
 
EVALUATIONS DURING THE TRIAL 
7.2.1 
FIRST DOSE FOR PK (DAY -7 TO DAY -4) SCHEDULE 
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.  
Intensive PK assessments are outlined in detail in Section 7.7 or the Laboratory Manual.  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.     


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The following assessments will be conducted predose on the first day of dosing unless 
performed within the preceding 3 days or unless noted otherwise below.  Dosing should be 
delayed if the eligibility criteria are no longer met:  
• 
Optional tumor biopsy for exploratory PD assays, if not done during screening (See 
Section 8.2.4) 
• 
AEs and concomitant medications.  AEs must be monitored and recorded in the 
eCRF from the first dose of SRA737 administration.  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, WHO performance status, temperature, pulse rate, seated BP.  
• 
Laboratory tests (blood/urine/tissue samples):   
o Hematology:  CBC with differential count 
o Biochemistry:  Sodium, potassium, chloride, magnesium, adjusted calcium, 
phosphate, urea, creatinine, total protein, albumin, direct and indirect 
bilirubin, LDH, alkaline phosphatase, alanine aminotransferase and/ or 
aspartate aminotransferase, non-fasting glucose 
o Urinalysis:  glucose, protein and blood 
o Pregnancy testing (WOCBP only):  serum or urine test is acceptable.  More 
frequent pregnancy tests may be conducted if required per local regulations. 
o Troponin:  Troponin T or I (subject should be followed for the same 
parameter) 
o Serum tumor markers (as clinically relevant, eg, CA-125 for ovarian cancer, 
PSA for prostate cancer, CEA for colorectal cancer, CA19-9 for pancreatic 
cancer, AFP for liver and other cancers, and others as clinically indicated. 
o CTCs for mCRPC subjects only. 
o PK time points:  Predose, 1, 2, 4, 6, 8, 12, 24, and 48 hours after the first 
dose. For subjects in the Expansion Cohorts, the 12-hour time point may be 
omitted with sponsor’s approval.   
o ctDNA for exploratory analyses (in a subset of up to 33 subjects). 


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o Blood sample should be collected and submitted for additional exploratory 
analyses (such as mutational burden). 
• 
ECG (replicates, centrally-read):    
o ECGs will be performed at the intervals noted in Section 7.7) until the 
Sponsor has sufficient data to adequately explore the association of SRA737 
exposure and QTc prolongation.   
o ECGs will be performed as a 5-minute continuous read in accordance with 
directions from sponsor or designee.  At time points at which ECG and blood 
draws are required, the ECG will be performed first.  The ECG must be 
transmitted electronically to a central laboratory and is to be centrally 
reviewed by an independent reviewer. 
 
If the Day -7 to Day -4 visit is eliminated, the following assessments and sample collections 
should be done pre-dose on Cycle 1 Day 1: 
• 
Optional tumor biopsy for exploratory PD assays (See Section 8.2.4) 
• 
Pregnancy testing (WOCBP only):  serum or urine test is acceptable.  More frequent 
pregnancy tests may be conducted if required per local regulations. 
• 
Serum tumor markers (as clinically relevant, eg, CA-125 for ovarian cancer, PSA for 
prostate cancer, CEA for colorectal cancer, CA19-9 for pancreatic cancer, AFP for 
liver and other cancers, and others as clinically indicated. 
• 
CTCs for mCRPC subjects only. 
• 
ctDNA for exploratory analyses (in a subset of up to 33 subjects). 
• 
Blood sample should be collected and submitted for additional exploratory analyses 
(such as mutational burden). 
• 
Height and weight. 
7.2.2 
STANDARD EVALUATIONS FOR EACH CYCLE 
The standard evaluations and sample collections for each cycle are listed below: 
• 
AEs and concomitant medications (detailed in Section 7.2.1): all visits 
• 
Symptom directed physical examination, if clinically indicated:  Day 1 of each cycle: 
predose 
• 
WHO performance status: Day 1 of each cycle: predose  
• 
Temperature, seated BP and pulse rate:  Days 1, 8, 15, and 22 of Cycle 1, and 
Day 1 of each cycle thereafter 


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• 
ECG (locally-read):  Cycles 1, 2, and then every third subsequent cycle, Day 1 
predose.  
• 
ECG (replicates, centrally-read) –Cycle 1 Day 22 only: predose, 1, 2, 4, 6, and 24 
hours postdose. Note: Centrally-read ECGs will be performed at the intervals noted 
above in addition to locally-read ECGs until the sponsor has sufficient data to 
adequately explore the association of SRA737 exposure and QTc prolongation.  If 
the Sponsor stops collection of centrally-read ECGs, locally-read ECGs will continue 
to be performed.    
• 
ECHO:  Cycle 2, Day 1 only.  All subsequent cardiac monitoring should be done at 
the investigator’s discretion.   
• 
Laboratory tests (blood/urine samples):   
Blood draws for laboratory tests will be performed predose.  At time points at which 
both blood draws and ECGs are required, ECGs should be done first. Samples 
should be collected on the days indicated below, unless an acceptable window for 
sample collection is stated e.g. within 72 hours prior to the first dose of each cycle for 
hematology, biochemistry, and troponin. Subjects must be instructed not to take 
SRA737 before attending the clinic on those days they will attend for routine blood 
samples. SRA737 should only be taken once all clinic assessments have been 
completed:   
o Hematology (CBC with differential count):  Hematology assessments should 
be repeated weekly for the cycle following an intra-subject dose escalation, 
where applicable. 
– 
Cycle 1 to Cycle 3:  Days 1 (up to 72 hours predose), 8, 15, and 22   
– 
Cycle 4 onwards:  Days 1 (up to 72 hours predose) and 15 
o Biochemistry (detailed in Section 7.1.2):   
– 
Cycle 1 and 2:  Days 1 (up to 72 hours predose), 8, 15, and 22   
– 
Cycle 3 to Cycle 6:  Days 1 (up to 72 hours predose) and 15 
– 
Cycle 7 onwards:  Day 1 (up to 72 hours predose) 
o Troponin T or Troponin I (subject should be followed for the same 
parameter):  
– 
Cycle 1: Day 1 (up to 72 hours pre-dose), and Day 8 
– 
Cycle 2: Day 1 (up to 72 hours pre-dose) 
– 
Cycle 6: Day 1 (up to 72 hours pre-dose) 
o Urinalysis including glucose, protein and blood:  Day 1 of each cycle (may be 
performed up to 72 hours prior to the first dose of each cycle) 


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o Blood sample for additional exploratory analyses (such as mutational 
burden):  Cycles 3 and 6, Day 1 predose 
o ctDNA for exploratory analyses (from a subset of up to 33 subjects):  Cycle 3, 
Day 1 predose  
o CTCs for mCRPC subjects only:  End of every 4 weeks ± 1 week   
o Serum tumor markers (if applicable, eg, CA-125 for ovarian cancer, PSA for 
prostate cancer, CEA for colorectal cancer, CA19-9 for pancreatic cancer, 
AFP for liver and other cancers, and others as clinically indicated): repeated 
every 4 weeks ± 1 week after Cycle 1 Day 1) 
o Intensive PK schedule: 
 
Intensive PK Assessments 
Continuous 
schedule 
• C1 Days 1, 8, and 15:  Predose 
• C1 Day 22:  Predose, 1, 2, 4, 6, 8, 12, and 24 hours postdose. For subjects 
in the Expansion Cohorts, the 12-hour time point may be omitted with 
Sponsor’s approval 
Subsequent cycles, Day 1:  Predose  
Alternate 
dosing 
schedules 
• C1 Day 1:  Predose 
• PK will also be collected on Cycle 1 Day 8 or at a day at the end of the first 
week’s dosing as determined by the Sponsor in consultation with the 
investigator.   
Time points:  Predose, 1, 2, 4, 6, 8, 12, and 24 hours postdose. For 
subjects in the Expansion Cohorts, the 12-hour time point may be omitted 
with Sponsor’s approval 
Subsequent cycles, Day 1:  Predose 
Note: The Sponsor may reduce or eliminate the requirement for PK sampling once sufficient 
data to evaluate the PK of SRA737 have been collected and analyzed. If this occurs, the 
modified requirements will be documented by an update to the Laboratory Manual. 
 
• 
Repeat of clinical assessments (if applicable) performed at baseline:  This must be 
repeated at the end of every 4 weeks (± 1 week) after Cycle 1 Day 1.  Refer to 
Section 9. 
• 
Repeat of radiological assessments performed at baseline: Radiological 
assessments must be repeated every 8 weeks (± 1 week) after Cycle 1 Day 1.  
Subjects with bone metastases being followed by bone scans will have scans every 
8 weeks (± 1 week) for the first 6 months and then every 16 weeks (± 2 weeks) 
thereafter. Assessment may be discontinued if PD was shown on a previous scan. 
Refer to Section 9. 
• 
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. 


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• 
If an optional tumor biopsy was taken at baseline for additional PDn analysis, a 
second biopsy should be collected 2 to 8 hours after dosing at one timepoint from 
Cycle 1 Day 15 through Cycle 1 Day 22 (See Section 8.2.4). 
 
SAFETY FOLLOW-UP (SFU) VISIT 
If a subject discontinues the IMP for any reason, a Safety Follow-up (SFU) visit should be 
completed.  Evaluations at the SFU visit should be performed 30 days ± 7 days after the last 
dose of SRA737.  If the subject begins a new anticancer treatment within 30 days of the last 
administration of the IMP, 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 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. 
• 
A symptom-directed physical examination including WHO performance status, 
temperature, pulse rate, seated BP and weight 
• 
Laboratory tests (blood/urine samples):   
o Hematology tests:  CBC with differential count detailed in Section 7.1.2 
o Biochemistry tests: detailed in Section 7.1.2 
o Troponin T or Troponin I: detailed in Section 7.1.2 
o Urinalysis: detailed in Section 7.1.2 
o Blood sample for additional exploratory analyses (such as mutational burden) 
o ctDNA for exploratory analyses (from a subset of up to 33 subjects) 
o CTCs for mCRPC subjects only unless PD was previously documented  
o Serum tumor marker (if applicable, eg, CA-125 for ovarian cancer, PSA for 
prostate cancer, CEA for colorectal cancer, CA19-9 for pancreatic cancer, 
AFP for liver and other cancers, and others as clinically indicated must be 
repeated) unless PD was previously documented 
o Urine or serum pregnancy test  
• 
ECG (locally-read) 
• 
ECHO  


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• 
Clinical (if applicable) and radiological assessment of disease, unless PD was 
indicated on a previous study scan or radiological disease assessments were 
conducted within the past 6 weeks.  
• 
Compliance: the subject’s most recent diary card must be collected and checked for 
completeness and compliance in taking SRA737.  
 
LONG-TERM FOLLOW-UP 
For subjects who 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.  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: 
• 
SAEs assessed by the investigator as related to SRA737 
• 
First subsequent cancer therapy (if applicable) 
• 
Laboratory tests (blood samples):   
o Serum tumor markers (if applicable), unless PD was previously documented 
o CTCs (for mCRPC subjects only), unless PD was previously documented 
• 
Clinical disease evaluations, unless PD was previously documented 
• 
Radiographic disease assessments, unless PD was previously documented 
• 
Disease and survival updates, where available 
 
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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SCHEDULE OF EVENTS 
Observation / Investigation 
Screening evaluations – 
to be within [x] days of 
first dose (as noted) 
First dose 
for 
Intensive 
PK 
Treatment phase 
(28-day cycle) 
Evaluations for each day 
Safety 
Follow-up 
Long-term Follow-
up 
N/A 28 days 
7 days 
Single 
day, 
Day -7 to 
Day -4 
1 
8 
15 
22 
30 days ± 7 
days after 
last dose of 
SRA737 
Every 16 weeks 
± 2 weeks 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
SAEs from informed consent.  AEs from first dose of SRA737.   
Continually review 
X (b) 
X(c) 
Concomitant treatments 
From date of informed consent.  Continually review 
X(c) 
Availability / Submission of tumor tissue and ctDNA 
for tumor profiling (d), and MSI status (e) 
X 
 
 
 
 
 
 
Determination of HPV status (HNSCC and SCCA) 
X 
 
 
 
 
 
 
Radiological disease assessment 
 
X (f) 
 
 
End of every 8 weeks  
(± 1 week) from C1D1 
X (f, m) 
X (f, m) 
Clinical disease assessment (if applicable) 
 
 
X 
 
End of every 4 weeks 
(± 1 week) from C1D1 
X (m) 
X (m) 
Disease and survival updates (where available) 
 
 
 
 
 
 
X 
Physical examination (g)  
 
 
Complete 
 
Symptom-directed, predose 
on D1 of each cycle - repeat 
as clinically indicated 
Symptom-dire
cted 
 
Temperature, seated BP, and pulse 
 
 
 
X (a) 
X 
C1 
C1 
C1 
X 
 
Height 
 
 
 
X (a, n) 
 
 
 
 
 
 
Weight 
 
 
 
X (a, n) 
 
 
 
 
X 
 
WHO performance status 
 
 
X 
X (a) 
X 
 
 
 
X 
 
ECHO (h)  
 
X 
 
 
C2 
 
 
 
X 
 


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Observation / Investigation 
Screening evaluations – 
to be within [x] days of 
first dose (as noted) 
First dose 
for 
Intensive 
PK 
Treatment phase 
(28-day cycle) 
Evaluations for each day 
Safety 
Follow-up 
Long-term Follow-
up 
N/A 28 days 
7 days 
Single 
day, 
Day -7 to 
Day -4 
1 
8 
15 
22 
30 days ± 7 
days after 
last dose of 
SRA737 
Every 16 weeks 
± 2 weeks 
ECG (i) 
 
X 
(Locally-
read) 
 
Refer to Section 7.7 for time points 
(local and central) 
X (Locally-
read) 
 
Pregnancy test (j) 
 
 
X 
X (a, n) 
 
 
 
 
X 
 
Serum tumor markers (if applicable, eg, CA-125, 
PSA, CEA, CA19-9, AFP, others as indicated) 
 
 
 
X (a, n) 
End of every 4 weeks 
(± 1 week) from C1D1 
X  
X (m) 
Samples for biochemistry  
 
 
X 
X (a) 
X (k) 
X (k) 
X (k) 
X (k) 
X 
 
Samples for hematology  
 
 
X 
X (a) 
X (l) 
X (l) 
X (l) 
X (l) 
X 
 
Troponin T or I 
 
 
 
X (a) 
C1 
C2 
C6 
C1 
 
 
X 
 
Urine sample for urinalysis 
 
 
 
X (a) 
X 
 
 
 
X 
 
Blood sample for CTCs (mCRPC subjects only) 
 
X 
 
X (a, n) 
End of every 4 weeks (± 1 
week) 
X 
X (m) 
Blood sample for ctDNA for exploratory analysis 
Refer to Section 7.7 for time points 
X 
 
Blood sample for Exploratory Analyses (Mutational 
Burden) 
Refer to Section 7.7 for time points 
X 
 
Tumor Tissue for Optional Exploratory PD 
Refer to Section 7.7 for time points 
 
 
Blood sample for PK  
 
 
 
Refer to Section 7.7 for time points 
 
 
SRA737 administration 
 
 
 
X (a) 
Continuous daily dosing or 
as specified in alternate 
dosing schedule 
 
 
SRA737 Diary Card 
 
 
 
 
Should be reviewed at each 
visit 
X 
 
 
 
 


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a. Assessments scheduled to occur for the first dose for PK (given on a single day between Day -7 to Day -4) will be conducted on the first day of dosing unless 
performed within 72 hours prior or noted otherwise for the specific assessment in Section 7.2.1.  Dosing should be delayed if eligibility criteria are no longer 
met.  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 SFU visit.  
Monthly follow-up will continue until the event resolves, returns to baseline, stabilizes, or the subject discontinues from study. 
c. Only new SAEs assessed by the investigator as related to SRA737 and first subsequent anticancer therapy will be collected. 
d. Availability of suitable archival tumor tissue or planned biopsy for fresh tumor tissue acquisition for tumor profiling must be confirmed.  When archival material 
was collected more than 18 months ago, the ability to collect fresh tumor tissue should be discussed with the sponsor.  Submission prior to or during 
Screening (the 28-day window does not apply) with confirmation of positive results is required to determine eligibility for Expansion Cohort subjects.  Archival 
tumor tissue should be requisitioned for submission by Cycle 1 Day 1 for Dose Escalation subjects. See Section 7.1.1 for more details.  
A blood sample for ctDNA tumor profiling will be obtained from all screened subjects within 28 days prior to the first dose. If prospective analysis is performed, 
results must be available prior to the first dose of SRA737. If retrospective analysis will be performed, results are not required to be available prior to the first 
dose of SRA737.  
e. For CRC subjects and other subjects as clinically relevant whose MSI status is unknown, determination of MSI status will be performed on archival tumor 
tissue or fresh tumor tissue submitted for tumor profiling during Screening.   
f. Screening assessment to be conducted within 35 days of Cycle 1 Day 1. Follow-up radiological assessments must be repeated at the end of every 8 weeks 
(± 1 week) after Cycle 1 Day 1. Subjects with bone metastases being followed by bone scans will have scans every 8 weeks (± 1 week) for the first 6 months 
and then every 16 weeks (± 2 weeks) thereafter. During Long-term Follow-up, assessments will be done every 16 weeks, unless requested more frequently by 
the sponsor or investigator. Assessment may be discontinued if PD was shown on a previous scan. 
g. Complete physical examination to be performed within 7 days of the first dose. Subsequent examinations on Day 1 of each cycle (and additionally as clinically 
indicated) may be symptom directed. 
h. ECHO will be done at Screening, Cycle 2 Day 1 (± 3 Days), and at the SFU visit.  All subsequent cardiac monitoring will be done at the investigator’s 
discretion. 
i. All subjects will have locally-read ECGs. Centrally-read ECGs will also be performed - see Section 7.7 for detailed time points. Centrally-read ECGs may be 
eliminated by the Sponsor once sufficient data have been collected and analyzed. If this occurs, the modified requirements will be documented by an update 
to the appropriate study documents.  
j. Pregnancy test: For women of childbearing potential.  More frequent pregnancy tests may be conducted if required per local regulations. 
k. Biochemistry should be performed on Days 1, 8, 15 and 22, during Cycles 1 and 2.  The frequency can be reduced to Days 1 and 15 from Cycle 3 onwards at 
the discretion of the investigator, and reduced again to once a month (predose on Day 1) from Cycle 7 onwards.  Laboratory tests can be performed up to 
72 hours prior to the first dose of each cycle (Day 1).  
l. Hematology should be performed on Days 1, 8, 15 and 22, during Cycles 1 to 3.  Hematology assessments will be repeated weekly for the cycle following an 
intra-subject dose escalation, where applicable. The frequency can be reduced to Days 1 and 15 from Cycle 4 onwards at the discretion of the investigator.  
Laboratory tests can be performed up to 72 hours prior to the first dose of each cycle.  
m. Disease assessments will be discontinued in the case of PD or if subsequent anti-cancer therapy is initiated. 
n. Assessment to be carried out on Cycle 1 Day 1 in the event the Day -7 to Day -4 visit is eliminated. 


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SCHEDULE OF SECONDARY AND EXPLORATORY ASSESSMENTS 
 
ctDNA for 
Exploratory 
Analyses 
(a) 
Intensive 
PK (c) 
Central 
ECG 
Local 
ECG 
Exploratory 
Analyses 
(Mutational 
Burden) 
Optional 
Exploratory 
PD (Tumor 
Tissue) 
Screening (-28 days of first dose) 
 
 
 
X 
 
Optimally 
within 7 days 
prior to first 
dose of 
SRA737. May 
also be done 
at Screening. 
Day -7 to Day -4  
(First dose for PK) 
(b) 
Predose 
X (f) 
X 
X  
 
X (f) 
1h ±15min 
 
X 
 
 
 
 
2h ±15min 
 
X 
X 
 
 
 
4h ±15min 
 
X 
 
 
 
 
6h ±15min 
 
X 
 
 
 
 
8h ±15min 
 
X (e) 
 
 
 
 
12h ±15min 
 
X (e) 
 
 
 
 
24h ±1h 
 
X 
 
 
 
 
48h ±1h 
 
X 
 
 
 
 
Cycle 1 Day 1 
Predose 
 
X 
 
X 
 
 
Cycle 1 Days 8, 15 
Predose 
 
X 
 
 
 
 
Cycle 1 Day 22 (c) 
Predose 
 
X 
X 
 
 
 
1h ±15min 
 
X 
X 
 
 
 
2h ±15min 
 
X 
X 
 
 
2 to 8h post-
dose at one 
timepoint from 
C1D15 
through 
C1D22 
4h ±15min 
 
X 
X 
 
 
6h ±15min 
 
X 
X 
 
 
8h ±15min 
 
X (e) 
 
 
 
12h ±15min 
 
X (e) 
 
 
 
 
24h ±1h 
 
X 
X 
 
 
 
Subsequent cycles 
Day 1 
Predose 
C3 
X  
 
X(d) 
C3, C6 
 
SFU Visit 
X 
 
 
X 
X 
 
Note:  Centrally-read ECGs will be performed at the intervals noted above in addition to locally-read ECGs until 
the Sponsor has sufficient data to adequately explore the association of SRA737 exposure and QTc 
prolongation.  If the Sponsor stops collection of centrally-read ECGs, locally-read ECGs will continue to be 
performed.  At time points at which both blood draws and ECGs are required, ECGs should be done first.   
Refer to the Laboratory Manual for further instructions on all assay sample collection, specific timings, handling 
and storage. 
a. 
Blood sample for exploratory ctDNA analysis will be collected for exploratory analyses for up to 33 
subjects, prior to the first dose of SRA737, Cycle 3 Day 1, and SFU visit.   
b. 
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. 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.  
c. 
The Sponsor may reduce the requirement for PK sampling once sufficient data to evaluate the PK of 
SRA737 have been collected and analyzed If this occurs, the modified requirements will be documented by 
an update to the Laboratory Manual.  For Alternative Dosing schedules, instead of Cycle 1 Day 22, 
additional PK and centrally-read ECG will be collected on Cycle 1 Day 8 or at a day at the end of the first 
week’s dosing as determined by the Sponsor in consultation with the investigator. 


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d. 
Locally-read ECGs will be performed at Screening; Cycle 1 Day 1, Cycle 2 Day 1, and then every third 
cycle Day 1; and at SFU. 
e. 
For subjects in the Expansion Cohorts, the 12 hour time point may be omitted with Sponsor’s approval.   
f. 
Assessment to be carried out on Cycle 1 Day 1 in the event the Day -7 to Day -4 visit is eliminated. 
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS  
 
PHARMACOKINETICS 
Approximately 2 mL of blood will be collected from all subjects at each time point.  For the 
intensive PK schedule, up to 9 time points taken over a 48-hour time period on Day -7 to 
Day -4; predose sampling at Cycle 1 Days 1, 8, and 15; up to 8 time points taken over a 
24 hour-time period at Cycle 1 Day 22; and all subsequent cycles at Day 1 will be collected.  
(See Section 7.2.2 for schedule for alternative dosing schedules). 
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. If this occurs, the modified requirements will be documented by an 
update to the Laboratory Manual. 
If one of these designated sampling times is missed a sample should be taken as soon as 
possible.  
Please refer to the Laboratory Manual for further instructions on all assay sample collection, 
specific timings, handling and storage. 
 
PHARMACODYNAMICS 
8.2.1 
TUMOR PROFILING 
To identify genetic alterations 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 DNA damage response and repair, 
archival or fresh tumor tissue and ctDNA for tumor profiling will be collected during 
Screening.  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. 


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8.2.2 
EXPLORATORY ANALYSES OF ctDNA 
To evaluate changes in biomarkers between baseline and end of treatment, blood will be 
obtained serially throughout the study (Day -7 to Day -4 dosing day, Cycle 3 Day 1, and 
SFU visit) for an exploratory ctDNA assay for up to 33 subjects.  Blood samples will be 
processed and analyzed at the Northern Institute for Clinical Research (NICR) laboratories.   
8.2.3 
ADDITIONAL EXPLORATORY ANALYSES  
Additional exploratory analyses may be performed.  Blood will be obtained serially 
throughout the study (Day -7 to Day -4 dosing day; Cycles 3 and 6, Day 1; and SFU visit) for 
assays which may include but not limited to the following:  immune profiling, markers of 
genetic instability including microsatellite instability, neoantigens, and mutational burden.   
8.2.4 
ADDITIONAL PHARMACODYNAMIC ASSAYS 
Optional tumor biopsies for additional pharmacodynamic analysis may be taken 2 to 8 hours 
after dosing at one timepoint from Cycle 1 Day 15 through Cycle 1 Day 22 (inclusive) if a 
biopsy was taken at baseline (within 7 days of the first dose).  
Where applicable, assays for inhibition of Chk1 and other PD markers associated with 
induction of replication stress and ATR/Chk1 signaling in tumor samples will follow agreed 
upon SOPs and validated methods. Markers to be evaluated include, but are not limited to: 
total Chk1 and evidence of DNA damage (pSer296Chk1, pSer317Chk1, pSer345Chk1, total 
H2A.X and gamma-H2A.X). 
Refer to the laboratory manual for specific details on sample collection, handling, storage, 
and shipping requirements.       
9 
ASSESSMENT OF EFFICACY 
 
MEASUREMENT OF DISEASE 
Disease must be measured according to the RECIST v1.1 criteria provided in Appendix 2 for 
subjects with solid tumors, according to the revised IWG criteria (Cheson 2007) for subjects 
with NHL, and for subjects with mCRPC, using a composite of any one of the following:  A) 
Measurable disease per RECIST v1.1; B) Increasing PSA; or C) CTC count of 5 or more 
cells per 7.5ml of blood. 


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TIMING AND TYPE OF TUMOR 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.  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.  The interval between the last anti-cancer therapy and these measurements 
should be at least 4 weeks when possible.  All clinical measurements and serum tumor 
markers that may be utilized to assess response must be performed within 1 week prior to 
the first dose of SRA737. 
The determination of CR and PR requires confirmation by a subsequent assessment at least 
4 weeks after the original determination.  Stable Disease (SD) determination requires that 
the relevant criteria be met at least once, a minimum of 6 weeks after study entry.   
Copies of any radiological assessments must be available for external independent review if 
requested by the Sponsor or Sponsor’s designee. 
9.2.1 
BASELINE EVALUATIONS 
Baseline evaluations must include radiological measurements of lesions appropriate to the 
nature of the malignancy.  This may include:  CT scan, liver CT scan, abdominal CT scan, 
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 dimensions 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, Assessment 
of disease response). 


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9.2.2 
EVALUATIONS DURING AND AFTER THE END OF TREATMENT 
Tumor assessments must be repeated every 8 weeks or more frequently, when clinically 
indicated.  Subjects with bone metastases being followed by bone scans will have scans 
every 8 weeks (± 1 week) for the first 6 months and then every 16 weeks (± 2 weeks) 
thereafter.  During Long-term Follow-up, assessments for subjects who have not yet 
progressed and who have not initiated alternative anti-cancer therapy will be done every 16 
weeks, unless requested more frequently by the sponsor or investigator. All lesions 
measured at baseline must be measured at every subsequent disease assessment, and 
recorded clearly on the scan reports.  All non-measurable lesions noted at baseline must be 
noted on the scan report as present or absent. All subjects, who are removed from the study 
treatment for reasons other than PD, should be re-evaluated at the time of treatment 
discontinuation, unless a tumor assessment was performed within the previous four weeks.  
Subjects will be followed for PD until disease progression 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 selected and recorded at baseline and 
comment on the non-target lesions in accordance with RECIST v 1.1 criteria or the revised 
IWG criteria, as applicable. 
 
TUMOR RESPONSE 
All subjects who have measurable disease, receive at least one cycle of SRA737 and have 
a baseline plus at least 1 post-baseline 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.  Stable Disease (SD) determination requires 
that the relevant criteria be met at least once, a minimum of 6 weeks after the initial dose of 
SRA737 is given.  
Should rapid tumor progression occur before the completion of 4 weeks of treatment 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.  


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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 
 
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.   
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). 


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• 
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. 
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional 
• 
AEs 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 study drug. 
10.1.2 
SERIOUS ADVERSE EVENTS 
An SAE is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death 
• 
is life-threatening* 
• 
requires in-patient hospitalization or prolongs existing in-patient hospitalization (some 
hospitalizations are exempt from SAE reporting – eg, hospital admissions planned 
prior to 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 


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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 SRA737 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 of SRA737 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 of SRA737. 
• 
Medication error (any unintentional error in the dispensing or administration of 
SRA737). 
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 relevant regulatory 
authorities relating to suspected unexpected serious adverse reactions consistent with 
relevant legislation or regulations, including the applicable US FDA Code of Federal 
Regulations (CFR), 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. 


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Highly probable 
• Starts within a time related to the IMP administration and 
• No obvious alternative medical explanation 
Probable 
• Starts within a time related to the IMP administration and 
• Cannot be reasonably explained by known characteristics of the 
subject’s clinical state 
Possible 
• Starts within a time related to the IMP administration and 
• A causal relationship between the IMP and the AE is at least a 
reasonable possibility 
Unlikely 
• 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 
• 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 PK 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. 
 
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.  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’s 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 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 
Safety Follow-up 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) all 
SAE and any AEs that have been assessed as related to the IMP.  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. 
 
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:  GlobalSAEInbox@chiltern.com  
Refer to your country-specific contact information in the 
Study Manual for the Sponsor Medical Monitor 
Email:  medicalmonitorSRA737-01@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 


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this to the Sponsor or Sponsor designee’s Pharmacovigilance Department on a new SAE 
report form.  
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, 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 
Ethics Committee/Institutional Review Board (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.   
 
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. 


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When possible, the NCI-CTCAE v4.03, definitions should be used to assess the severity of 
an AE. 
 
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. 
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:  GlobalSAEInbox@chiltern.com  
Refer to your country-specific contact information in the 
Study Manual for the Sponsor Medical Monitor 
Email:  medicalmonitorSRA737-01@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, Medicines and Healthcare Products Regulatory Agency) and the applicable RECs 
within the required timeframes (eg, 3 days of USM initiation in the UK). 
 
PREGNANCY REPORTING 
Female subjects who become pregnant during the trial or treatment period must have study 
treatment stopped immediately. 
The investigator must make every effort to try and ensure that a subject or a partner of a 
subject does not become pregnant during the trial and for 6 months after their final dose of 
SRA737.  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 


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information about appropriate medically approved contraception.  Two forms of medically 
approved contraception must be used as described in Appendix 4.  
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, 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 provides consent. 
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 patient safety. There will be no 
adjustment to significance levels for reviews of the accumulating data during the trial.  The 
planned reviews will occur at the following time points:  
• 
At the completion of patient follow-up for the last subject enrolled at the end of the 
dose escalation 
• 
At the completion of the expansion cohort for each indication 
The final analysis will be conducted after one of the following conditions is met: 


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• 
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.   
 
ANALYSIS POPULATIONS 
11.1.1 
SAFETY EVALUABLE POPULATON 
All enrolled subjects who receive at least 1 dose of SRA737 will be evaluable for safety. 
11.1.2 
RESPONSE EVALUABLE POPULATON 
All enrolled subjects who have measurable disease, receive at least 75% of 1 cycle of study 
medication, and have a baseline assessment of disease plus at least 1 post-baseline 
disease assessment will be evaluable for response.  All subjects who were enrolled into one 
of the 6 indication-specific expansion cohorts will be evaluable for response if they have 
measurable, prospectively-selected genetically-defined tumors as specified in Section 4, 
received at least 75% of 1 cycle of study medication, have a baseline assessment of 
disease and at least 1 post-baseline disease assessment.     
In addition, subjects who have measurable disease and receive at least 75% of 1 cycle of 
study but develop disease progression, intolerable toxicity, or death prior to the post-
baseline assessment will also be considered evaluable and will be classified as 
nonresponders. 
11.1.3 
PHARMACOKINETICS EVALUABLE POPULATON 
All subjects who receive at least 1 dose of SRA737 and provide 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 the full dose and does not vomit within 4-hours 
postdose. 
11.1.4 
PHARMACOKINETICS/CORRECTED QT INTERVAL EVALUABLE 
POPULATON 
All enrolled subjects who receive at least 1 dose of SRA737 and for whom adequate QTc 
and ECG data are available will be evaluable for PK/QTc analyses.   


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11.1.5 
PHARMACODYNAMICS EVALUABLE POPULATON 
All enrolled subjects who receive at least 1 dose of SRA737 who have evaluable data for 
each specific PDn assessment will be evaluable for PDn. 
 
STATISTICAL ANALYSES 
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 informed consent.  Safety variables will 
be summarized by descriptive statistics.  Laboratory variables will be described using the 
NCI-CTCAE v4.03.  The MTD for each schedule tested, if reached, and the RP2D and 
schedule will be described.  
Treatment-emergent AEs will be reported for each dose level and coded using a current 
version of the MedDRA thesaurus, presented as tables of incidence of AEs by body system 
and by worst 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.  
Efficacy endpoints will be evaluated using RECIST v1.1 criteria, or for subjects with NHL, 
the revised IWG criteria (Cheson 2007), or for subjects with mCRPC, a composite response 
rate defined as any one of the following (Scher 2016):  
• 
Best response based on RECIST v1.1 
• 
PSA decrease of ≥50% 


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• 
CTC count conversion   
Absolute values for PSA and CTCs will be recorded at baseline and response will be 
analyzed based on percentage of change.   
Descriptive analyses of the distribution of ORR, DCR, DOR, TTR, TTP, PFS per 
RECIST v1.1, the revised IWG criteria, or a composite of any one of the following:  
A) Response based on RECIST v1.1; B) PSA decrease of ≥ 50%; or C) CTC count 
conversion, as applicable, and OS will be prepared.  
The ORR will be summarized using binomial proportions and confidence intervals computed 
by the method of Wilson.  The examples below display the CI estimates for response within 
each indication-specific group of approximately 20 enrolled to an expansion cohort. i.e. at 
the 95% CI, 0 of 20 responses observed excludes an ORR of 16%.  
Numerator 
Denominator 
Proportion 
Lower 
Upper 
0 
20 
0 
0 
0.161 
1 
20 
0.05 
0.009 
0.236 
2 
20 
0.10 
0.028 
0.301 
3 
20 
0.15 
0.052 
0.360 
4 
20 
0.20 
0.081 
0.416 
5 
20 
0.25 
0.112 
0.469 
6 
20 
0.30 
0.145 
0.519 
7 
20 
0.35 
0.181 
0.567 
8 
20 
0.40 
0.219 
0.613 
9 
20 
0.45 
0.258 
0.658 
10 
20 
0.50 
0.299 
0.701 
11 
20 
0.55 
0.342 
0.742 
12 
20 
0.60 
0.387 
0.781 
13 
20 
0.65 
0.433 
0.819 
14 
20 
0.70 
0.481 
0.855 
15 
20 
0.75 
0.531 
0.888 
16 
20 
0.80 
0.584 
0.919 
17 
20 
0.85 
0.640 
0.948 
18 
20 
0.90 
0.699 
0.972 
19 
20 
0.95 
0.764 
0.991 
20 
20 
1 
0.839 
1 
The distribution of DOR, in the subset of subjects responding will be summarized using 
Tukey’s five number summary, including the minimum, mean, median, maximum and 


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standard deviation.  Time to response will be summarized using Tukeys’ five 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 next-generation sequencing (NGS) techniques, either retrospectively or 
prospectively, subjects enrolled into one of the indication-specific cohort expansions, and 
subjects defined by dose level to which they were enrolled.  Additional subgroups of interest 
may also be identified, and the ORR will be estimated, as described in the Statistical 
Analysis Plan.   
Duration of response is defined as the time from first evidence of PR or better to disease 
progression or death.  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. 
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 rules will be defined in the SAP.  The 
statistical analysis of OS and PFS will be prepared using the Kaplan Meier estimator, and 
variance estimated using the Greenwood Estimator.  
All other efficacy variables will be further defined in the statistical analysis plan.   
11.2.4 
PK/QTC 
Time-matched ECG measurements and PK samples will be collected after a single dose of 
SRA737 on Day -7 to Day -4 and during Cycle 1 (See Section 7.7 for the Schedule of 
Secondary and Exploratory Assessments).   
A concentration-effect model will evaluate the relationship between plasma concentrations 
and the mean change from Baseline in QTcF for all subjects in the PK/QTc study. 
Plasma concentrations of SRA737 will be determined using a validated bioanalytical method 
and summarized using descriptive statistics.  Pharmacokinetic parameters, including but not 
limited to Cmin, Cmax, Tmax, AUC, t½, total body clearance, and apparent volume of distribution, 
will be determined using non-compartmental method(s).  PK data generated from this study 


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may be used in conjunction with PK data from other clinical studies in future meta-analyses 
for population PK assessment.  These data will be reported separately. 
11.2.5 
PHARMACODYNAMICS 
11.2.5.1 
Tumor Profiling 
Archival and/or fresh tumor biopsy samples and blood samples for ctDNA tumor profiling will 
be obtained at Screening 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 relationship between the presence 
and type of genetic alteration and clinical outcome (response) will be explored. 
11.2.5.2 
Exploratory Analyses of ctDNA 
Blood will be collected from a subset of approximately 33 subjects for exploratory analyses 
of ctDNA for mutations relating to resistance to Chk1 inhibitor therapy.  Based on the timing 
and availability of the ctDNA results, a separate statistical analysis plan may be prepared for 
the analysis of resistance to Chk1 inhibitor therapy. 
11.2.5.3 
Additional Exploratory Analyses  
Blood obtained serially for the purposes of additional exploratory analyses may be analyzed 
for but not limited to the following:  immune profiling, markers of genetic instability including 
microsatellite instability, neoantigens, and mutational burden.   
11.2.5.4 
Additional Pharmacodynamic Assays 
For subjects who had optional tumor biopsies for additional pharmacodynamic analysis 
taken at baseline and 2 to 8 hours after dosing at one timepoint from Cycle 1 Day 15 
through Cycle 1 Day 22 (inclusive). Inhibition of Chk1 and other PD markers in tumor 
samples will be measured. Markers to be evaluated include but are not limited to: total 
Chk1, evidence of DNA damage (pSer296Chk1, pSer317Chk1, and Gamma-H2AX). 


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Based on the timing and availability of the PDn assay analyses, a separate statistical 
analysis plan may be prepared for these analyses. 
 
SAMPLE SIZE 
The study will enroll up to 170 subjects in total including an estimated 30–50 subjects during 
dose escalation and 6 indication-specific expansion cohorts each consisting of 
approximately 20 prospectively-selected genetically-defined subjects.  The sample size for 
dose escalation is based on assumptions of the likely MTD based on allometric scaling and 
will depend on the number of dose levels required to establish the MTD and RP2D.  The 
final number of subjects enrolled into the trial will depend on the number of dose levels, the 
number of subjects who participate in both the Dose Escalation and Cohort Expansion 
phases, and potentially alternative dose schedules explored. 
A sample size of 20 subjects enrolled in each indication-specific expansion cohort will permit 
confirmation that the 95% confidence intervals around an observed ORR in each cohort is 
± 16%.    
12 
STUDY ADMINISTRATION 
This trial is conducted under a clinical trial authorization, and approval from the MHRA and 
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 and its designee.  
Applicable regulatory requirements are described in this section. 
 
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, the site should contact 
the Sponsor or Sponsor’s designee to discuss this. 
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 must be 
received before the amendment can be implemented and incorporated into the protocol if 
necessary. 


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SERIOUS BREACH OF GOOD CLINICAL PRACTICE (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 MHRA within seven 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. 
 
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 safety information becomes available during the study, 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. 
• 
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. 


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• 
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 signed copy of the 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). 
 
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 regulation and guidelines 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. 
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. 


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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. 
 
END OF STUDY 
The ‘end of trial’ is defined as the date when the last subject has completed the Safety 
Follow-up visit or the long-term follow-up visit (whichever is later).   
It is the responsibility of the Sponsor to inform the relevant Health Authorities 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: 
• 
The drug is considered too toxic to continue treatment before the required number of 
subjects has 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. 
 
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. 


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During the trial a Clinical Research Associate (CRA) will be responsible for monitoring data 
quality in accordance with applicable 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 
• 
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 on-site 
audits. 
Principal Investigators conducting this trial accept the potential for inspection by the MHRA 
or other Regulatory Authorities. 
 
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 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.   


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Some source data may exist only electronically and be entered, or loaded directly into the 
eCRF. 
 
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 referenced in 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 Good Clinical Practice (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. 
 
ETHICAL CONSIDERATIONS 
Before starting the trial, the protocol and subject ICD must receive the favorable opinion of the 
assigned REC. 
It is the Principal Investigator’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. 
The Sponsor, Chief Investigator, and Principal Investigator must ensure that the trial is 
carried out in accordance with the GCP principles, all applicable local regulations, and the 
ICH GCP guidelines. 


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 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 (Eisenhauer 2009) or for any subject with NHL, using the revised 
International Working Group (IWG) criteria (Cheson 2007). 
Revised RECIST guideline (v 1.1) 
Note that this is an abridged version of the RECIST criteria.  Please refer to the Eisenhauer 
2009 article for detailed appendices and if in doubt. 
Measurability of tumor at baseline 
1.1. 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 
as follows: 
1.1.1. Measurable 
Tumor 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 caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers 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, 


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abdominal 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: 
• 
Tumor 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 calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 


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Method of assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging based 
evaluation should always be done rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and ≥10mm 
diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color 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 (eg, for body scans).  More 
details concerning the use of both CT and MRI for assessment of objective tumor 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 


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independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 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 utilization of these techniques for objective tumor evaluation is not advised.  However, 
they can be useful to confirm complete pathological response when biopsies are obtained or 
to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
Tumor markers:  
Tumor markers alone cannot be used to assess objective tumor response.  If markers are 
initially above the upper normal limit, however, they must normalize for a 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 tumor types such as germ cell tumors, where 
known residual benign tumors can remain).  When effusions are known to be a potential 
adverse effect of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met criteria for response or 
stable disease in order to differentiate between response (or stable disease) and 
progressive disease. 
2. Tumor response evaluation 
2.1 Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements.  


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Measurable disease is defined by the presence of at least one measurable lesion (as 
detailed above in Section 1).   
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 
(2009). 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor.  Pathological nodes which are defined 
as measurable and may be identified as target lesions must meet the criterion of a short axis 
of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a 
node is involved by solid tumor.  Nodal size is normally reported as 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, sagittal or coronal).  The smaller of these 
measures is the short axis.  For example, an abdominal node which is reported as being 
20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. 
In this example, 20 mm should be recorded as the node measurement.  All other 
pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered 
non-target lesions.  Nodes that have a short axis <10 mm are considered non-pathological 
and should not be recorded or followed. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the 
sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.  
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 (eg, 
‘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 


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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 <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 (eg, 
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 


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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. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor 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 tumor 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 


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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 tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’, an increase in lymphangitic disease from localized to widespread, or may be 
described in protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal 
progression’ is seen, the 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 tumor (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 


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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: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
• 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  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.   


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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 Prod. 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. 
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. 


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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 = not evaluable.  
 
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 = not evaluable.  
(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 


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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 ‘early progression, 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 to a biopsy in cases where a residual radiographic abnormality is 
thought to represent fibrosis or scarring.   
For equivocal findings of progression (eg, 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 randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of PD). 


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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 dyspnea (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 dyspnea (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 dyspnea (or fatigue, palpitation or anginal pain) 
Class IV  subjects with cardiac disease resulting in inability to carry out physical 
activity without discomfort; symptoms of dyspnea (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 PARTNERS OF WOCBP 
The risks of treatment with SRA737 during pregnancy have not been evaluated.  Please 
refer to the latest version of the Investigator’s Brochure 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 for at least 24 consecutive months (ie, has 
had menses at any time in the preceding 24 consecutive months). Of note, 
amenorrhea following cancer therapy does not rule out childbearing potential. 
Contraceptive Requirements for Females and Female Partners of Male Subjects 
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 after the last dose of SRA737.   
WOCBP partners of male subjects should use a reliable form of birth control from the date of 
the male partner’s 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* 


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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. 
*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. 
** Vasectomized 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 vasectomized 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 first administration of SRA737 throughout the trial and for 6 
months after administration of the last dose of SRA737.  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 administration of the last dose of SRA737. 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 after the first administration of 
study drug and for at least 6 months after the last dose. 
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. 


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Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are 
outlined in Section 10.6. 
 
 


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APPENDIX 5.  LIST OF QT PROLONGATION DRUGS AND DRUG METABOLIZED BY 
CYP1A2 
List of known QT 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 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Flecainide 
Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine 
Antiarrhythmic 
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 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Roxithromycin (Only 
on Non US Market) 
Rulide, Xthrocin, Roxl-150, Roxo, 
Surlid, Rulide, Biaxsig, Roxar, 
Roximycinv, Roxomycin, Rulid, 
Tirabicin, Coroxin 
Antibiotic 
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 


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Generic Name 
Brand Name (Partial List) 
riluzole 
Rilutek, Teglutik 
ropivacaine 
Naropin 
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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APPENDIX 6 GENETIC PREDICTORS OF SRA737 SENSITIVITY 
A combination of gene mutations documented or predicted to enhance sensitivity to Chk1 
inhibition/loss is required for enrollment into the Cohort Expansion Phase of this study. 
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. 
CCNE1 gene amplification (or alternative genetic alteration with similar functional effect) is required for the 
CCNE1 gene amplification-specific HGSOC cohort  
3. 
Loss of function mutations are desired for this gene 
Other genetic predictors can be added to this list, including 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 
MSI. 
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. 
 


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APPENDIX 7 PROSTATE CANCER CLINICAL TRIALS WORKING GROUP (PCWG) AND 
EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (ESMO) GUIDANCE  
 
 
 
Definition of increasing PSA per PCWG 2 and 3: 
 
For patients who manifest disease progression solely as a rising PSA 
level, a sequence of rising values at least 1 week apart with a minimum 
level of 2.0 ng/mL are required for trial entry. 
 
Reference: Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148–1159 
 
 
 
Definition of platinum refractory disease (in ovarian cancer) per ESMO guidance: 
 
The GCIG 4th Ovarian Cancer Consensus Meeting, defines: 
 
‘platinum-refractory’ as patients progressing during therapy or within 
4 weeks after the last dose; 
 
‘platinum-resistant’ patients progressing within 6 months of platinum-
based therapy. 
 
Reference: Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial 
ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals 
of Oncology. 2013;24(Suppl6):vi24–vi32 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
A PHASE 1/2 TRIAL OF SRA737 (A CHK1 INHIBITOR) ADMINISTERED ORALLY IN 
SUBJECTS WITH ADVANCED CANCER 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 
Protocol Version and 
Date: 
SRA737-01 
Version 8.0: 10JAN2018 
 
Name of Test Drug: 
SRA737 
Sponsor: 
Sierra Oncology, Inc. 
6701 Commerce Center Drive, Plymouth, MI 48170 
Analysis Plan Date: 
22JAN2021 
Analysis Plan Version: 
Version 1.0 
 
Version Number 
Summary of Changes 
Version Date 
1.0 
Original SAP 
22JAN2021 
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22 JAN 2021 
APPROVAL SIGNATURE PAGE, continued 
Protocol Title: 
A PHASE 1/2 TRIAL OF SRA737 (A CHK1 INHIBITOR) 
ADMINISTERED ORALLY IN SUBJECTS WITH 
ADVANCED CANCER 
Sponsor: 
Sierra Oncology, Inc 
Protocol Number: 
SRA737-01 
SAP Version / Date: 
Version 1.0 / 22JAN2021  
 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with the 
statistical methodology described in the protocol and the clinical development plan. 
 
 
Dr. Mark Kowalski, Chief Medical Officer  
 
Date 
 
Rafe Donahue, Senior Director, Biometrics 
 
Date 
 
Bill Donaldson, Vice President, Global Regulatory Affairs 
 
Date 
 
 
DocuSign Envelope ID: 3AFE754B-7CAB-4693-98E5-1702C33A804E
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08-Feb-2021 | 15:41 PST
02-Feb-2021 | 08:59 PST


 
Sierra Oncology, Inc. 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
OVERVIEW ...............................................................................................................10 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objective(s) ...............................................................................................10 
2.3. 
Exploratory Objective(s) ............................................................................................10 
3. 
STUDY METHODS ...................................................................................................11 
3.1. 
Overall Study Design and Plan ...................................................................................11 
3.2. 
Administration of Study Drug ....................................................................................11 
3.3. 
Study Procedures ........................................................................................................12 
4. 
STUDY ENDPOINTS ................................................................................................12 
4.1. 
Primary Endpoints ......................................................................................................12 
4.2. 
Secondary Endpoints ..................................................................................................13 
4.3. 
Exploratory Endpoints ................................................................................................13 
5. 
DATA CAPTURE AND PROCESSING ...................................................................13 
6. 
ANALYSIS AND REPORTING ...............................................................................13 
6.1. 
Interim Analysis ..........................................................................................................13 
6.2. 
Final Analysis .............................................................................................................14 
7. 
SAMPLE SIZE DETERMINATION .........................................................................14 
8. 
ANALYSIS POPULATIONS ....................................................................................14 
8.1. 
Safety Evaluable Population .......................................................................................14 
8.2. 
Response Evaluable Population ..................................................................................14 
8.3. 
Pharmacokinetics Evaluable Population.....................................................................15 
8.4. 
Pharmacokinetics/Corrected QT Interval Evaluable Population ................................15 
8.5. 
Pharmacodynamics Evaluable Population ..................................................................15 
9. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS ......................16 
9.1. 
General Principles for Data Analysis .........................................................................16 
9.1.1. 
Multicenter Study .......................................................................................................16 
9.1.2. 
Testing Strategy and Multiplicity Adjustments ..........................................................16 
9.1.3. 
Examination of Subgroups .........................................................................................16 
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9.2. 
General Data Handling Conventions ..........................................................................16 
9.2.1. 
Data Displays for Reporting .......................................................................................16 
9.2.2. 
Reporting Conventions ...............................................................................................18 
9.2.3. 
Early Withdrawal and Missing Data ...........................................................................18 
9.2.4. 
Analysis Visiting Windows ........................................................................................19 
9.3. 
Data Definition and Deviations ..................................................................................19 
9.3.1. 
Baseline and Change from Baseline ...........................................................................19 
9.3.2. 
Study Day and Duration .............................................................................................20 
10. 
SUBJECTS BASELINE CHARACTERISTICS, DEMOGRAPHICS AND 
MEDICATIONS .........................................................................................................20 
10.1. 
Subject Disposition and Withdrawals .........................................................................20 
10.2. 
Protocol Deviation ......................................................................................................20 
10.3. 
Demographics and Other Baseline Characteristics .....................................................21 
10.4. 
Medical History and Concomitant Diseases ...............................................................21 
10.5. 
Prior and Concomitant Medication .............................................................................22 
11. 
EFFICACY ANALYSIS ............................................................................................22 
11.1. 
Overall Response ........................................................................................................22 
11.1.1. 
Overall Response Rate ................................................................................................22 
11.1.2. 
Time to Response (TTR) ............................................................................................23 
11.1.3. 
Duration of Response (DOR) .....................................................................................24 
11.1.4. 
Duration of Stable Disease .........................................................................................24 
11.1.5. 
Change in Target Tumor Size .....................................................................................24 
11.1.6. 
Response Criteria for mCRPC Subjects .....................................................................24 
11.2. 
Time to Progression (TTP) .........................................................................................24 
11.3. 
Progression-free Survival (PFS) .................................................................................25 
11.4. 
Overall Survival (OS) .................................................................................................25 
12. 
SAFETY ANALYSIS ................................................................................................26 
12.1. 
Extent of Exposure and Compliance ..........................................................................26 
12.2. 
Adverse Events ...........................................................................................................26 
12.3. 
Laboratory Evaluations ...............................................................................................28 
12.4. 
Serum Tumor Markers ................................................................................................28 
12.5. 
Vital Signs ..................................................................................................................29 
12.6. 
ECG ............................................................................................................................29 
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12.7. 
Physical Examination .................................................................................................29 
12.8. 
Echocardiogram (ECHO) ...........................................................................................30 
13. 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL .......................30 
14. 
REFERENCES ...........................................................................................................30 
15. 
PROGRAMMING CONSIDERATIONS ..................................................................30 
15.1. 
General Considerations ...............................................................................................31 
15.2. 
Table, Listing, and Figure Format ..............................................................................31 
15.2.1. 
General ........................................................................................................................31 
15.2.2. 
Headers .......................................................................................................................31 
15.2.3. 
Footnotes.....................................................................................................................32 
15.2.4. 
Display Titles ..............................................................................................................32 
15.2.5. 
Column Headers .........................................................................................................32 
15.3. 
Body of the Data Display ...........................................................................................33 
15.3.1. 
General Conventions ..................................................................................................33 
15.3.2. 
Table Conventions ......................................................................................................33 
15.3.3. 
Listing Conventions ....................................................................................................34 
15.3.4. 
Figure Conventions .....................................................................................................34 
16. 
TABLE OF CONTENTS FOR DATA DISPLAY .....................................................35 
16.1. 
Output Tables ..............................................................................................................35 
16.2. 
Output Figures ............................................................................................................36 
16.3. 
Output Listings ...........................................................................................................37 
 
 
 
 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Data Display for Study Population and Efficacy ........................................................17 
Table 2: 
Data Display for Safety ..............................................................................................17 
Table 3: 
Confirmed Response per RECIST 1.1 ........................................................................22 
Table 4: 
Event and Censoring Rules for PFS ...........................................................................25 
Table 5: 
Analysis Visit Windowing Rules for Tumor Markers ................................................28 
Table 6: 
List of Output Tables ..................................................................................................35 
Table 7: 
List of Output Figures .................................................................................................36 
Table 8: 
List of Output Listings ................................................................................................37 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CI 
Confidence Interval 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CTC 
Circulating Tumor Cell 
ctDNA 
Circulating Tumor Deoxyribonucleic Acid 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
HGSOC 
High Grade Serous Ovarian Cancer 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
MTD 
Maximum Tolerated Dose 
NA 
Not Available 
NE 
Not Evaluable 
NGS 
Next Generation Sequencing 
NHL 
Non-Hodgkin Lymphoma 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
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Abbreviation 
Description 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PDn 
Pharmacodynamics 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
RP2D 
Recommended Phase 2 Dose 
SAP 
Statistical Analysis Plan 
SCCA 
Squamous Cell Carcinoma of the Anus 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
TEAE 
Treatment Emergent Adverse Events 
TLF 
Table, Listing, and Figure 
TTP 
Time to Progression 
TTR 
Time to Response 
WHO 
World Health Organization 
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1. 
OVERVIEW 
The purpose of the Statistical Analysis Plan (SAP) for this study is to provide a framework for 
statistically rigorous study data analysis in support of the protocol objectives, without bias or 
analytical deficiencies.   
Specifically, this Plan has the following purpose: 
To prospectively (a priori) outline the types of analyses and presentations of data that will form 
the basis for conclusions to be reached that will answer the study objectives outlined in the 
protocol and to explain in detail how the data will be handled and analyzed, adhering to 
commonly-accepted standards and practices of biostatistical analysis in the pharmaceutical 
industry. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
• To establish the safety profile of SRA737 
• To determine the maximum tolerated dose (MTD) with 1 or more schedules of 
administration of SRA737 
• To propose a recommended Phase 2 dose and schedule of SRA737 
• To evaluate the preliminary efficacy of SRA737 including efficacy in prospectively-
selected genetically-defined subjects enrolled into indication-specific expansion 
cohorts 
2.2. 
Secondary Objective(s) 
• To characterize the pharmacokinetic profile of SRA737 
• To assess the relationship between response and the presence of selected genetic 
alterations detected in tumor tissue and/or circulating tumor deoxyribonucleic acid 
(ctDNA) 
2.3. 
Exploratory Objective(s) 
• To investigate the pharmacodynamics (PDn) of SRA737 in tumor tissue 
• To investigate the pharmacodynamics of SRA737 in surrogate tissues such as blood 
or peripheral blood mononuclear cell (PBMCs) 
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• To explore possible clinical predictors of outcomes  
• To explore the relationship between exposure (Pharmacokinetics) and QT/QTc, other 
electrocardiogram (ECG) parameters and cardiovascular safety findings 
3. 
STUDY METHODS 
3.1. 
Overall Study Design and Plan  
This is a multicenter, first-in-human, Phase 1/2, open-label, dose-escalation trial in subjects with 
advanced solid tumors or non-Hodgkin lymphoma (NHL), with cohort-expansion phase in 6 
indication-specific expansion cohorts. The trial consists of 2 stages: 
Stage 1: Dose escalation phase 
Utilizing an accelerated titration design, cohorts consisting initially of a single subject will 
receive escalating doses of SRA737, starting in Cohort 1 with 20 mg/day administered orally on 
a continuous daily dosing schedule in 28-day cycles. The dose will be escalated in each 
subsequent cohort until the MTD has been identified, unless determined otherwise by the 
Sponsor in consultation with the Chief Investigator, for example, if an alternative schedule is 
pursued instead. Once a SRA737-related, Grade 2 toxicity is observed in a dose escalation cohort 
during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts 
will follow a rolling 6 design. 
Stage 2: Cohort expansion phase 
Subjects with the following tumor indications will be enrolled into the Cohort Expansion Phase 
to facilitate a preliminary exploration of the efficacy of SRA737::  
• Previously treated metastatic colorectal cancer (CRC) 
• High grade serous ovarian cancer (HGSOC); further designated as those without 
CCNE1 gene amplification and those with CCNE1 gene amplification (or alternative 
genetic alteration with similar functional effect) 
• Metastatic castration-resistant prostate cancer (mCRPC) 
• Advanced non-small cell lung cancer (NSCLC) 
• Head and neck squamous cell carcinoma (HNSCC) and squamous cell carcinoma of 
the anus (SCCA) 
3.2. 
Administration of Study Drug 
SRA737 will be administered orally on a continuous daily dosing schedule in 28-day cycles. 
Alternate dosing schedules may also be explored. Subjects may continue to receive treatment as 
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long as none of the treatment discontinuation criteria are met as defined in Section 5.6 of the 
protocol. 
3.3. 
Study Procedures  
Refer to protocol Section 7.6 and 7.7 for schedule of assessments. There are five distinctive 
phases in the study 
• Screening evaluations (After signing informed consent, and prior to first dose) 
• First dose for intensive PK (single day, Day -7 to Day -4) 
• Treatment phase (28-day cycles) 
• Safety follow-up (30 days after last dose of SRA737) 
• Long-term follow-up (every 16 weeks) 
4. 
STUDY ENDPOINTS 
Study endpoints corresponding to the study objectives are listed below. Secondary endpoints and 
exploratory endpoints will be summarized and analyzed in separate reports and analysis plan for 
those endpoints will not be included in this document. As a result, the analysis datasets and 
outputs corresponding to these endpoints will not be included within the scope of this SAP. 
4.1. 
Primary Endpoints 
• Safety parameters including adverse events (AEs), laboratory tests, and vital signs 
• MTD: the highest dose at which ≤ 33% of subjects have a dose limiting toxicity 
(DLT) in a cohort of up to 6 subjects 
• Recommended Phase 2 Dose (RP2D) 
• Objective response rate (ORR) 
• Disease control rate (DCR) 
• Time to response (TTR) 
• Duration of response (DOR) 
• Progression-free survival (PFS) 
• Time to progression (TTP) 
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• Overall survival (OS) 
If there are no subjects with response (complete or partial response), TTR and DOR related 
summaries and listings will not be generated. 
4.2. 
Secondary Endpoints 
• Plasma concentration-time profile and calculation of pharmacokinetic (PK) 
parameters including, but not limited to: AUCinf, AUCtau, Cmax, Cmin, Tmax, and t1/2 
• ORR and gene alterations in tumor tissue or ctDNA at baseline as measured by next 
generation sequencing (NGS) 
4.3. 
Exploratory Endpoints 
• 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 
• Proof of target engagement and changes in mechanism of action biomarkers between 
baseline and on treatment with SRA737, including but not limited to: pS317 Chk1, 
pS345 Chk1, total Chk1, gammaH2AX and RAD51 
• Characteristics such as performance status, prior therapy, indication and other known 
or potential prognostic or predictive factors 
• Association of QT, QTc, blood pressure (BP), heart rate, other ECG intervals with 
time-matched PK concentrations. Profile of QTc over the dosing interval 
5. 
DATA CAPTURE AND PROCESSING 
Clinical study data will be captured on electronic case report forms (eCRF) and maintained in a 
Medidata Rave clinical database.  The study data will be stored on the SAS server to facilitate 
further downstream activities. The study data will be mapped using study data tabulation model 
(SDTM). Data points used for summaries and analyses will be mapped from SDTM to analysis 
data model (ADaM).  
6. 
ANALYSIS AND REPORTING 
6.1. 
Interim Analysis 
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 
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adjustment to significance levels for reviews of the accumulating data during the trial. The 
planned reviews will occur at the following time points: 
• At the completion of subject follow-up for the last subject enrolled at the end of the 
dose escalation 
• At the completion of the expansion cohort for each indication.  
6.2. 
Final Analysis 
The final analysis will be conducted after one of the following conditions is met: 
• The trial is terminated early. 
• The end of trial, which is defined as the date when the last subject has completed the 
Safety Follow-up visit or the long-term follow-up visit (whichever is later). 
Additional analysis may be conducted for regulatory, publication, or decision making purposes.  
7. 
SAMPLE SIZE DETERMINATION 
The study will enroll up to 170 subjects in total including an estimated 30–50 subjects during 
dose escalation and 6 indication-specific expansion cohorts each consisting of approximately 20 
prospectively-selected genetically-defined subjects. The sample size for dose escalation is based 
on assumptions of the likely MTD based on allometric scaling and will depend on the number of 
dose levels required to establish the MTD and RP2D. The final number of subjects enrolled into 
the trial will depend on the number of dose levels, the number of subjects who participate in both 
the Dose Escalation and Cohort Expansion phases, and potentially alternative dose schedules 
explored. A planned sample size of 20 subjects enrolled in each indication-specific expansion 
cohort will permit confirmation that the 95% confidence intervals around an observed ORR in 
each cohort is ± 16%. 
8. 
ANALYSIS POPULATIONS 
8.1. 
Safety Evaluable Population 
Safety evaluable population includes all enrolled subjects who receive at least 1 dose of 
SRA737. Subjects who received the single dose for PK evaluation but never received study 
treatment during the treatment phase are also included in this population. 
8.2. 
Response Evaluable Population 
Response evaluable population includes all enrolled subjects who satisfy all of the following 
conditions. Two sets of criteria are defined for the 2nd condition and hence two response 
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evaluable populations will be defined: (a) is the original definition per protocol, used in 
statistical outputs (unless specified otherwise) and (b) is the alternative definition used in 
exploratory efficacy analysis as described in the CSR. To differentiate the two definitions in the 
outputs the population line in the TLFs will be “Response Evaluable Population” for definition 
(a) and “Response Evaluable Population (Alternative Definition)” for definition (b). 
1. Have measurable disease and assessment at baseline (for inclusion in expansion cohorts, 
subjects also need to meet the appropriate protocol criteria for genetically-defined tumor) 
2. Two sets of criteria are defined below (a or b) based on the dosing information 
a. Received at least 75% of 1 cycle of study medication, OR 
b. An alternative definition might be used for some exploratory efficacy analysis: 
Received at least 75% of cycle 1 study medication at ≥ 300 mg or continued on-study 
after 2 cycles of treatment at any dose level.  
3. Have at least one post-baseline disease assessment OR discontinued treatment due to 
adverse event or disease progression or death 
8.3. 
Pharmacokinetics Evaluable Population 
All subjects who receive at least 1 dose of SRA737 and provide at least 1 evaluable PK 
concentration will be included in the PK analysis. Plasma concentration data will be eligible for 
inclusion into PK analyses if the subject receives the full dose and does not vomit within 4-hours 
postdose. Because the endpoints using this population are not reported in the SAP this population 
will not be included in the ADaM datasets. 
8.4. 
Pharmacokinetics/Corrected QT Interval Evaluable Population 
All enrolled subjects who receive at least 1 dose of SRA737 and for whom adequate QTc and 
ECG data are available will be evaluable for PK/QTc analyses. Because the endpoints using this 
population are not reported in the SAP this population will not be included in the ADaM 
datasets. 
8.5. 
Pharmacodynamics Evaluable Population 
All enrolled subjects who receive at least 1 dose of SRA737 who have evaluable data for each 
specific PDn assessment will be evaluable for PDn. Because the endpoints using this population 
are not reported in the SAP this population will not be included in the ADaM datasets. 
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9. 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS 
9.1. 
General Principles for Data Analysis 
9.1.1. 
Multicenter Study 
The summaries and analyses will be conducted by pooling data from all study centers. If it is 
identified that a site has disproportionate number of protocol deviations additional summaries 
excluding the site in question might be carried out. 
9.1.2. 
Testing Strategy and Multiplicity Adjustments 
No formal multiplicity adjustment will be performed. All statistical results such as p-values and 
confidence interval (CI) are supportive in nature. 
9.1.3. 
Examination of Subgroups 
Efficacy analyses based on the subgroups defined by tumor type and genetic criteria may be 
carried out. Additional subgroups might be added if identified during the course of the trial. 
9.2. 
General Data Handling Conventions 
9.2.1. 
Data Displays for Reporting 
For tables and figures the data will be displayed as shown in the following tables. Any 
abbreviation used in the column text will be displayed in full description text in the footnote of 
the output. 
Unless specified otherwise all tables will have corresponding listings supporting the table 
summaries. The default ordering of the listings is by disease categories, site ID, subject ID, test 
or parameter name (if applicable), sequence number (AE, medical history, or medication), date 
of event or date of collection (if applicable). 
For study population and efficacy, the columns will be grouped by the primary tumor type 
regardless if a subject was enrolled under escalation or expansion stage. 
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Table 1: 
Data Display for Study Population and Efficacy 
Column Text 
Display 
Description 
Verbatim terms included in the grouping 
(including misspelling and specific terms present in the clinical data) 
Display 
Order 
CRC 
Metastatic Colorectal Cancer  
    Metastatic colorectal 
    Metastatic Colorectal Carcinoma With Abdomial* Mass 
    Colorectal Adenocarcinoma 
1 
HGSOC 
High Grade Serous Ovarian Cancer 
    Platinum resistant ovarian 
    Carcinosarcoma Of Ovary – CCNE1 Amplification: No 
    High grade serous ovarian cancer 
    Platinum-Resistant High Grade Papillary Serous Carcinoma Of The Ovary 
    Serous Adenocarcinoma Peritoneum/Ovary 
2 
NSCLC 
Advanced Non-small cell Lung Cancer 
    Advanced non small cell lung 
3 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
    Metastatic castration resistent* prostate 
    Prostate Adenocarcinoma 
    Adenocarcinoma of Prostate 
4 
HNSCC/SCCA 
 
Head and Neck Squamous Cell Carcinoma 
    Head and neck squamous cell 
5 
Squamous cell carcinoma of the anus 
Other 
Disease types not included in the previous columns 
6 
Overall 
All subjects in the population 
7 
* Misspelling are present in the clinical database and will be kept verbatim for programming purposes 
For safety summaries, the columns will be group based on Cycle 1 Day 1 total dose level. For 
subjects without Day 1 treatment they will be included in the “<=800mg” column. 
Table 2: 
Data Display for Safety  
Column Text 
Display 
Description 
Display 
Order 
<=800mg 
SRA737 daily total dose <= 800 mg 
1 
>800mg 
SRA737 daily total dose > 800 mg, including BID dosing frequency 
2 
Overall 
All subjects in the population 
3 
 
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9.2.2. 
Reporting Conventions 
The general programming considerations for tables, listings, and figures (TLFs) are provided in 
Section 15. Actual formats and layouts may be altered slightly to accommodate actual data or 
statistics. Minor format changes will not require updates to the SAP. The TLF numbering and 
general content follow the ICH E3 guidelines. 
In general, continuous variables will be summarized to include the population sample size (N), 
number of subjects with available data (n), arithmetic mean, standard deviation, median, 
minimum, Q1, Q3 and maximum values. Categorical variables will be summarized by the 
population size (N), number of subjects in each category, and the percentage of subjects in each 
category. A missing category will be added as the last category if appropriate.  
The data analyses will be conducted using the SAS® System (SAS Institute Inc., Cary, NC) 
version 9.4 or above. The eClinical Solutions’ standard operating procedures will be followed for 
the validation of all SAS programs and outputs. 
9.2.3. 
Early Withdrawal and Missing Data 
All subjects who withdrew early from the study will be included in the reporting if they meet the 
definition of the analysis population specified in Section 8, regardless whether they were 
replaced for the purpose of DLT assessment.  
In general, missing data will not be imputed and only observed values will be analyzed except 
for the data mentioned below. 
If the date of diagnosis on the cancer diagnosis CRF page is partially missing, it will be imputed 
using the following rules for the purpose of calculating “Time Since Initial Diagnosis” summary. 
• If only the day part is missing, day 15 will be used for imputation 
• If both day and month parts are missing, July 1st will be used for imputation 
If the relationship of an AE record is missing the AE will be considered “Related” to the study 
treatment for reporting purpose. If the Common Terminology Criteria for Adverse Events 
(CTCAE) grade of an AE is missing every effort should be made to acquire the information from 
the investigator. Grade 3 will be assigned to a missing grade for reporting purposes. 
In general, missing or partial dates will not be imputed except for AE or medication start and end 
date. 
The general imputation rules of partial missing date for both AE and concomitant medication are 
detailed below: 
For AE or medication start date 
If the year portion is missing no imputation will be performed. 
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If the day portion is missing, the following rules will be implemented:  
• Impute with first day of the month if the year and month of the start date is not equal to 
the year and month of the first study treatment (including PK dose) 
• Impute with date of first study treatment if the year and month of the start date is the 
same as the date of the first study treatment (including PK dose) 
If the month portion is missing, the following rules will be implemented:  
• Impute with first day of the year if the year of the start date is not equal to the year of the 
first study treatment (including PK dose) 
• Impute with date of first study treatment if the year of the start date is the same as the 
date of the first study treatment (including PK dose) 
For AE or medication end date 
If the year portion is missing no imputation will be done. 
If the day or month portion is missing: 
• Impute with the last day of the month (or of the year). If the imputed date is later than 
the date of death, the death date will be used to impute the end date. 
9.2.4. 
Analysis Visiting Windows 
No analysis visit window will be defined for safety data or efficacy data except for the tumor 
marker data. All post-baseline radiological disease assessments will be used for analyses 
purpose. Nominal clinical visits that are defined in the protocol “Schedule of Event” will be used 
for summary of safety endpoints. Any unscheduled safety data will not be included in the by-
visit summary and will be included in the listings.  
9.3. 
Data Definition and Deviations 
9.3.1. 
Baseline and Change from Baseline 
In general, the last recorded value prior to the first study treatment will serve as the baseline 
measurement for the safety endpoints such as lab, vital signs, and electrocardiograms (ECGs). 
The first treatment could be the first dose for PK collection or, if PK dose is not implemented, 
the first dose during the treatment phase. If there are multiple results collected on the same day, 
the collection done at later time, with the repeat status, or with a later sequence number will be 
used.  
Change from baseline will be calculated as the post baseline value minus the baseline value. 
Percentage change from baseline will be calculated as the change from baseline divided by the 
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baseline value, multiplied by 100. If either the baseline or post-baseline value is missing, then 
change from baseline and percentage change from baseline will be set to missing. 
9.3.2. 
Study Day and Duration 
Study day is relative to the start date of the first treatment of the treatment phase. As stated above 
subjects may have the first dose for intensive PK purpose prior to the first treatment of the 
treatment phase. In such cases the study day will not align with the very first dose subjects 
received. It is set up this way to be consistent with the protocol “Day” definition and to avoid 
confusion in the listings when the study day is used. There is no study Day 0 defined.  
• For an assessment that occurred on or after the study treatment:   
Study day = Date of assessment – date of first study treatment in treatment phase + 1 
• For an assessment that occurred prior to the study treatment:   
Study day = Date of assessment – date of first study treatment in treatment phase 
A duration between any two dates (such as AE duration) expressed in days will be calculated 
using the following conventions: Duration = later date – earlier date + 1. 
10. 
SUBJECTS BASELINE CHARACTERISTICS, DEMOGRAPHICS 
AND MEDICATIONS 
10.1. 
Subject Disposition and Withdrawals 
Subject disposition will be summarized for all screened subjects. The summary for the screened 
population will include number of subjects who received at least one study treatment and who 
were screen failures.  
Disposition summary will be based on the safety evaluable population. The following categories 
will be presented: treatment discontinuation and reasons, study discontinuation and reasons. 
Number of subjects received Cycle 1 day 1 dose, included, and not included in the response 
evaluable population (both definitions) and reason for exclusion will be summarized.  
10.2. 
Protocol Deviation 
Protocol deviations were collected in the protocol deviation log. Major protocol deviations will 
be summarized by site and by deviation categories. All deviations, both major and minor, will be 
listed. Major protocol deviations are those in the deviation log that had a level classified as 
“Level 2”. All the other deviations will be classified as minor protocol deviations. 
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10.3. 
Demographics and Other Baseline Characteristics  
All demographic and baseline characteristic data will be summarized using descriptive statistics 
for safety evaluable population.  
The summary table for demographics and baseline characteristics will include the following 
information: 
• Age (years), age category (<65, ≥65 years)  
• Sex (male, female)  
• Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
• Race (eCRF collected race. If more than one race was checked it will be reported as 
“Other”)  
• Weight (kg) and height (cm) collected at baseline 
• World Health Organization (WHO) performance status at baseline 
Baseline cancer characteristics will include the following: 
• Time since initial cancer diagnosis (months)  
• Stage at screening  
Prior cancer treatment includes prior anti-cancer therapy, prior radiotherapy, and prior surgical 
procedures. If there are more than one prior anti-cancer therapy collected for a subject, the last 
one (based on regimen start date) will be summarized including the following:  
• Received prior anti-cancer therapy 
• Line of Therapy (1, 2, 3, 4, 5, 6+) 
• Reason for discontinuation of anti-cancer therapy (CRF terms) 
• Prior radiotherapy (yes, no) 
• Prior surgical procedures (yes, no) 
10.4. 
Medical History and Concomitant Diseases  
Medical history was not coded. Details of each medical history will be listed for the safety 
evaluable population.  
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10.5. 
Prior and Concomitant Medication 
Prior and concomitant medications will be summarized for the safety evaluable population. 
Medications will be coded using the World Health Organization (WHO) Drug B2-Sept 2016 
version. These medications will be further classified as follows.  
• Prior medication is defined as those medications that started prior to the study treatment 
(collected within 28 days prior to the first dose). If medications started prior to the study 
treatment and were ongoing after the study treatment, they will be considered as both 
prior and concomitant medications.  
• Concomitant medication is defined as those taken on or after the study treatment. If 
medications started prior to the study treatment and were ongoing after the study 
treatment, those medication will be considered as concomitant medication as well.  
If a medication’s start date is completely missing, it will be counted in both prior and 
concomitant summaries. The number and percentage of subjects taking prior and concomitant 
medications will be summarized by Anatomical Therapeutical Chemical (ATC) Levels 2 and 
preferred terms (standardized drug name) by descending frequency based on all the subjects in 
the population. 
11. 
EFFICACY ANALYSIS 
Unless specified otherwise all efficacy analyses will be based on the response evaluable 
population. An alternative definition of response evaluable population is defined in Section 8.2 
and additional efficacy summaries may be repeated using the alternative definition if the 
differences are deemed clinically meaningful. 
11.1. 
Overall Response 
11.1.1. 
Overall Response Rate 
Overall response rate will be assessed by the investigator per RECIST criteria version 1.1. Partial 
or complete response should be confirmed by a repeat tumor imaging assessment not less than 4 
weeks from the date the response was first documented. The confirmed responses will be derived 
based on the overall responses by timepoint using the logics below: 
Table 3: 
Confirmed Response per RECIST 1.1 
Initial 
Response 
Subsequent Timepoint 
Confirmed Response 
Complete 
Response (CR) 
CR at least 4 weeks after initial CR (or consecutive 
CRs with at most one NE in between with the last CR 
at least 4 weeks after initial CR) 
CR 
CR less than 4 weeks 
SD 
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Initial 
Response 
Subsequent Timepoint 
Confirmed Response 
PD or  
Not Evaluable (NE) or no subsequent assessment 
SD if CR is at least 6 weeks 
from Cycle 1 Day 1, 
otherwise PD or NE  
Partial 
Response (PR) 
PR/CR at least 4 weeks after initial PR (or consecutive 
PRs/CRs with NEs in between with the last PR/CR at 
least 4 weeks after initial PR) 
PR 
PR/CR less than 4 weeks, or SD 
SD 
PD or  
NE or no subsequent assessment 
SD if PR is at least 6 weeks 
from Cycle 1 Day 1, 
otherwise PD or NE  
Stable Disease 
(SD) 
PD or  
NE, SD, or no subsequent assessment 
SD if SD is at least 6 weeks 
from Cycle 1 Day 1, 
otherwise PD or NE 
Progressive 
Disease (PD) 
Any assessment or no subsequent assessment 
PD 
The best overall confirmed response will be the best confirmed response from the above 
following the order of CR > PR > SD > PD > NE 
The best overall response will be summarized for the following endpoints with count and 
percentage: 
• CR 
• PR 
• SD 
• PD 
• NE 
• ORR (CR + PR) with 95% CI (Wilson method [1]) 
• DCR (CR + PR + SD) with 95% CI (Wilson method) 
11.1.2. 
Time to Response (TTR) 
Time to response is define as time from Cycle 1 Day 1 to the date of first best overall confirmed 
response of CR or PR and will be summarized as a continuous outcome. Subjects without CR or 
PR as the best confirmed response are not included in the TTR summary. Summary of TTR may 
not be generated if there are not enough subjects with responses to create meaningful summaries. 
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11.1.3. 
Duration of Response (DOR) 
Duration of response is defined as time from the first best overall confirmed response of CR or 
PR to the date of disease progression or death. If a subject did not experience the event, DOR 
will be censored. The event and censoring rules for DOR will be the same as the rules for PFS 
(Section 11.3). DOR will be analyzed using the Kaplan-Meier method. The output will include 
count and percentage of subjects with events or censored outcome including the type of event 
and censoring. Median DOR and 95% CI based on log-log transformation will be provided. 
Landmark analyses of DOR at various timepoints may be carried out if of clinical interest. 
Kaplan-Meier plot supporting the table summary may also be generated. 
Subjects without CR or PR as the best confirmed response are not included in the DOR analyses. 
Summary of DOR may not be generated if there are not enough subjects with responses to create 
meaningful summaries. 
11.1.4. 
Duration of Stable Disease 
Duration of stable disease is defined as time from Cycle 1 Day 1 to the date of disease 
progression or death. If a subject did not experience the event, duration of stable disease will be 
censored. The event and censoring rules for duration of stable disease will be the same as the 
rules for PFS (Section 11.3). Duration of stable disease will only be presented in the listing that 
supports the exploratory efficacy analyses. 
Duration of disease is only defined for subjects with any CR, PR, or SD prior to the first PD or 
subjects who did not experience PD. 
11.1.5. 
Change in Target Tumor Size 
At each timepoint of imaging assessment the sum of the longest diameter of all the target lesions 
are derived. The change and percentage change from baseline to the post-baseline nadir will be 
summarized. A waterfall plot of best percent change from baseline (from baseline to nadir) by 
tumor type cohorts will be provided. 
11.1.6. 
Response Criteria for mCRPC Subjects 
In addition to the RECIST criteria, response for subjects with mCRPC will also be evaluated by 
prostate specific antigen (PSA) and Circulating Tumor Cell (CTC). The PSA and CTC data will 
be presented in listings for mCRPC subjects to facilitate the review of the responses. 
11.2. 
Time to Progression (TTP) 
Time to progression is defined as time from the Cycle 1 Day 1 to the earliest date of radiographic 
disease progression per RECIST 1.1. If a subject did not experience progressive disease, TTP is 
censored at the last imaging assessment. TTP will be analyzed using the Kaplan-Meier method. 
The output will include count and percentage of subjects with events or censored outcome 
including the type of event and censoring. Median TTP and 95% CI based on log-log 
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transformation will be provided. Landmark analyses at various timepoints may be carried out if 
of clinical interest. Kaplan-Meier plot supporting the table summary may also be generated. 
In addition to TTP by RECIST 1.1 criteria based only on the radiographic assessments, a second 
definition of TTP which incorporates the clinical progression will be used. The clinical 
progression is based on the medical review of the reasons of treatment discontinuation or study 
continuation. If a subject is considered having clinical progression the date of treatment or study 
discontinuation will be used as date of clinical progression and the TTP is defined as time from 
Cycle 1 Day 1 to the earliest date of clinical or radiographic disease progression.     
11.3. 
Progression-free Survival (PFS) 
Progression-free survival is defined as time from Cycle 1 Day 1 to the earliest date of 
radiographic disease progression per RECIST 1.1 or death, whichever happens first. The detailed 
event and censoring rules are shown in the table below following the hierarchical order of the 
logic: 
Table 4: 
Event and Censoring Rules for PFS 
Situation 
Date of Progression or Censoring 
Outcome 
Death or progression after more 
than 1 missed imaging visit 
Date of last adequate assessment 
before missed visits 
Censored 
Death or progression without 
more than 1 missed visit 
Earliest date of death or progression 
Event 
No Death or progression 
Date of last imaging assessment 
Censored 
No post-baseline assessment 
Date of Cycle 1 Day 1 
Censored 
PFS will be analyzed using the Kaplan-Meier method. The output will include count and 
percentage of subjects with events or censored outcome including the type of event and 
censoring. Median PFS and 95% CI based on log-log transformation will be provided. Landmark 
analyses at various timepoints may be carried out if of clinical interest. Kaplan-Meier plot 
supporting the table summary may also be generated. 
11.4. 
Overall Survival (OS) 
Overall survival is defined as time from the Cycle 1 Day 1 to the date of death. If a subject 
doesn’t have a recorded death in the database, OS will be censored at the date at which the 
subject is last known to be alive. The last known alive date is based on searching the last date 
from the following CRF forms: 
• Treatment start and end date from the continuous dosing page 
• Treatment start date from the first dose page 
• Date of off-treatment 
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• Date of follow-up or date of death from the follow-up page 
• Date of visits 
OS will be analyzed using the Kaplan-Meier method. The output will include count and 
percentage of subjects with death or censored outcome. Median OS and 95% CI based on log-log 
transformation will be provided. Landmark analyses at various timepoints may be carried out if 
of clinical interest. Kaplan-Meier plot supporting the table summary may also be generated. 
12. 
SAFETY ANALYSIS 
All safety analyses will be based on the safety evaluable population. 
12.1. 
Extent of Exposure and Compliance 
Duration of treatment is defined as from the date of first dose in the treatment phase to the date 
of last dose taken from the SEA737 drug administration CRF page. If a subject only received the 
first dose for PK, the duration of treatment will be set to 1 day. In addition to the numeric 
summary of duration of treatment, the count and percentage of the following intervals will be 
presented: 
• >= 4 weeks 
• >= 8 weeks 
• >= 12 weeks 
• >= 16 weeks 
• >= 20 weeks 
Cycle 1 compliance is used as part of the definition of the response evaluable population and will 
be summarized as numeric result and categorical result (≥ 75% and < 75%). Cycle 1 compliance 
is from the SRA737 drug administration form for both QD and BID frequencies. For subject 
without compliance information on the CRF, the compliance will be calculated as follows: 
Compliance = (Cycle 1 last dose date - first dose date + 1 - days when dose was not given) / 28 
*100% 
12.2. 
Adverse Events 
Adverse events will be coded using MedDRA version 19.1. 
An AE will be considered a treatment emergent adverse event (TEAE) if it begins or worsens in 
severity after the first dose of study treatment (including the dose for PK purpose). Partial AE 
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start dates will be imputed as detailed in Section 9.2.3. If an AE start date is completely missing 
it will be considered a TEAE. 
Summary tables will be based on TEAEs. The incidence of TEAEs will be presented using 
counts and percentages of subjects with TEAEs and tabulated by SOC and PT. SOC will be 
sorted in descending frequency and PT within SOC will be sorted by descending frequency 
based on the incidence of all subjects in the population. If a subject has multiple occurrences 
(start and stop) of an event associated with a specific SOC or PT within a SOC, a subject will 
only be counted once in the incidence count for the SOC or PT within SOC respectively. 
An overall summary table of AEs will be presented detailing the number and percentage of 
subjects for the following categories. One additional overall summary of AEs by disease 
categories instead of Cycle 1 total dose with the same AE categories below will also be 
presented. 
• At least one TEAE; 
• At least one Treatment-Related TEAE; 
• At least one Grade ≥ 3 TEAE  
• At least one Grade ≥ 3 Treatment-Related TEAE; 
• At least one Serious TEAE; 
• At least one Serious Treatment-Related TEAE; 
• At least one Serious AE Occurred Prior to First Dose 
• At least one TEAE leading to Treatment Withdrawn; 
• At least one Treatment-Related TEAE leading to Treatment Withdrawn; 
Except for all TEAEs which will be summarized by SOC and PT, the incidence of all other 
TEAEs by PT will be presented for the following in descending frequency based on the 
incidence of all subjects in the population. 
• All TEAEs;  
• Treatment-related TEAEs;  
• TEAEs with Grade ≥ 3; 
• Treatment-related TEAEs with Grade ≥ 3; 
• Serious TEAEs; 
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• Treatment-related serious TEAEs; 
• Serious AEs Occurred Prior to First Dose 
• TEAEs leading to Treatment Withdrawn 
• Treatment-related TEAEs leading to Treatment Withdrawn 
A Treatment related AE is defined as an AE for which the investigator classifies the relationship 
to study treatment as being “Highly probable”, “Probable”, or “Possible” on Adverse Event 
eCRF. Missing relationship and toxicity grade will be imputed per Section 9.2.3. 
12.3. 
Laboratory Evaluations 
Biochemistry and hematology laboratory tests are scheduled to be collected before the first dose 
for PK, at Day 1, 8, 15, and 22 for each cycle (frequency could be reduced at later cycles), and at 
the safety follow-up (30 days after the last dose).  Troponin T or I are collected before the first 
dose for PK, Day 1 and Day 8 of Cycle 1 and Day 1 of Cycle 2 and Cycle 6, and at the safety 
follow-up. Urinalysis is collected before the first dose for PK, Day 1 of each cycle, and at the 
safety follow-up. 
All continuous laboratory parameters in biochemistry and hematology will be summarized 
descriptively by actual value at each scheduled visit and the corresponding changes from 
baseline. The maximum post-baseline and minimum post-baseline (including both scheduled and 
unscheduled results) will also be provided before the by-visit summary. All parameters will be 
summarized in SI units.  
Shift tables from baseline to visit will be provided for hematology and chemistry parameters to 
display low, normal, high, and missing values by treatment group in a 3-by-3 contingency table. 
Denominators for percentages will be the number of subjects with non-missing data at the 
specific assessment and baseline. 
Urinalysis results will only be provided in the listing. 
12.4. 
Serum Tumor Markers 
Serum tumor markers are scheduled to be collected before the first dose for PK and at the end of 
every 4 weeks (+/- 1 week) from Cycle 1 Day 1. Given there are no designated visit for tumor 
marker collection, the following windowing rules will be applied for summary purpose. 
Table 5: 
Analysis Visit Windowing Rules for Tumor Markers 
Analysis Visit Name 
Target Study Day 
Visit Windowing 
Baseline 
NA 
Last assessment prior to first dose 
End of Cycle 1 
28 
21 to 35 
End of Cycle 2 
56 
49 to 63 
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Analysis Visit Name 
Target Study Day 
Visit Windowing 
End of Cycle n 
28 * n 
(28 * n - 7) to (28 * n + 7) 
Once the analysis visit windowing rules are applied, the result closest to the target study day will 
be used for summary purpose. If multiple results have the same distance to the target study day 
the later one will be used. If both results fall on the same day, the one with the larger sequence 
number will be used. 
CEA, PSA, and CA-125 will be summarized descriptively by actual value at each analysis visit 
and change from baseline at each post-baseline visit. All other tumor markers will be listed only.   
12.5. 
Vital Signs 
Vital sign data including blood pressure, pulse rate, and body temperature are collected before 
the first dose for PK, Day 1, 8, 15, and 22 of Cycle 1, Day 1 of the subsequent cycles, and at the 
safety follow-up. 
For all parameters, actual values and change from baseline will be presented for scheduled visits 
using descriptive statistics for continuous variables.  
12.6. 
ECG 
Both central and local ECG data are collected in this study. Local ECGs are collected at 
screening, Cycle 1 Day 1, Cycle 2 Day 1, every third cycle Day 1, and at the safety follow-up. 
Central ECGs are collected at pre-dose and 2 hours after the first PK dose and at pre-dose, 1, 2, 
4, 6, and 24 hours after the Cycle 1 Day 22 dose.  
Both local and central ECGs include ventricular rate, QRS rate, QT interval, QTcF interval, PR 
interval, RR interval, and interpretation. Local ECG parameters will be presented using the 
actual values and change from baseline for each of the scheduled visits using descriptive 
statistics for continuous variables. If triplicates are collected for ECG parameters, the average 
value of the triplicates and the last interpretation will be used for reporting purpose.  
The Central ECGs will be analyzed with the PK data to explore the exposure-QTc relationship in 
a separate report and will not be covered in this SAP. 
12.7. 
Physical Examination 
A complete physical examination is performed and data is collected at Screening. Subsequent 
physical examination is only carried out as symptom directed. Since abnormal physical 
examination results are recorded as medical history or adverse events, no additional summaries 
or listings will be provided for physical examination.   
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12.8. 
Echocardiogram (ECHO) 
ECHO is collected at Screening, Cycle 2 Day 1, and at the safety follow-up. ECHO includes left 
ventricular ejection fraction and result interpretation.  ECHO results will be listed only. 
13. 
CHANGES FROM ANALYSES PLANNED IN THE PROTOCOL 
The following are the changes from the analyses planned in the protocol 
• Protocol section 3.6 defined 6 indication-specific cohorts in the expansion phase. The 
summaries based on the disease types will be adjusted based on the actual enrollment. 
Refer to Section 9.2.1 for the definition of each disease type. 
• Exploratory objectives and endpoints related to biomarkers in protocol Section 3.1.3 
and SAP Section 4.3 were not collected in the study.  
• In protocol Section 3.1.3 and SAP Section 4.3 one of the exploratory endpoints is 
“Association of QT, QTc, blood pressure, heart rate, other ECG intervals with time-
matched PK concentrations. Profile of QTc over the dosing interval”. A summary PK 
report and QTc report will be provided in the clinical study report, but separate 
analysis of the endpoints listed here will not be done. 
• In protocol Section 11 and SAP Section 6.1 timing of interim analyses are specified. 
These interim analyses will not be presented and justification will be provided in the 
clinical study report. 
• Alternative definition of response evaluable population was added in Section 8.2. 
14. 
REFERENCES 
[1] E. B. Wilson, “Probable Inference, the Law of Succession, and Statistical Inference,” J. Am. 
Stat. Assoc., vol. 22, no. 158, pp. 209–212, Jun. 1927, doi: 
10.1080/01621459.1927.10502953. 
 
15. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures, and statistical analyses will be generated using SAS® for 
Windows, Release 9.4 (SAS® Institute Inc., Cary, NC, USA).  Computer-generated table, listing 
and figure output will adhere to the following specifications.   
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15.1. 
General Considerations 
• One SAS program can create several outputs.  
• Each output will be stored in a separate file. 
• Output files will be delivered in rtf and pdf format. Tables, Listings and Figures will 
be combined in separate files. 
• Numbering of TFLs will follow ICH E3 guidance  
15.2. 
Table, Listing, and Figure Format 
15.2.1. 
General 
• All TLFs will be produced in landscape format, unless otherwise specified. 
• All TLFs will be produced using the Courier New font, size 9 
• The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, size 9. 
• Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• TLFs will be in black and white (no color), unless otherwise specified 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used. 
• Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they are 
appropriate to help display math symbols (e.g., μ). Certain subscripts and superscripts 
(e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
15.2.2. 
Headers 
• All output should have the following header at the top left of each page:  
− Sierra Oncology, Inc. SRA737-01  
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• All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• The date the output was generated should appear along with the program name as a 
footer on each page. 
15.2.3. 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• Footnotes should always begin with “Note:” if an informational footnote, or [1], [2], 
[3], etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• Subject specific footnotes should be avoided, where possible. 
• Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be used 
to display footnotes, and only those essential to comprehension of the data will be 
repeated on each page.  
• The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, and 
the listing source (i.e., ‘Cross-Reference: Listing 16.X.X.X, SAS Program: 
T_XXX.sas, Generated: DDMMMYYYYTHH:MM). 
15.2.4. 
Display Titles 
• Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be used 
to identify TLFs with related contents. The title is centered. The analysis population 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the table contents. 
• Column headers. There will be 1 blank line between the last title and the solid line. 
15.2.5. 
Column Headers 
• For numeric variables, include “unit” in column or row heading when appropriate. 
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• Analysis set sizes will be presented for each treatment group in the column heading as 
(N = xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
15.3. 
Body of the Data Display 
15.3.1. 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• Whole numbers (e.g., counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
• If there are no data to report for a particular display (ie no deaths or fatal AEs) then a 
table will be produced with the planned title and the phrase “no data to report” will be 
displayed in the body of the table. 
15.3.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum 
and minimum category should be presented in the table, even if n=0 for all treatment 
groups in a given category that is between the minimum and maximum level for that 
parameter. For example, the frequency distribution for toxicity grade of an adverse 
event. 
• Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 subject 
represented in 1 or more groups should be included. 
• An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• Unless otherwise specified, the estimated mean and median for a set of values should 
be printed out to 1 more significant digit than the original values, and standard 
deviations should be printed out to 2 more significant digits than the original values. 
The minimum and maximum should report the same significant digits as the original 
values.  
• P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 
decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
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value should be less than 0.0001 then present as <0.0001. If the p-value is returned as 
>0.999 then present as >0.999 
• Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, 
for all percentages, the number of subjects in the analysis population for the treatment 
group who have an observation will be the denominator. Percentages after zero 
counts should not be displayed and percentages equating to 100% should be presented 
as 100%, without any decimal places.  
15.3.3. 
Listing Conventions 
• Missing data should be represented on subject listings as either a hyphen (“-”) or as 
“N/A”, whichever is appropriate. 
• Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). 
Missing portions of dates should be represented on subject listings as dashes (--
JUL2000). Dates that are missing because they are not applicable for the subject are 
output as “N/A”, unless otherwise specified. 
• All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• Units will be included where available 
15.3.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits and/or time will be displayed 
on the X-axis and endpoint (e.g., change from baseline) values will be displayed on 
the Y-axis. 
• The same symbol and line type will be used for each treatment group across figures. 
 
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16. 
TABLE OF CONTENTS FOR DATA DISPLAY 
16.1. 
Output Tables 
Table 6: 
List of Output Tables 
Title 
Population 
 
Study Population  
14.1.1 
Subject Disposition  
Screened 
14.1.2 
Demographics and Baseline Characteristics  
Safety 
14.1.3.1 
Prior Medication  
Safety 
14.1.3.2 
Concomitant Medication  
Safety 
14.1.3.3 
Major Protocol Deviations 
Safety 
14.1.4 
Reasons for Exclusion from Analysis 
Safety 
Efficacy Endpoints  
 
14.2.1.1 
Best Overall Response per RECIST 1.1 
Response 
14.2.1.2 
Target Lesion Change from Baseline to Nadir 
Response 
14.2.2.1 
Time to Progression per RECIST 1.1 
Response 
14.2.2.2 
Time to Progression Incorporating Clinical Progression 
Response 
14.2.2.3 
Progression-free Survival per RECIST 1.1 
Response 
14.2.3.1 
Overall Survival 
Response 
Safety Endpoints 
Exposure 
14.3.1 
Extent of Exposure and Compliance 
Safety 
Adverse Events 
14.3.2.1.1 
Overall Summary of Subjects with Adverse Events 
Safety 
14.3.2.1.2 
Overall Summary of Subjects with Adverse Events by Disease Categories 
Safety 
14.3.2.2 
Summary of Subjects with Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety 
14.3.2.3 
Summary of Subjects with Treatment-Emergent Adverse Events by Preferred Term 
Safety 
14.3.2.4 
Summary of Subjects with Treatment-Related Treatment-Emergent Adverse Events 
by Preferred Term 
Safety 
14.3.2.5 
Summary of Subjects with Treatment-Emergent Adverse Events with Grade ≥ 3 by 
Preferred Term 
Safety 
14.3.2.6 
Summary of Subjects with Treatment-Related Treatment-Emergent Adverse Events 
with Grade ≥ 3 by Preferred Term 
Safety 
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Title 
Population 
 
14.3.2.7 
Summary of Subjects with Serious Treatment-Emergent Adverse Events by 
Preferred Term 
Safety 
14.3.2.8 
Summary of Subjects with Serious Treatment-Related Treatment-Emergent 
Adverse Events by Preferred Term 
Safety 
14.3.2.9 
Summary of Subjects with Serious Adverse Events Occurred Prior to First Dose by 
Preferred Term 
Safety 
14.3.2.10 
Summary of Subjects with Treatment-Emergent Adverse Events Leading to 
Treatment Withdrawn by Preferred Term 
Safety 
14.3.2.11 
Summary of Subjects with Treatment-Related Treatment-Emergent Adverse Events 
Leading to Treatment Withdrawn by Preferred Term 
Safety 
Laboratory data 
14.3.3.1 
Hematology Laboratory Parameters 
Safety 
14.3.3.2 
Shift Table of L/N/H Classification for Hematology Laboratory Parameters from 
Baseline  
Safety 
14.3.3.3 
Biochemistry Laboratory Parameters 
Safety 
14.3.3.4 
Shift Table of L/N/H Classification for Biochemistry Laboratory Parameters from 
Baseline  
Safety 
14.3.3.5 
Tumor Marker Parameters 
Safety 
Other Safety 
14.3.4 
Vital Sign Parameters 
Safety 
14.3.5 
Local Electrocardiograms Parameters 
Safety 
Note:  PK and QTc reports will be provided in the clinical study report. Separate analysis of these endpoints will 
not be done. 
16.2. 
Output Figures 
Table 7: 
List of Output Figures 
Title 
Population 
 
Efficacy Endpoints  
Response 
14.2.1.1 
Waterfall Plot of Target Lesion Best Change from Baseline  
Response 
14.2.1.2 
Kaplan Meier Plot of Time to Progression per RECIST 1.1 
Response 
14.2.1.3 
Kaplan Meier Plot of Time to Progression Incorporating Clinical Progression 
Response 
14.2.1.4 
Kaplan Meier Plot of Progression-free Survival per RECIST 1.1 
Response 
14.2.1.5 
Kaplan Meier Plot of Overall Survival 
Response 
 
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16.3. 
Output Listings 
Table 8: 
List of Output Listings 
Title 
Population 
 
Study Population 
 
16.2.1.1 
Listing of Subject Disposition  
Safety 
16.2.1.2 
Listing of Subject Demographics and Baseline Characteristics 
Safety 
16.2.1.3 
Listing of Medical History  
Safety 
16.2.1.4 
Listing of Prior and Concomitant Medications 
Safety 
16.2.1.5 
Listing of Prior Anti-cancer Therapies 
Safety 
16.2.1.6 
Listing of Protocol Deviations 
Safety 
16.2.1.7 
Listing of Analysis Populations 
Safety 
16.2.1.8 
Listing of Subject Disposition in Escalation Stage 
Safety 
16.2.1.9 
Listing of Genetic Alternation 
Safety 
 
Efficacy 
 
16.2.2.1 
Listing of Lesions Measurements and Responses by Timepoint 
Response 
16.2.2.2 
Listing of Time to Progression  
Response 
16.2.2.3 
Listing of Time to Progression Incorporating Clinical Progression 
Response 
16.2.2.4 
Listing of Progression-free Survival 
Response 
16.2.2.5 
Listing of Overall Survival 
Response 
16.2.2.6 
Listing of WHO Performance Status 
Response 
16.2.2.7 
Listing of Data for Exploratory Analysis 
Response 
16.2.2.8 
Listing of Prostate Specific Antigen 
Response 
16.2.2.9 
Listing of Circulating Tumor Cell 
Response 
 
Safety  
 
16.2.3.1 
Listing of Treatment Exposure and Compliance 
Safety 
16.2.3.2.1 
Listing of Adverse Events 
Safety 
16.2.3.2.2 
Listing of Serious Adverse Events 
Safety 
16.2.3.2.3 
Listing of Serious Adverse Events Occurred Prior to First Dose 
Safety 
16.2.3.2.4 
Listing of Treatment-Related Treatment Emergent Adverse Events Leading to 
Treatment Withdrawn 
Safety 
16.2.3.2.5 
Listing of Dose Limiting Toxicity Adverse Events  
Safety 
16.2.3.2.6 
Listing of Death 
All Subjects 
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Title 
Population 
16.2.3.3 
Listing of Hematology Laboratory Results 
Safety 
16.2.3.4 
Listing of Biochemistry Laboratory Results 
Safety 
16.2.3.5 
Listing of Urinalysis Laboratory Results 
Safety 
16.2.3.6 
Listing of Tumor Marker Results 
Safety 
16.2.3.7 
Listing of Vital Sign Results 
Safety 
16.2.3.8 
Listing of ECG Results 
Safety 
16.2.3.9 
Listing of ECHO Results 
Safety 
Note:  
PK and QTc reports will be provided in the clinical study report. Separate listing of these data will not 
be done. 
 
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Signature Adoption: Pre-selected Style
Signature ID: 
07AAF4F0-E0FB-4525-9F75-A8DAD1E5FB12
Using IP Address: 108.49.215.5
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 02-Feb-21 | 08:25
Viewed: 08-Feb-21 | 15:40 
Signed: 08-Feb-21 | 15:41
Electronic Record and Signature Disclosure: 
      Accepted: 07-May-20 | 07:56
      ID: 21c2d81a-76e2-4d6d-8b8f-7c068bf0f908


Signer Events
Signature
Timestamp
Rafe Donahue
rdonahue@sierraoncology.com
Senior Director, Biometrics
Sierra Oncology
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
12B50A68-A167-40FC-A6A4-B68D7767248E
Using IP Address: 206.251.220.141
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 02-Feb-21 | 08:25
Viewed: 02-Feb-21 | 08:58 
Signed: 02-Feb-21 | 08:59
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
02-Feb-21 | 08:25
Certified Delivered
Security Checked
02-Feb-21 | 08:58
Signing Complete
Security Checked
02-Feb-21 | 08:59
Completed
Security Checked
08-Feb-21 | 22:28
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Sierra Oncology Inc.- GxP Account (we, us or Company) may be required by 
law to provide to you certain written notices or disclosures. Described below are the terms and 
conditions for providing to you such notices and disclosures electronically through the DocuSign 
system. Please read the information below carefully and thoroughly, and if you can access this 
information electronically to your satisfaction and agree to this Electronic Record and Signature 
Disclosure (ERSD), please confirm your agreement by selecting the check-box next to ‘I agree to 
use electronic records and signatures’ before clicking ‘CONTINUE’ within the DocuSign 
system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 25-Mar-20 | 16:50
Parties agreed to: Mark Kowalski


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Sierra Oncology Inc.- GxP Account:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: itadmin@sierraoncology.com 
 
To advise Sierra Oncology Inc.- GxP Account of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at itadmin@sierraoncology.com and 
in the body of such request you must state: your previous email address, your new email 
address.  We do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Sierra Oncology Inc.- GxP Account  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to itadmin@sierraoncology.com and in 
the body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Sierra Oncology Inc.- GxP Account  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to itadmin@sierraoncology.com and in the body of such request you must 
state your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Sierra Oncology Inc.- GxP Account as described above, you 
consent to receive exclusively through electronic means all notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided 
or made available to you by Sierra Oncology Inc.- GxP Account during the course of 
your relationship with Sierra Oncology Inc.- GxP Account.