A Multi-Center Phase II Study Testing the Activity of Olaparib and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 2018.108    
Targeting Resistant Prostate Cancer With ATR 
and PARP Inhibition (TRAP Trial) 
   NCT03787680
 

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Drug Substance               AZD6738 
Study Number                 UMCC 2018.108 
Version Number              4.1 
Date                                 27JUN2023 
A Multi-Center Phase II Study Testing the Activity of Olaparib 
and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant 
Prostate Cancer. 
Short Title: Targeting Resistant prostate cancer with ATR and PARP 
inhibition (TRAP trial) 

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PROTOCOL SYNOPSIS 
 
A Multi-Center Phase II Study Testing the Activity of Olaparib 
and AZD6738 (ATR Inhibitor) in Metastatic Castration-Resistant 
Prostate Cancer. 
 
 
Principal Investigator/Sponsor-Investigator  
Zachery Reichert, M.D., Ph.D. 
University of Michigan, Department of Medical Oncology 
1500 East Medical Center Drive, SPC 5848 
Ann Arbor, MI 48109-5848 
(734)-764-3066  
(734)-647-8903 
Email: zreiche@med.umich.edu   
 
IND: 141954 
 
Coordinating Center: University of Michigan 
 
 
 
 
Biostatistician 
Thomas Braun, PhD  
University of Michigan  
M4063 SPH II  
1415 Washington Heights  
Ann Arbor, MI 48109-2029  
(734) 936-9844  
Email: tombraun@umich.edu    
 
 
 

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Study site(s) and number of subjects planned 
The study will enroll 47 evaluable patients from 4 academic centers.   
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
1/2019 
 
Estimated date of last subject completed 
4/2021 
 
 
Study design 
This is a phase II Simon 2-stage study evaluating the response rate for the combination of 
AZD6738 (ceralasertib) and olaparib for patients with metastatic castration-resistant prostate 
cancer (mCRPC) who are DNA repair proficient (DRPro) and deficient (DRDef).  Patients are 
DRDef based on somatic mono- or bi-allelic loss of ATM, somatic biallelic loss of either 
BRCA1 or BRCA2 OR known mono- or biallelic germline loss in ATM, BRCA1 or BRCA2.  
Objectives 
Primary Objectives: 
Outcome Measures: 
To determine the response rate of the 
combination of olaparib and AZD6738 in 
mCRPC patients who are DNA repair 
proficient (DRPro, e.g. intact ATM, BRCA1 
and BRCA2).  
The rate of response (CR/PR) per radiographic 
response according to RECIST v1.1 or PSA (≥50% 
decline) in DRPro patients. 
 
Secondary Objective: 
Outcome Measure: 
To determine the response rate of the 
combination of olaparib and AZD6738 in 
mCRPC patients who are DNA repair deficient 
(mono- or biallelic somatic ATM loss or 
biallelic somatic loss of BRCA1 or BRCA2 
OR known mono- or biallelic germline loss of 
ATM, BRCA1, or BRCA2).  
The rate of response (CR/PR) per radiographic 
response according to RECIST v1.1 or PSA (≥50% 
decline) in DRDef patients. 
 
All of the below secondary objectives will be calculated for the DRPro, DRDef patients separately. 
Objective progression-free survival (combined 
radiographic and clinical progression-free 
survival)  
The objective progression-free survival is the 
duration of time from start of treatment to date of 
progression (based only on radiographic progression 
or clinical decline/death). 
Objective radiographic disease response rate 
The rate of achieving a radiographic response 
according to RECIST v1.1. 
PSA progression-free survival  
Composite of survival and duration of PSA control as 
defined by time from start of therapy to first PSA 
increase ≥ 25% and ≥2 ng/ml above the nadir and 
confirmed by a second value at or beyond 4 weeks 
later. 

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PSA response rate for ≤ 0.2 ng/ml, 50% 
decline, 90% decline from entry PSA and 
confirmed 4 weeks later 
The rate of achieving the aforementioned PSA value 
or percent decline compared to PSA at entry. 
Duration of combined radiographic and PSA 
response 
Time from first documented response (RECIST v1.1 
CR/PR or PSA decline ≥50%) until death, recurrent 
or progressive disease (based on RECIST v1.1) or 
first PSA increase ≥ 25% and ≥2 ng/ml above the 
PSA nadir. 
 
Safety Objective: 
Outcome Measure: 
To evaluate the quantitative and qualitative 
tolerability of the combination within the 
combined, DRPro and DRDef patients. 
AE summaries and treatment exposure by genetic 
subtype 
 
Exploratory Objective: 
Outcome Measure: 
To evaluate the predictive capacity of 
circulating analytes within both genetic 
cohorts. 
Circulating tumor DNA sequencing/quantification, 
circulating tumor cell number, circulating tumor cell 
composite gene expression by pooled RT-PCR.   
 
Target subject population 
Patients with progressive, metastatic, castration-resistant prostate cancer who received a) at 
least one line of systemic therapy for mCRPC or b) failed ongoing second generation anti-
hormonal therapy (e.g. abiraterone) in the hormone-sensitive or non-metastatic castration 
resistant phases of disease.  They must remain on continuous LHRH agonist/antagonist, unless 
they have undergone orchiectomy. 
Duration of treatment 
Patients must have washed out of any prior systemic therapy for either 3 weeks or 5 half-lives 
(whichever is longest), excluding prednisone, LHRH agonist/antagonists, bisphosphonate or 
RANKL inhibitor. The median duration of study per patient is estimated to be approximately 
12 months.  
Investigational product, dosage and mode of administration 
Olaparib, 300 mg by mouth, twice a day, days 1-28 of a 28-day cycle.  
AZD6738, 160 mg by mouth, daily, days 1-7 of a 28-day cycle. 
Statistical methods 
For the DRPro population (characterized through study sequencing or previously completed), 
using an Optimal Simon 2-stage design, this cohort will be 35 total patients with an interim for 
futility after 17 DRPro patients have been accrued.  If 2 or more responses are seen in the first 
stage, then the second stage will open and accrue 18 more DRPro patients.  If 5 or more patient 
responses are seen out of the 35 DRPro patients, then the combination treatment will be 
deemed interesting for further study in a DRPro population.  The null response rate from the 

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TOPARP-A study is 6%.  The current design will detect at 80% power, a response rate of 20% 
or greater with 5% one-sided type I error.  
 
For the DRDef population (characterized through study sequencing or previously completed), 
using a Mini-Max Simon 2-stage design.  A set of 12 DRDef will be treated and if 6 or more 
responses are seen, this would support consideration to expand (with amendment or new 
protocol) with another 13 patients or a completely separate trial.  
 
Principal analyses will report the response rate (CR/PR) per radiographic response according to 
RECIST v1.1 or PSA (≥50% decline) in DRPro and DRDef patients.  The cohorts will be 
separated for all efficacy analyses.  
 
 

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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 11 
1. 
INTRODUCTION ................................................................................................ 14 
1.1 
Background .............................................................................................................. 14 
 
1.1.1     Pre-clinical experience .............................................................................. 15 
 
1.1.2     Toxicology and safety pharmacology summary ....................................... 15 
 
1.1.3     Clinical experience .................................................................................... 16 
1.2 
Research Hypothesis .............................................................................................. 16 
 
1.2.1     Rationale for patient population and single arm design ............................ 16 
 
1.2.2 
Rationale for olaparib dose ....................................................................... 17 
 
1.2.3     Rationale for AZD6738 dose .................................................................... 17 
 
1.2.4     Rationale for circulating correlative studies ............................................. 17 
1.3 
Benefit, Risk and Ethical Assessment.................................................................... 18 
 
2. 
STUDY OBJECTIVES ........................................................................................ 18 
2.1 
Primary Objective ..................................................................................................... 18 
2.2 
Secondary Objectives ............................................................................................. 18 
2.3 
Safety Objectives ................................................................................................... 19 
2.4 
Exploratory Objectives ............................................................................................ 19 
 
3. 
STUDY PLAN AND PROCEDURES ................................................................ 19 
3.1 
Overall Study Design and Flow Chart ........................................................................ 19 
3.2 
Registration Flow Chart ......................................................................................... 20 
3.3 
Patient Registration ................................................................................................ 20 
 
3.3.1     Informed consent ...................................................................................... 21 
 
3.3.2     Confirmation of clinical/laboratory eligibility .......................................... 21 
 
3.3.3     Confirmation of 12-lead ECG eligibility and safety ................................. 21 
 
3.3.4     Registration biopsy  .................................................................................. 22 
 
3.3.5     DNA repair designation flow chart ........................................................... 22 
 
3.3.6     Molecular DNA repair status designation ................................................. 22 
 
3.3.7     Anticipated enrolment ............................................................................... 22 
 
4.0 
PATIENT SELECTION CRITERIA ................................................................ 23 
4.1 
Inclusion Criteria ................................................................................................... 23 
4.2 
Exclusion Criteria .................................................................................................. 24 
4.3 
Restrictions During the Study ................................................................................ 26 
 
4.3.1     Contraception ............................................................................................ 26 
 
4.3.2     Concomitant treatments ............................................................................ 27 
 
5.0 
STUDY CALENDAR .......................................................................................... 29 
5.1 
Subject Enrollment and Initiation of Study Therapy ............................................. 30 

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5.2 
Procedures for Handling Subjects Incorrectly Enrolled or Initiated on 
Investigational Product .......................................................................................... 31 
5.3 
Treatments .............................................................................................................. 31 
 
5.3.1     Identity of investigational products........................................................... 31 
 
5.3.2     Treatment plan .......................................................................................... 31 
 
5.3.3     Agent administration ................................................................................. 31 
 
5.3.4     Labelling ................................................................................................... 31 
 
5.3.5     Storage ...................................................................................................... 32 
5.4 
Management of Toxicity ........................................................................................ 32 
 
5.4.1     Toxicities that require discontinuation from protocol therapy ................. 32 
 
5.4.2     Dose levels for olaparib and AZD6738 .................................................... 32 
 
5.4.3     Hematologic Day 1 dosing requirements .................................................. 33 
 
5.4.4     Management of anemia ............................................................................. 33 
 
5.4.5     Management of neutropenia, leukopenia and thrombocytopenia ............. 35 
 
5.4.6     Management of non-hematologic toxicity ................................................ 35 
 
5.4.7     Management of new or worsening pulmonary symptoms ........................ 36 
 
5.4.8     Management of nausea and vomiting ....................................................... 36 
 
5.4.9     Management of diarrhea ........................................................................... 37 
 
5.4.10   Renal toxicity ............................................................................................ 37 
 
5.4.11   Management of hepatic toxicity ................................................................ 37 
 
5.4.12   Management of cardiovascular abnormalities .......................................... 38 
 
5.4.13   Drug interruptions for intercurrent non-toxicity related events ................ 38 
 
5.4.14   Management of prolonged hematologic toxicities while on study 
treatment ................................................................................................................ 39 
5.5 
Treatment Compliance ........................................................................................... 39 
5.6 
Discontinuation of Investigational Product ........................................................... 39 
 
5.6.1     Procedures for discontinuation of a subject from investigational 
product ................................................................................................................... 40  
 
5.6.2     Duration of follow-up ............................................................................... 40 
5.7     Patient Removal from Study......................................................................................... 40 
 
5.7.1     Screen failures ........................................................................................... 40 
 
5.7.2     Off study criteria ....................................................................................... 40 
5.8     Patient Replacement  .................................................................................................... 42 
 
6. 
DRUG INFORMATION ..................................................................................... 41 
6.1 
Olaparib .................................................................................................................. 41 
6.2      
AZD6738 ............................................................................................................... 43 
 
7. 
COLLECTION OF STUDY VARIABLES ....................................................... 44 
7.1 
Recording of Data .................................................................................................. 44 
7.2 
Record Retention ................................................................................................... 45 
7.3 
Data and Safety Monitoring ................................................................................... 45 
7.4 
Quality Assurance and Audits................................................................................ 46 
7.5 
Clinical Monitoring Procedures ............................................................................. 46 
7.6 
Efficacy .................................................................................................................. 47 
 
7.6.1     PSA ........................................................................................................... 47 
 
7.6.2     Response evaluation criteria in solid tumors (RECIST) ........................... 47 

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7.6.3     Definitions ................................................................................................. 48 
 
7.6.4     Disease parameters .................................................................................... 48 
 
7.6.5     Methods for evaluation of measurable disease ......................................... 49 
 
7.6.6     Methods of evaluation of bone disease ..................................................... 50 
 
7.6.7     Progression/response criteria .................................................................... 50 
 
             7.6.7.1     Evaluation of target lesions ....................................................... 50 
 
             7.6.7.2     Evaluation of non-target lesions ............................................... 50 
 
             7.6.7.3     Outcomes based on radionuclide bone scans ............................ 51 
 
             7.6.7.4     Outcomes based on post-therapy PSA changes ........................ 51 
 
             7.6.7.5     Definition of progression based on pain ................................... 52 
 
             7.6.7.6     Progression-free survival .......................................................... 52 
 
7.6.8     Evaluation of best overall response .......................................................... 52 
 
7.6.9     Duration of combined radiographic and PSA response ............................ 53 
 
7.7 
SAFETY ................................................................................................................ 53 
 
7.7.1     Adverse event reporting requirements ...................................................... 53 
 
7.7.2     Definition of adverse events ..................................................................... 54 
 
7.7.3     AZD6738 adverse events of special interest ............................................. 54 
 
7.7.4     Olaparib adverse events of special interest ............................................... 55 
 
7.7.5     Definitions of serious adverse events ....................................................... 55 
 
7.7.6     Expected adverse events ........................................................................... 56 
 
7.7.7     Unexpected adverse events ....................................................................... 56 
 
7.7.8     Suspected unexpected adverse reactions................................................... 56 
 
7.7.9     Adverse event characteristics .................................................................... 56 
7.7.9.1     CTCAE term ............................................................................. 56 
7.7.9.2     Attribution of the AE ................................................................ 56 
 
7.7.10     Reporting of serious adverse events ....................................................... 56 
 
             7.7.10.1     Reporting procedures for multi-site trials ............................... 56 
 
             7.7.10.2     Reporting procedures to AstraZeneca ..................................... 57 
 
             7.7.10.3     Reporting procedures to FDA ................................................. 57 
 
7.7.11   Routine reporting ...................................................................................... 57 
 
7.7.12   Reporting of unanticipated problems ........................................................ 57 
 
7.7.13   Paternal exposure ...................................................................................... 58 
 
7.7.14   Genetics ..................................................................................................... 58 
 
7.7.15   Circulating correlative analytes ................................................................ 58 
 
7.7.16   Specimen banking ..................................................................................... 58 
 
8. 
ROLES AND RESPONSIBILITIES .................................................................. 58 
8.1 
Sponsor Investigator .............................................................................................. 58 
8.2 
Participating Sites .................................................................................................. 59 
8.3 
Coordinating Center ............................................................................................... 59 
 
9. 
ETHICAL AND REGULATORY REQUIREMENTS .................................... 59 
9.1 
Ethical Conduct of the Study ................................................................................. 59 
9.2 
Subject Data Protection .......................................................................................... 60 
 
9.3 
Informed Consent ................................................................................................... 60 

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9.4 
Changes to the Protocol and Informed Consent Form ........................................... 60 
9.5 
Protection of Privacy .............................................................................................. 61 
9.6 
Terminating or Modifying the Study ..................................................................... 61 
 
10. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...... 61 
10.1 
Study Endpoints ..................................................................................................... 61 
 
10.1.1     Analysis of the primary endpoint ............................................................ 61 
 
10.1.2     Analysis of the secondary endpoints ....................................................... 61 
 
10.1.3     Correlative objectives ............................................................................. 62 
10.2 
Analysis Populations .............................................................................................. 62 
 
10.2.1     Response-to-treatment populations ......................................................... 62 
 
10.2.2     Safety population .................................................................................... 63 
10.3 
Safety Analysis ...................................................................................................... 63 
 
10.3.1     Evaluation of adverse events................................................................... 63 
 
10.3.2     Evaluation of serious adverse events and premature withdrawals .......... 63 
 
10.3.3     Extent of exposure .................................................................................. 64 
 
10.3.4     Early stopping ......................................................................................... 64 
 
10.3.5     Statistical procedures .............................................................................. 64 
 
10.3.6     Sample size calculation ........................................................................... 64 
 
10.3.7     Derived variables .................................................................................... 64 
10.4 
Data Monitoring Committee .................................................................................. 65 
 
11. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED ................ 65 
11.1 
Overdose ................................................................................................................ 65 
11.2 
Paternal Exposure .................................................................................................. 66 
 
12. 
LIST OF REFERENCES .................................................................................... 67 
 
13. 
APPENDICES ...................................................................................................... 68 
 
LIST OF TABLES 
TABLE 1   
Dose Modification Table for AZD6738 ................................................... 32 
TABLE 2   
Dose Modification Table for Olaparib ..................................................... 33 
TABLE 3 
Day 1 minimum hematologic criteria ....................................................... 33 
TABLE 4 
Dose interruption and stopping criteria  ................................................... 38 
TABLE 5 
Best overall response for patients with measurable disease (i.e. 
target disease) ........................................................................................... 52 
TABLE 6 
Best overall response for patientes with non-measurable disease 
(i.e. non-target disease) ............................................................................. 53 
TABLE 7 
Categories for response to treatment ........................................................ 63  
TABLE 8 
Drugs known to be inhibitors and inducers of CYP3A ............................ 73 

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TABLE 9 
Drugs known to be inhibitors or inducers of Pgp ..................................... 74 
TABLE 10 
Drugs known to be inhibitors or inducers of BCRP ................................. 75 
TABLE 11 
Drugs known to be metabolized by CYP3A4 and have a narrow 
therapeutic index....................................................................................... 75 
TABLE 12 
Drugs known to be metabolized by CYP2B6 and have a narrow 
therapeutic index....................................................................................... 76 
TABLE 13 
Drugs known to be substrates of OATP1B1 ............................................ 76 
TABLE 14 
Drugs known to be substrates of BCRP ................................................... 77 
 
LIST OF FIGURES 
FIGURE 1 
Clonogenic survival of AZD6738 and AZD6738/olaparib in 
DRDef and DRPro cell lines .................................................................... 15 
 
LIST OF APPENDICES 
Appendix A: Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ............................................................................ 69 
Appendix B: Guidelines regarding potential interactions with concomitant 
medications ............................................................................................... 73 
Appendix C: Acceptable birth control methods .................................................................... 78 
Appendix D: Genomics research ........................................................................................... 79 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
Abbreviation or Special Term 
Explanation 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
APTT 
Activated Partial Thromboplastin Time 
AR 
Androgen Receptor 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
ATM 
Mutated in Ataxia Telangiectasia 
ATR 
Ataxia telangiectasia and Rad3-related protein 
AUC 
Area Under the Curve 
BID 
Twice a Day 
BRCA1 
Breast Cancer 1 Gene 
BRCA2 
Breast Cancer 2 Gene 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CHK1 
Checkpoint Kinase 1 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form (electronic/paper) 
CRPC 
Castration-Resistant Prostate Cancer 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Event 
ctDNA 
Circulating Tumor DNA 
CYP 
Cytochrome P  
DNA 
Deoxyribonucleic acid 
DRPro 
DNA repair defect negative 
DRDef 
DNA repair defect positive 
DSMC 
Data and Safety Monitoring Committee 
EC 
Ethics Committee, synonymous to Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC) 

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ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
ESMO 
European Society of Medical Oncology 
FDA 
Federal Drug Administration 
FU 
Follow up 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
γH2AX 
Gamma-Histone 2AX 
Hb 
Hemoglobin 
HDPE 
High-density Polyethylene 
ICH 
International Conference on Harmonisation 
IND 
Investigational new Drug 
INR 
International Normalized Ratio 
IP 
Investigational Product  
IRB 
Institutional Review Board 
IV or iv 
Intravenously 
LDH 
Lactate Dehydrogenase 
LHRH 
Luteinizing Hormone Releasing Hormone  
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
mHSPC 
Metastatic Hormone-Sensitive Prostate Cancer 
MDS 
Myelodysplastic Syndrome 
MIAP 
Michigan IND/IDE Assistance Program 
MRI 
Magnetic Resonance Imaging 
MSPM 
Multi-Site Project Manager 
NCCN 
National Comprehensive Cancer network 
NCI 
National Cancer Institute 
OATP1B1 
Organic Anion Transporting Polypeptide 1B1 
PARP 
Poly (ADP-Ribose) Polymerase 
PCWG 
Prostate Cancer Working Group 3 
PD 
Progressive Disease 
PE 
Physical Exam 
PFS 
Progression Free Survival 
Pgp 
P-glycoprotein 
PHL 
Potential Hy’s Law 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin Time 

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RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious adverse event  
SOP 
Standard Operating Procedures 
ULN 
Upper Limit of Normal 
URI 
Upper Respiratory Infection 
WBC 
White Blood Cells 
 

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1. 
INTRODUCTION 
 
Background 
In 2017, approximately 26,000 men are estimated to have died from prostate cancer in the 
United States, making it the third leading cause of cancer death in men [1].  Prostate cancer is 
an androgen driven disease, yielding a high initial response rate to androgen deprivation 
therapy (ADT) in the metastatic setting.  Despite survival advances through the addition of 
docetaxel chemotherapy or abiraterone (testosterone biosynthesis inhibitor) to ADT in this 
hormone-sensitive phase of disease, many men will have their disease progress despite the low 
testosterone environment.  This is termed metastatic castration-resistant prostate cancer 
(mCRPC).  Multiple therapy options exist and include further androgen targeting therapies 
(abiraterone, enzalutamide), immunotherapy (sipuleucel-T), bone directed therapies (Radium-
223, bisphosphonates, RANKL inhibitor) and chemotherapies (docetaxel, cabazitaxel).  These 
drugs often improve oncologic symptoms, yet the median survival gains of each remains 
around 3 months.  The need for new options remains great.   
 
Precision oncology (matching tumor specific genetic changes to drugs targeting those 
alterations/pathways) is revolutionizing cancer care.  Preliminary results have shown this 
strategy may be effective in prostate cancer by targeting DNA repair pathways.  Approximately 
20% of mCRPC patients have germline or somatic loss of DNA repair genes (dominated by 
BRCA2, ATM) rendering them DNA repair deficient (DRDef) [2]. Targeting this DRDef 
population with poly (ADP-ribose) polymerase (PARP) inhibitors has shown promise in two 
phase II studies.  The first was an unselected trial where DRDef patients were uniquely 
sensitive to olaparib (a PARP inhibitor) resulting in an 88% response rate (based on CTC 
number, radiographic and PSA effects).  DNA repair defect negative (DRPro) patients had only 
a 6% response rate [3].  A separate trial suggests activity, but wasn’t designed or powered 
towards that hypothesis.  When treated with abiraterone, prednisone and veliparib (a PARP 
inhibitor), 12 of 13 (92.3%) DRDef patients had a PSA decline of >50% and 10 of 11 (90.9%) 
DRDef patients with measurable disease had a RECIST response. This compares favorably to 
DRPro patients who had a 64.7% PSA response rate and 40% RECIST response to the same 
combination [4].  Finally, retrospective analysis of excellent responder patients treated with 
platinum agents (cisplatin or carboplatin) also found them to be DRDef (BRCA2 carriers), 
further supporting targeting DNA repair in this population. [5].   
 
The problem remains, that only 20% of mCRPC patients are DRDef.  To simulate this genomic 
requirement, combinations of DNA repair targeting agents have been attempted. Cisplatin and 
cisplatin/gemcitabine were combined with olaparib but hematologic toxicity was limiting [6, 
7].  Carboplatin and carboplatin/paclitaxel were combined with a PARP inhibitor (rucaparib or 
olaparib) with a better tolerability profile, but unknown benefit [8, 9]. Various carboplatin 
combinations remain in clinical study.  Although small in number, responses seen in these 
early clinical trials remain in DRDef patients.  The 80% DRPro patients in prostate cancer 
remain without a proven DNA targeting regimen.   
 
Ataxia telangiectasia and Rad3-related protein (ATR) is an attractive DNA repair target 
candidate due to its involvement in cell cycle checkpoint regulation, stalled replication fork 
resolution, single strand break repair (with Replication Protein A) and double strand break 

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repair (with ATR Interacting Protein).  With the high prevalence of prostate cancer and known 
role for DNA repair targeting, it is an ideal scenario to test ab ATR/PARP inhibitory 
combination. 
 Pre-clinical experience 
AZD6738 is a potent inhibitor of the ATP-kinase domain of ATR with a purified target IC50 of 
1 nM.  Its closest off-target in vitro kinase inhibition is mammalian Target of Rapamycin 
(mTOR) at 370 nM, while the majority of kinases are in the µM range.  Selectivity remains in 
cellular assays.  Mechanistic validation was done by monitoring the decline of phosphorylated 
CHK1 (ATR’s target in cell-cycle regulation) and rise in γH2AX (marker of double stranded 
DNA repair) with increasing doses of AZD6738 by western blot.  Exposure to AZD6738 also 
causes S-phase arrest due to extensive DNA damage by flow cytometry.  Cell-lines with 
deficient ATM function showed a 5x lower GI50 concentration.  To overcome this genetic 
requirement, AZD6738 was combined with multiple chemotherapies.  Focusing on the olaparib 
combination, this resulted in synergistic activity for 50% of tested cell lines, while only 
additive for the remaining. Of note, none showed reduced efficacy in combination.  Cell lines 
with lower ATM expression had higher synergy scores, suggesting DRDef cancers respond 
stronger to the combination, yet 
DRPro lines remained additive.   
 
To further genetically narrow the 
DNA repair proficiency vs deficiency 
argument, MiaPaCa2 cells with a 
stable doxycycline-inducible RAD51 
shRNA knockdown (resulting in a 
DRDef signature), were tested with 
and without doxycycline.  AZD6738 
resulted in decreased clonogenic 
survival as monotherapy for both DRDef and DRPro lines.  The combination also showed 
improved effects at lower doses of AZD6738 with olaparib (Figure 1).   
 
The combination of AZD6738 and olaparib has also been tested in vivo in several triple-
negative DRDef breast cancers xenograft models with similar effect.  A mutated ATM line 
resulted in 100% growth inhibition for the combination, with only 30% (AZD6738) or 0% 
(olaparib) growth inhibition for monotherapy.  Two BRCA2 deficient lines also had exquisite 
sensitivity to the doublet with variable monotherapy results.   
 Toxicology and safety pharmacology summary  
AZD6738 and olaparib are cleared via CYP3A4.  Adverse events of AZD6738 in dogs, guinea 
pigs or rats resulted in weight loss, decreased food consumption, bone marrow suppression (all 
lines), biliary epithelial degeneration, degenerative changes in male reproductive tissues, 
hypotension, tachycardia, delayed gastric emptying, vomiting, or diarrhea.  AZD6738 was not 
mutagenic in the Ames test, but was positive in the in vitro mouse lymphoma assay and in vitro 
micronucleus assay in human lymphocytes consistent with its known DNA repair inhibition.   
 

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Bone marrow suppression typically manifested as neutropenia and/or thrombocytopenia, which 
were the main dose limiting toxicities.  Improved regimens consisting of a 7-day AZD6738 and 
28-day olaparib exposure with dose reductions, delays and supportive care (e.g. transfusions) 
mitigated many side effects.  Upon drug discontinuation, no persistent effects were noted.  
Grade 3-4 toxicities observed in one or more patients include anemia, ascites, anorexia, 
abdominal pain, intestinal obstruction leukopenia, dehydration and syncope.  Other less severe 
side effects include fatigue, nausea, vomiting, dizziness, diarrhea, asthenia and blood creatinine 
increase.    
 Clinical experience 
There is extensive clinical data regarding olaparib monotherapy with its approval and use in 
ovarian and breast cancer [10-12].  AZD6738 is in phase 2 development and has been 
combined with olaparib in dose-finding studies, with expansions in gastric cancer and breast 
cancer are ongoing.  Within the phase I study of the combination, 6 patients (15%) had a 
confirmed RECIST complete or partial response and each was DRDef.  Due to the variable 
doses exposed, and low percentage of prostate cancer patients within the phase I trial (<10%), a 
prostate cancer specific trial is presented. 
 
Research Hypothesis 
This is an open label, single arm study design, with two subspecified genetic cohorts: DRPro 
and DRDef patients.  Each cohort is separated in the statistical analysis for efficacy but 
combined for tolerability.  The rationale for drug efficacy for both cohorts is covered in Section 
1.1. The historical data discussed in Section 1.1 describes the futility of single agent DNA 
repair targeting in DRPro disease, such that the focus is on evaluating activity of the 
combination.  
 
To define the cohorts, patients with previous mCRPC or mHSPC metastatic tissue based 
tumoral testing and those with known germline BRCA2, BRCA1 or ATM loss will not require 
a new biopsy. Patients with an unknown tumor status will undergo a metastatic site biopsy to 
evaluate DNA repair status.  If a biopsy is unable to be done because of procedural risk or a 
biopsy is attempted and yields insufficient tissue, patients may (if available) undergo 
circulating tumor DNA testing (e.g. Tempus)  for exploratory purposes. No circulating tumor 
DNA assay is used to designate DNA repair status. All patients undergoing circulating tumor 
DNA testing will be designated as DRPro.  These choices reflect the real world challenges of 
tumoral diagnostics in prostate cancer patients, yet utilizes our knowledge that most patients 
are DRPro. Of note, if circulating tumor DNA or metastatic site sequencing finds a BRCA1, 
BRCA2 or ATM mutation, the local study team is recommended to refer the patient to genetic 
counseling for further workup.  For full discussion of DNA repair status designation, see 
Section 3.3.   
 Rationale for patient population and single arm design 
The patient population studied is mCRPC patients who have effectively failed one or more 
prior lines of established mCRPC therapy.  The studied agents are not anticipated to have 
overlapping resistance patterns with other mCRPC therapies, such that no specific mCRPC 
directed drug exposure is required or avoided.  Patients treated with prior PARP inhibitors or 
DNA-damage response agents (e.g. cisplatin, carboplatinum) are excluded.  The choice of at 

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least one prior therapy is to maintain clinical equipoise for a drug combination without 
previous record of effect, while acknowledging the known overlapping resistance patterns 
between current mCRPC directed therapies and also financial limitations some patients 
experience regarding access to second generation anti-androgens.  Chemotherapy and its 
expected toxicities are also not preferred for many patients, allowing the study to be offered 
prior to chemotherapy.  Two unique scenarios are patients who are treated with second-
generation anti-androgen therapies (e.g. abiraterone) during the hormone-sensitive phase of 
disease or non-metastatic castration resistant phase of disease.  Patients progressing while 
continually on these therapies have effectively failed one line of classical mCRPC therapy, and 
thus are allowed to enter directly into the study at diagnosis of mCRPC.  
 
Clinically within prostate cancer, single agent DNA repair targeting in DRPro was 
unsuccessful with PARP inhibitor monotherapy, but showed some efficacy in DRDef [3].  
Unfortunately, only ~20% of mCRPC patients are DRDef- leaving the majority of patients 
without benefit.  There is preclinical support for activity with the combination in DRPro.  With 
this clinical and preclinical support requiring multiple perturbations of DNA repair (either 
genetic or pharmacologic) for success, single agent AZD6738 is unlikely to be effective- hence 
why the combination only is being tested.   
 
Rationale for olaparib dose 
The starting olaparib dose is 300 mg by mouth, twice a day, for days 1-28 of a 28-day cycle.  
This dose is the active and tolerated dose seen previously in other DRDef or platinum sensitive 
cancers [10, 12].  It is tolerated with the below AZD6738 dose and schedule with hematologic 
toxicity being the main challenge. 
 
Rationale for AZD6738 dose 
The dose of AZD6738 is 160 mg by mouth daily for days 1-7 of a 28-day cycle.  This dose 
maintains a mean steady state concentration above the IC90 for ATR in vivo during the 
treatment week.  A one out of four weeks schedule is required to manage toxicity.  Dose 
limiting toxicities are reviewed in Section 1.1.2.  
 
Rationale for circulating correlative studies 
Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are unique biologic 
samples as they attempt to recapitulate the tumor heterogeneity into a single blood draw. These 
liquid biopsy approaches provide an opportunity to develop blood-based predictive or 
prognostic biomarkers that could obviate the need for tumor-directed biopsies. By combining 
ctDNA with both morphologic and possible DNA/RNA-based analyses of CTCs, the 
mutational and transcriptional tumor landscape may be determined. Furthermore, evaluating 
the concordance of a serum sample to the metastatic biopsy will allow for both: validation of 
the liquid-based approach and likely identification of patients harboring DNA repair defects 
that are not present in the single metastatic site biopsied. These analyses will be collected prior 
to treatment in order to develop these assays as predictive biomarkers of response and during 
treatment to monitor alterations in circulating disease. CTC and ctDNA analyses will also be 
done at the end of treatment to explore mechanisms of resistance. These correlative studies are 
exploratory in nature only.  

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The ctDNA and CTC analyses to correlate with response to treatment and clinical 
characteristics of disease, will be done for all patients enrolled into treatment. DNA 
modifications of these samples (e.g., epigenetic or otherwise) and noncoding elements (e.g., 
telomere length, introns) may be investigated with the above goals in the future as excess tissue 
and blood specimens will be banked. Correlation of these tumor characteristics can also be 
compared retrospectively to each patient’s clinical course. Published algorithms of the above 
data for olaparib response will be validated and new ones created/tested.  
 
Previous tissue obtained either in routine care OR left over when the on-study biopsy was 
performed may be requested. This will be labeled by study ID only and may be utilized by the 
coordinating center or shared with sponsor. If samples are shared with sponsor, they will NOT 
be utilized for next generation sequencing analyses to avoid genetic privacy concerns.  Patients 
may opt-out of the request for prior tissue and/or sharing of prior/study tissue with sponsor. 
Left over tissue from the biopsy will be sent to coordinating center (after sequencing completed 
at TEMPUS). 
 
 
Benefit, Risk and Ethical Assessment 
The combination of olaparib and AZD6738 has been demonstrated as safe and tolerable in 
patients with a range of solid tumors. Toxicity is manageable with effective monitoring of 
patients, especially effects on the bone marrow, and both IMPs may be dose modified if 
necessary.  There is preclinical support in vitro for activity with the combination in DRPro and 
DRDef, with a paucity of existing clinical data for prostate cancer uniquely.  PARP inhibition 
has demonstrated efficacy in DRDef prostate cancer patients but resistance still develops [3]. 
The AZD6738/olaparib combination has been explored clinically in the ongoing AstraZeneca 
phase I/IIa study, and found to be safe [13].  
 
mCRPC is a challenging field as current therapies appear to have overlapping mechanisms of 
resistance (e.g. androgen receptor amplification for enzalutamide and abiraterone) and 
chemotherapy (e.g. docetaxel, cabazitaxel) is not viable nor preferred by many patients.  
Hence, it has created an opportunity to try novel combinations after failure of a single line of 
therapy.  Resistance patterns may also be emerging earlier in the disease course as some 
mCRPC patients will have seen secondary hormonal agents earlier (mHSPC) and thus may 
benefit from trial agents in the frontline mCRPC setting.    
2. 
STUDY OBJECTIVES 
 
Primary Objective 
Primary Objective: 
Outcome Measure: 
To determine the response rate of the 
combination of olaparib and AZD6738 in 
mCRPC patients who are DNA repair 
proficient (DRPro, e.g. intact ATM, BRCA1 or 
BRCA2).  
The rate of response (CR/PR) per radiographic 
response according to RECIST v1.1 or PSA (≥50% 
decline) in DRPro patients. 

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Secondary Objectives 
Secondary Objective: 
Outcome Measure: 
To determine the response rate of the 
combination of olaparib and AZD6738 in 
mCRPC patients who are DNA repair deficient 
(mono- or biallelic somatic ATM loss OR 
biallelic somatic loss of BRCA1 or BRCA2 
OR known mono or biallelic germline loss of 
ATM, BRCA1, or BRCA2).  
The rate of response (CR/PR) per radiographic 
response according to RECIST v1.1 or PSA (≥50% 
decline) in DRDef patients. 
 
All of the below secondary objectives will be calculated for the DRPro, DRDef patients separately. 
Objective progression-free survival (combined 
radiographic and clinical progression-free 
survival)  
The objective progression-free survival is the 
duration of time from start of treatment to date of 
progression (based only on radiographic progression 
or clinical decline/death). 
Objective radiographic disease response rate 
The rate of achieving a radiographic response 
according to RECIST v1.1. 
PSA progression-free survival  
Composite of survival and duration of PSA control as 
defined by time from start of therapy to first PSA 
increase ≥ 25% and ≥2 ng/ml above the nadir and 
confirmed by a second value at or beyond 4 weeks 
later. 
PSA response rate for ≤ 0.2 ng/ml, 50% 
decline, 90% decline from entry PSA and 
confirmed 4 weeks later 
The rate of achieving the aforementioned PSA value 
or percent decline compared to PSA at entry. 
Duration of combined radiographic and PSA 
response 
Time from first documented response (RECIST v1.1 
CR/PR or PSA decline ≥50%) until death, recurrent 
or progressive disease (based on RECIST v1.1) or 
first PSA increase ≥ 25% and ≥2 ng/ml above the 
PSA nadir. 
 
Safety Objectives 
Safety Objective: 
Outcome Measure: 
To evaluate the quantitative and qualitative 
tolerability of the combination within the 
combined, DRPro and DRDef patients. 
AE summaries and treatment exposure by genetic 
subtype 
 
Exploratory Objectives 
Exploratory Objective: 
Outcome Measure: 
To evaluate the predictive capacity of 
circulating analytes within both genetic 
cohorts. 
Circulating tumor DNA sequencing/quantification, 
circulating tumor cell number, circulating tumor cell 
composite gene expression by pooled RT-PCR.   

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3. 
STUDY PLAN AND PROCEDURES 
 
Overall Study Design and Flow Chart 
This is a single-arm study evaluating the response of DRPro and DRDef patients with mCRPC.  
Patients whose DNA repair status is known or unknown may enroll.  If they require biopsy, 
their DNA repair status is described and patient directed into the correct cohort.  Patients are 
allowed to have one or more prior lines of therapy for mCRPC.  If they became castration-
resistant while on second generation androgen pathway inhibitors within the mHSPC phase of 
disease, they may enroll.   
 
Registration Flow Chart 
 
 
 
Patient Registration 
Before initiating screening, the scope and requirement of the trial must be reviewed with each 
patient.  Patients should understand the inherent risks of the trial therapies, required diagnostics 
(biopsy if needed), alternative treatment options, their right to privacy and also the right to 
withdraw from study for any reason.  Once this is done and the patient is estimated to meet 
eligibility criteria (excluding the DNA repair status and completing washout period for prior 
drug or radiation- this may complete while awaiting biopsy/results), they may sign and date an 
IRB-approved inform consent which meets the requirement of the Code of Federal Regulations 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50). No study-specific procedures 
will be undertaken until a signed consent form has been completed. 
 
Patient registration for this trial will be centrally managed by the Coordinating Center of the 
University of Michigan Rogel Cancer Center as described below. 
 

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A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on a Screening and 
Enrollment Log.  
 
It is the responsibility of the local site investigator to determine patient eligibility prior to 
submitting patient registration request to the Coordinating Center.  After patient eligibility has 
been determined by the local site, a copy of the completed Eligibility Worksheet together with 
all the pertinent de-identified source documents will be submitted by the requesting site to the 
Coordinating Center, by email to CTSU-Oncology-Multisite@med.umich.edu.    
 
The Multi-Site Project Manager (MSPM) of the Coordinating Center will review the submitted 
documents and process the registration. Sites should inform the Multi-Site Coordinator of a 
potential registration by 5 p.m. on the day prior to registration.  Same day registrations cannot 
be guaranteed.   
 
An email will be sent by the MSC to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In 
addition, a copy of the completed Eligibility Worksheet signed and dated by the MSPM, will 
be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in a Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
Informed consent  
Informed consent is obtained by following the procedures in Section 9.3 and within 24 hours 
after patients signs informed consent, sites will provide a complete signed informed consent 
form to coordinating site.   
 
Confirmation of clinical/laboratory eligibility 
After laboratory screening for eligibility is completed, an eligibility checklist (minus DNA 
repair status and time related events (washout, radiation, surgery)) will be submitted to the 
coordinating site.  The coordinating site will review and, if eligible, the patient is enrolled in 
the trial.     
 
If a prior biopsied mCRPC or mHSPC site was sequenced in a CLIA certified lab with a next-
generation sequencing platform, that is adequate for DNA repair status determination and the 
report should be submitted to coordinating site for review.  If the patient had a known germline 
loss of BRCA1, BRCA2, or ATM that is adequate (the official testing report must be 
submitted). If DNA repair status is unknown, patients should undergo genomic evaluation via a 
biopsy of a soft tissue metastatic deposit (preferred) or bone metastasis and submit it to 
Tempus Labs as specified in the laboratory manual.  If the biopsy yields insufficient tissue or 
the biopsy itself is unable to be performed secondary to procedural safety as deemed by local 
PI, the patient may undergo (if available at the time) circulating tumor DNA/germline DNA 
testing per the lab manual.  Due to the lack of predictive validation for circulating tumor DNA 
and delays in germline testing, any patient undergoing it will be designated DRPro (although 

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subgroup analyses can further explore its relevance).  If the analysis or tumor based testing 
shows any potentially inheritable defect, the treating provider is recommended to consider 
sending the patient to a genetic counselor for review.  
 
 
Confirmation of 12-lead ECG eligibility and safety 
ECGs are required at screening (triplicate), AND within 7 days prior to starting study 
treatment (ok for same day as C1D1) AND when clinically indicated.  The timing and number 
of ECGs may be adjusted in response to the emerging PK and safety profile.  Twelve-lead 
ECGs will be obtained.  All ECGs should be recorded with the patient in the same physical 
position.  For screening, triplicate ECGs are required.  After the screening of ECGs, only if the 
first ECG  QTC is prolonged (>450 ms by Fridericia), then on two  more ECG recordings 
separted by 5 minutes will be taken.  If the on-study first ECG has a normal QTC,  no further 
ECGs are required for that timepoint. A standardised ECG machine should be used and the 
patient should be examined using the same machine throughout the study, where feasible.  
After ECGs have been recorded, the Investigator or designated physician will review each of 
the ECGs and may refer to a local cardiologist if appropriate.  A copy should be filed in the 
patient’s medical records.  If an abnormal ECG finding at screening or baseline is considered to 
be clinically significant by the Investigator, it should be reported as a concurrent condition.  
For all ECGs details of rhythm, PR, R-R, QRS and QT intervals and an overall evaluation will 
be recorded. 
 
 
Registration biopsy 
Biopsy tissue should be processed and shipped to Tempus Labs as specified in the laboratory 
manual. The coordinator for Tempus Labs will inform the coordinating site Project Manager as 
well as the participating site whether the patient has adequate tissue for analysis.  
 
 
DNA repair designation flow chart 
 
 
 
 
Molecular DNA repair status designation 
DRDef requires mono or biallelic inactivation of ATM or biallelic inactivation of BRCA1 or 
BRCA2 via copy loss and/or loss of function mutations/insertions/deletions as interrogated by 
comparing the found alterations to published databases and primary literature by Tempus Labs. 
Germline loss of BRCA1, BRCA2 or ATM is adequate as it is known to uniformly be lost in 
the alternate allele for these patients. Monoallelic loss requires a deletion or mutation in the 
gene.  A biallelic deleterious defect is characterized by 2 deletions, 1 deletion + 1 mutation, or 

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2 mutations. Variants of unknown significance do not qualify.  See Section 3.3.5 for diagnostic 
workup to define DNA repair status.  
 
 
Anticipated enrollment 
The trial will stop accrual once the predesignated DRPro and DRDef patients have enrolled.  If 
one arm closes due to complete accrual or futility, the alternate arm may continue to enroll.  
Patients must start therapy AFTER DNA repair designation is reported  if one arm of the trial 
is closed or near closing (within 3 patients). Accrual for primary endpoint is 24 months 
duration of the study is 36 months.     
4. 
PATIENT SELECTION CRITERIA 
Subjects will be identified through routine care of patients within the participating tertiary 
cancer care centers.  Each subject should meet all of the inclusion criteria and none of the 
exclusion criteria for this study.  Under no circumstances are there exceptions to this rule. 
 
Inclusion Criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Male ages 18 years and older at time of signing the informed consent form 
3. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 42 
days prior to registration  
4. 
Histologic or cytologic proof of prostate adenocarcinoma (excluding small-cell or 
neuroendocrine pathologies) 
5. 
Metastatic prostate cancer on CT, MRI or Bone scan 
6. 
Must have disease progression (while testosterone level is under 50 ng/dl) on prior 
therapy prior to study entry defined as one (or more) of the following: 
a. PSA progression defined as continuously rising PSA values measured a 
minimum of 1 week apart with a minimal starting value of 1.0 ng/mL 
b. Progression of bidimensionally measurable soft tissue or nodal metastasis by CT 
or MRI based on RECIST, v1.1 
7. 
Prior treatment with at least one of the following: 
a. One line of therapy in mCRPC  
b. Second generation anti-androgen (e.g. abiraterone, enzalutamide or 
apalutamide) within the hormone-sensitive phase of disease AND progression 
occurs while on therapy 
8. 
Patients must be withdrawn from prior therapy for ≥3 weeks (patients may remain on 
prior prednisone up to 10 mg total daily exposure at provider’s discretion) at planned 
time of treatment start. 
9. 
Agree to undergo a biopsy of at least one metastatic site (if feasible) to determine DNA 
repair status, unless prior metastatic tissue underwent next-generation sequencing in a 
CLIA certified lab or known germline loss of BRCA1, BRCA2 or ATM.  If no site is 
reachable, or first biopsy insufficient/unsuccessful, circulating tumor DNA may be 
obtained. 

24 of 80 
 
10. Treated with continuous androgen deprivation therapy (either surgical castration or 
LHRH agonist/antagonist) with documented castrate level of serum testosterone (<50 
ng/dL). A stable dose of bisphosphonate or denosumab for bone metastases should be 
continued as long as started at least 5 days prior to C1D1 planned start day. 
11. At the time of planned treatment start (C1D1), at least 21 or more days will have 
elapsed from palliative radiation (with the exception of radiation to >30% of bone 
marrow or with a wide field of radiation, this requires 28 or more days).  
12. Patient must have normal organ and bone marrow function measured within 42 days 
prior to registration as defined below 
a. Hemoglobin ≥10 g/dL (with no blood transfusion or erythropoietin use within 
the past 42 days) 
b. Absolute neutrophil count ≥1.5x109/L 
c. Platelet count ≥100x109/L (with no platelet transfusions within last 42 days) 
d. Total bilirubin <1.5x ULN (unless the patient has documented Gilbert’s disease 
and <2.0x ULN should be used) 
e. AST or ALT ≤ 2.5x ULN, unless liver metastases are present in which case they 
cannot be ≥5x ULN 
f. Glomerular filtration rate (GFR) ≥51 mL/min, as assessed using the Cockcroft-
Gault equation 
13. Estimated life expectancy ≥16 weeks  
14. Male patients who are sexually active must be willing to use barrier contraception for 
the duration of the study and for 1 week after the last study drug administration, with all 
sexual partners. Male patients must use a condom during treatment and for 6 months 
after the last dose of study drug(s) when having sexual intercourse with a pregnant 
woman or with a woman of childbearing potential and must not donate sperm for 6 
months after the last dose of study drug.  Female partners of male patients should also 
use a highly effective form of contraception (see Appendix C) for 6 months after the 
last dose of study drug(s) if they are of childbearing potential. True abstinence is an 
acceptable form of contraception and must be documented as such.  
15. Patient is willing and able to comply with the protocol for the duration of the study, 
including undergoing biopsy (if warranted), treatment, scheduled visits and 
examinations 
 
Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled. 
1. 
A diagnosis of ataxia telangiectasia 
2. 
Prior treatment with a PARP inhibitor (e.g. olaparib, veliparib, niraparib, rucaparib), 
AZD6738 or other DNA-damage response agents (e.g. cisplatin or carboplatin) 
3. 
Cytotoxic chemotherapy, first- or second-generation antiandrogen or CYP17 inhibitors 
are not permitted within 21 days or 5 half-lives of registration (whichever is longest) of 
planned treatment start. For clarity, enzalutamide requires 5 weeks washout.      
4. 
Major surgery < 2 weeks prior to enrollment; patients must have recovered from any 
effects of major surgery  
5. 
Persistent toxicities (≥CTCAE Grade 2) caused by previous cancer therapy, besides 
Grade 2 alopecia and Grade 2 neuropathy (these are allowed). 

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6. 
Patients with current or prior MDS/AML or with features suggestive of MDS/AML 
7. 
Any other malignancy which has been active or treated within the past 3 years, with the 
exception of non-melanomatous skin cancer, or Ta bladder cancer  
8. 
Patients with active brain metastases are excluded because of unknown penetration into 
the CNS.  A confirmatory scan for asymptomatic patients is not required.  Patients with 
a history of treated central nervous system (CNS) metastases are eligible provided they 
meet all of the following criteria: disease outside the CNS is present, no clinical 
evidence of progression since completion of CNS-directed therapy, minimum 3 weeks 
between completion of radiotherapy and registration and recovery from significant 
(Grade ≥ 3) acute toxicity with no ongoing requirement for >10 mg of prednisone per 
day or an equivalent dose of other corticosteroid. If a patient must remain on steroids, 
they must have started the steady dose at least 28 days prior to treatment. Patients with 
spinal cord compression unless considered to have received definitive treatment for this 
and evidence of clinically stable disease for 28 days prior to study treatment. 
9. 
Any of the following cardiac disease currently or within the last 6 months:   
a. Unstable angina pectoris 
b. Congestive heart failure (by New York Heart Association ≥ Class 2) or known 
reduced LVEF < 55% 
c. Acute myocardial infarction 
d. Conduction abnormality not controlled with pacemaker or medication (e.g. 
complete left bundle branch block or third-degree heart block) 
e. Significant ventricular or supraventricular arrhythmias (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities 
are eligible).  
f. Uncontrolled hypertension (Grade 2 or above) requiring urgent (for example, 
adjusting medications within 24 hours) clinical intervention 
g. Patients at risk of brain perfusion problems, e.g. TIAs or history of pre-
syncope or syncopal episodes unexplained by reversible causes 
10. Mean resting corrected QT interval >450, obtained from 3 ECGs 2-5 minutes apart 
using the Fredericia formula.  Absence of any factors that increase the risk of QTc 
prolongation or risk of arrhythmic such as congenital long QT syndrome, immediate 
family history of long QT syndrome or unexplained sudden death under 40 year of age.  
Patients with relative hypotension (<90/60 mmHg) or previously known clinically 
relevant orthostatic hypotension defined as a postural hypotension ≥20 mmHg 
11. Concomitant use of known potent or moderate cytochrome P (CYP) 3A inhibitors (e.g. 
itraconazole, ciprofloxacin, diltiazem) require 2-week washout prior to planned C1D1.  
Concomitant use of strong or moderate CYP3A inducers (e.g. phenobarbital, 
enzalutamide, modafinil require 5-week washout for enzalutamide or phenobarbital and 
3 week washout for all others. See Appendix B for further information. 
12. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases 
that places the patient at unacceptable risk of toxicity or non-compliance. Examples 
include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled 
major seizure disorder, severe COPD, superior vena cava syndrome, extensive bilateral 
lung disease on High Resolution CT scan, severe Parkinson’s disease, active 
inflammatory bowel disease, psychiatric condition, immunocompromised patients or 
active infection including any patient known to have hepatitis B, hepatitis C and human 

26 of 80 
 
immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral 
drugs.  Screening for chronic conditions is not required. 
13. A known hypersensitivity to olaparib, AZD6738 or any excipient of the product or any 
contraindication to the combination anti-cancer agent as per local prescribing 
information 
14. Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with the absorption of the study medication, 
refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant 
bowel resection, with clinically significant sequelae that would preclude adequate 
absorption of AZD6738 
15. Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
16. Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria 
no.12) 
17. Involvement in the planning and/or conduct of the study 
18. Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
19. Previous enrolment in the present study. 
20. Has received a live vaccination with 2 weeks of enrollment.  
 
Procedures for withdrawal of incorrectly enrolled subjects see Section 5.7.  
 
Restrictions During the Study 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
• 
Patients must fast (water to drink only) from at least 2 hours prior to taking all doses of 
AZD6738 and also for 1-hour post-dose.   
• 
Olaparib tablets should be taken at the same time each day, approximately 12 hours 
apart with one glass of water.  The tablets should be swallowed whole and not chewed, 
crushed, dissolved or divided.  
• 
It is recommended that AZD6738 is taken at the same time as the morning dose of 
olaparib and with fasting at least 2 hours prior to taking the dose and at least 1 hour 
afterwards. The second dose of olaparib may be taken with or without food  
• 
If vomiting occurs shortly after AZD6738 or olaparib is swallowed, the dose should 
only be replaced if all of the intact tablets can be counted and then treatment resumed 
with the following scheduled dose. The scheduled dose can be taken up to 2 hours after 
the scheduled dose time. If greater than 2 hours, the missed dose should not be taken 
and patient should continue with next dose at allotted time. 
• 
Patients should not consume grapefruit juice or Seville oranges (including marmalade, 
juice, etc.) while participating in the study. 

27 of 80 
 
• 
Patients should be careful with driving within the first few days of starting therapy 
(cycle 1 only) due to risk of low blood pressure since tolerance is unknown. 
• 
Precautions are advised to limit duration of sun exposure to skin with protective 
clothing and sunscreen. 
 
Contraception 
Male patients must use a condom during treatment and for 6 months after the last dose of study 
drug(s) when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly effective 
form of contraception (as described in Appendix C) if they are of childbearing potential.  Male 
patients should not donate sperm throughout the period of taking study drug(s) and for 6 
months following the last dose of study drug(s). True abstinence is an acceptable form of 
contraception.  Please refer to Appendix C for further details 
 
Concomitant treatments 
 
AZD6738 is an investigational drug for which no data on in vivo interactions are currently 
available. Potential interaction is considered on the basis of preclinical in vitro data only.    
 
The lists of CYP and transporter inhibitors/inducers, and CYP and transporter substrates are 
available in Appendix B. They are not exhaustive and the absence of a drug from these lists 
does not imply that its combination with AZD6738 is safe. If AZD6738 is being administered 
in combination, potential interactions of the combination partner should also be considered. 
Olaparib also has concomitant interactions and may require dose reduction if a strong or 
moderate CYP3A is required for a short period while on study. 
• 
The principal enzyme for metabolizing AZD6738 is CYP3A, olaparib is also 
metabolized similarly Subjects should avoid concomitant drugs, herbal supplements 
and/or ingestion of foods known to modulate CYP3A activity from the time they enter 
the screening period until 28 days after the last dose of study treatment.  
• 
Prior to study medication, use of potent inducers or inhibitors of CYP3A are not 
permitted. For subjects taking any of these drugs (examples provided in Appendix B) 
the required wash-out periods before starting AZD6738 is described. 
• 
While on study medication, if there is no suitable alternative concomitant medication 
other than a potent inhibitor of CYP3A, the investigator must interrupt AZD6738 for 
the duration of the potent CYP3A inhibitor and wait for the required wash-out period 
(five half-lives) before dosing AZD6738 again. If potent CYP3A inducers are 
considered necessary for the patient’s safety and welfare, this may diminish the 
clinical efficacy of AZD6738 and the patient should be monitored carefully for any 
change in the efficacy of study treatment. Olaparib may also require adjustment. 
Refer to Appendix B for additional guidance. 
• 
AZD6738 is a Pgp substrate. Co-administration of Pgp inhibitors or inducers may 
affect exposure to AZD6738 and, therefore, should be minimized if possible. Refer to 
Appendix B for additional guidance. 

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• 
AZD6738 is a substrate and inhibitor of breast cancer resistance protein (BCRP). Co-
administration of BCRP inhibitors or inducers may affect exposure to AZD6738; 
therefore, it is recommended that the investigators should interrupt AZD6738 for the 
duration of on treatment necessary BCRP inhibitor or inducer and wait for the 
required wash-out period of the BRCP modulator (five half-lives) before dosing 
AZD6738 again. AZD6738 also may increase the serum levels of BCRP substrates.  
Refer to Appendix B for additional guidance. 
• 
AZD6738 is a potential inducer of CYP3A4 and CYP2B6. Caution should be applied 
with co-administration of drugs that are either completely metabolized by CYP3A4 
and/or CYP2B6, or that are substrates of CYP3A4 and/or CYP2B6 and also have a 
narrow therapeutic index. Investigators should be aware that the exposure of other 
drugs metabolized by CYP3A4 and/or CYP2B6 may be reduced. Refer to Appendix 
B for additional guidance. 
• 
AZD6738 is an inhibitor of OATP1B1. Caution should be applied with co-
administration of substrates of OATP1B1 as AZD6738 may increase their exposure. 
Refer to Appendix B for additional guidance. 
• 
The use of herbal supplements or ‘folk remedies’ (and medications and foods that 
significantly modulate CYP3A activity) is not allowed.  
• 
Anticoagulation therapy: subjects on warfarin may participate in this trial but it is 
recommended that their INR is monitored more frequently. 
• 
Primary G-CSF and erythropoietin use is not allowed. Secondary G-CSF may be used 
if required. 
• 
Radiotherapy is not permitted during the study with the exception of palliative 
radiotherapy for symptom control (drug dosing will need interrupting during this 
period) 
• 
No other chemotherapy (bone supportive agents are allowed), hormonal therapy 
(besides LHRH agonist/antagonist), other investigational product or live virus or 
bacterial vaccines are permitted (killed vaccines are allowed) other than the 
combination agent(s) in the study 
 
 

29 of 80 
 
5. 
STUDY CALENDAR 
 
 
 
Screening 
(Day -42 to 
Day -1) 
 
Cycle 1m, 2m 
 
Cycle 3+ 
Day 1m (-5 
to +3d) 
 
End of Treatment, 
30 (±3) Day FUm 
Long-
term 
FUj 
Day 1m  
(±3day 
for c2) 
Day 8m  
(±3 day) 
Informed Consent 
X 
 
 
 
 
 
Medical/Surgical 
History, 
Demographics, 
Height  Prior 
Histology (either 
report or clinician 
note as source) 
X 
 
 
 
 
 
Biopsy of 
Metastatic Disease 
Xa 
 
 
 
 
 
Peripheral blood 
for germline 
and/or circulating 
tumor DNA  
Xb 
 
 
 
 
 
PE, Vitalsi, 
Weight 
X 
Xm 
Xm 
Xm 
Xm 
 
Performance 
Status 
X 
X 
X 
X 
X 
 
Adverse Event, 
Toxicity 
Evaluations 
 
X 
X 
X 
X 
 
Medication 
Review  
X 
X 
X 
X 
X 
 
Study Drugc 
 
X 
X 
X 
 
 
Radiologic 
evaluations and 
measurementsd 
X 
(Must be ≤4 
weeks from 
C1D1 or 
repeated)k 
 
 
Xe 
 
 
ECG 
X 
(triplicate) 
Xg 
(C1D1 
only) 
 
 
 
 
Serum Chemistryf, 
LDH 
X 
X 
X 
(optional 
C2D8) 
X 
X 
 
PT (INR), APTT, 
Urinalysish 
X 
 
 
 
 
 
CBC with 
Differential 
X 
X 
X 
(optional 
C2D8) 
X 
X 
 
PSA 
X 
X 
 
X 
X 
 

30 of 80 
 
a. 
Biopsy must be done after patient has consented and registered to the study (unless pre-
existing, CLIA certified lab, next-generation sequencing of metastatic mCRPC biopsy has been 
completed or mCRPC tissue available to submit for testing).  Submitted tissue must be deemed 
adequate or fully reported prior to starting therapy. 
b. 
Peripheral blood is sent for either germline comparison (if tissue also completed) or 
exploratory analysis of circulating tumor DNA and germline DNA if biopsy failed or is unsafe 
(and analysis available). If the biopsy is attempted and has insufficient tissue, new blood may not 
need to be redrawn as it was sent with biopsy.   
c. 
For drug schedule see Section 1.2. 
d. 
Radiographic evaluation will include radionuclide bone scan, CT or MRI of abdomen and 
pelvis, and CT, CXR or MRI of the chest as appropriate.  All disease sites must be assessed using 
the same methodology as performed at baseline.  At the discretion of the investigator, additional 
radiological evaluations may be performed at an unscheduled time point.    
e. 
 While receiving therapy, radiologic tests are performed every 8 weeks (±1 week) from 
C1D1.  After the third scanning timepoint (~6 months), radiologic tests are performed every 12 
weeks (±1 week) from C1D1.   
f.  
Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, potassium, 
total protein, SGOT (AST), SGPT (ALT), sodium,  
g. 
ECG is required ≤7 days of C1D1(C1D1 is adequate). Within the study, triplicate is not 
required unless the first ECG has a prolonged QTC per section 3.3.3. 
 
h.  
Coagulation: activated partial thromboplastin time (APTT) will be performed at 
screening and if clinically indicated; international normalized ratio (INR) will be performed at 
screening and if clinically indicated. Patients taking warfarin may participate in this study; 
however, it is recommended that INR be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable. Each coagulation test result will be recorded in CRF. 
Urinalysis will assess Hb/erythrocytes/blood, Protein/Albumin, and Glucose and should be 
performed at screening. After screening, urinalysis will only be required if clinically indicated. 
i. 
Vitals include body temperature, blood pressure, pulse, respiratory rate, weight, height 
 
 
 
Screening 
(Day -42 to 
Day -1) 
 
Cycle 1m, 2m 
 
Cycle 3+ 
Day 1m (-5 
to +3d) 
 
End of Treatment, 
30 (±3) Day FUm 
Long-
term 
FUj 
Day 1m  
(±3day 
for c2) 
Day 8m  
(±3 day) 
Testosterone 
X 
 
 
 
 
 
Circulating 
Correlatives 
 
Xn 
 
C3D1 onlyn 
Xn 
 
Long-term follow-
up for MDS/AML 
or new primary 
malignancy 
reporting 
 
 
 
 
 
X 

31 of 80 
 
j.  
Follow all patients for MDS/AML and new primary malignancy assessment for up to 5 
years after the patient completes the study per Section 7.7.1.  
k.         To accommodate biopsy timing, the screening CT and bone scans to enroll allow for 
scans up to 6 weeks.  If by the time therapy starts (to accommodate delays) prior scans will be 
>4 weeks from the planned start date of treatment, they must be repeated prior to C1D1 (≤4 
weeks). 
m.        Due to COVID 19 exposure risks AND for ease of patient participation, virtual visits 
are allowed for ALL visits except C1D1 (with windows of ±3 days within C1 and C2, and -5: 
+3 for C3+). Regarding labs, local labs may be used with the same windows as visits (except 
for C2D8 where labs are optional). A single lab is preferred if possible, to minimize interlab 
variability. When the Morgan lab (see footnoten) is open, C1, C3D1 and EOT labs are preferred 
to be done at primary research sites to allow shipping of correlatives (but it is up to treating 
provider to balance tertiary care center COVID risks at that moment in time). Virtual visits 
should entail a video link with patients (via established, HIPAA compliant video visits). Phone 
visits are not preferred.  For virtual visits, PE, weight and vitals will not be collected and are 
NOT deviations.  See section 5.3.3 for drug shipping guidance.  
n. 
Due to COVID 19 exposure risks and guidance from the University of Michigan, the 
Morgan lab may have intermittent availability. The coordinating center (UMCCC) will update 
all sites with the status of the Morgan lab by email to keep sites aware on whether to collect 
specimens or not.  This flexibility will avoid repeat amendments and IRB backlogs.   
 
 
Subject Enrollment and Initiation of Study Therapy 
Subjects will be identified through routine care of patients within the participating cancer 
centers.  Each subject should meet all of the inclusion criteria and none of the exclusion 
criteria for this study.   
 
Procedures for Handling Subjects Incorrectly Enrolled or 
Initiated on Investigational Product 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  Where a subject does not meet all the eligibility 
criteria and incorrectly started on treatment, the Investigator should inform the coordinating 
site and PI immediately, and a discussion should occur between regarding whether to 
continue or discontinue the patient from treatment.  The coordinating site must ensure all 
decisions are appropriately documented. 
 
Treatments 
 
Identity of investigational products 
The AstraZeneca Pharmaceutical Development R&D Supply Chain or a third party 
distributor/contractor will supply AZD6738 and olaparib. 
 Investigational products 
Dosage form and strength(s) 
AZD6738 
20, or 80 tablet 
Olaparib 
100 or 150 mg tablet 

32 of 80 
 
 
 
 
 
Treatment plan 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
AZD6738 
160 mg 
Oral 
Once daily, Days 1-7 
28 Days 
Olaparib 
300 mg 
Oral 
Twice daily, Days 1-28 
 
 
 
 
 
 
Agent administration + distribution 
All treatment is rendered on an outpatient basis.  Reported side effects and potential risks are 
described in Section 6.1/6.2 and dose modifications in Section 5.4.  No other investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient’s malignancy (excluding LHRH agonists/antagonists).  The research 
staff will provide detailed instruction and training for the handling of study drugs and 
administration at the beginning of the study to each patient.  All dosages prescribed and 
dispensed to the patient and all dose changes during the study are recorded.  The patient should 
contact the Investigator if he is unable to take the study drugs as prescribed. 
 
Study drug may be shipped by each site’s research pharmacy (if they are able to) via certified 
temperature-controlled container for overnight delivery, with tracking number and delivery 
signature required. Consultation with local research pharmacy is required and coordinating 
center must be notified that the local IRB and site is able to do this PRIOR to implementing 
site-> subject shipments. Sites are required to submit to coordinating center the subject diary 
and associated shipment processes for each cycle. The drug dispensation log must be updated 
as required noting direct shipment and copy of signature of receipt is encouraged to be 
obtained (if possible), placed in study records and be available for monitoring. Any non-receipt 
by subject/household must be reported to study staff locally so that shipment can be tracked 
and drug accounted for. Any missed dose of study medication is to be managed per protocol. 
 
 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.   
  
Each bottle of AZD6738 and olaparib will have an investigational product label permanently 
affixed to the outside stating that the material is for clinical trial/investigational use only and 
should be kept out of reach of children. The label will include the dosing instructions and a 
space for the enrollment code (E-code) to be completed at the time of dispensing. 
The label will include the following information: 
blank lines for quantity of tablets to be taken 
enrollment code (E-code) 
date of dispensing 
Instructions stating that the AZD6738 tablets should be taken at approximately the 
same time each morning or evening 

33 of 80 
 
 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle and the Investigator Brochure specifies the 
appropriate storage. 
 
Management of Toxicity  
 
Toxicities that require discontinuation from protocol therapy 
Any toxicity observed during the course of the study should be managed in the first instance by 
interruption of the dose of study treatment and dose reductions if necessary.  Repeat dose 
interruptions are allowed as required for a maximum of 28 days on each occasion.  Treatment 
must be interrupted until the patient recovers completely or the toxicity reverts to NCI CTCAE 
grade 1 or 2 (depending on toxicity) or to the baseline CTCAE grade. If the required 
interruption is any longer than 28 days due to toxicity, the patient must be removed from the 
study. If at any point during study treatment, it becomes apparent that the tumor is not coming 
under control, patients are to be removed from study and treated as clinically indicated.  
 
Protocol therapy should be discontinued if a patient experiences: 
• Any CTCAE Grade 4 toxicity with the exception of: 
o CTCAE Grade 4 neutropenia of 5 days or fewer duration 
o CTCAE Grade 4 nausea, vomiting or diarrhea that resolves to Grade 3 in less 
than 72 hours in patients who have not received optimal anti-emetic or anti-
diarrheal therapy 
o CTCAE Grade 4 laboratory abnormalities that can be readily corrected within 
72 hours and do not result in hospitalization 
• CTCAE Grade 3 or 4 thrombocytopenia with bleeding requiring hospitalization 
 
Dose levels for olaparib and AZD6738 
Both drugs have two levels allowed for dose reductions and may be dose reduced stepwise per 
instructions below.  Once a dose is reduced, escalation is not permitted. All dose modification 
and interruptions (including any missed doses) and the reasons for the 
modifications/interruptions are to be recorded in the eCRF. Repeat dose interruptions are 
allowed as required, for a maximum of 4 weeks on each occasion. 
 
AZD6738 has a unique aspect in that its hematologic toxicity (specifically neutropenia, 
leukopenia, thrombocytopenia, see section 5.4.5) is schedule rather than dose-dependent.  For 
hematologic toxicities related to AZD6738 requiring a single dose reduction, the schedule is 
adjusted rather than the daily dose (see Table 1).  Non-hematologic toxicities requiring dose 
reductions (as both drugs would be lowered by one level), daily dose is lowered rather than 
schedule.  If both a hematologic (related to AZD6738 per 5.4.5) AND non-hematologic Grade 
3+ toxicity requiring dose reduction occur concurrently, both drugs are dose reduced.  Olaparib 
is reduced by one dose level, while if AZD6738 is on dose level 0 is reduced to dose level -2 at 
first reduction.    

34 of 80 
 
TABLE 1  Dose Modification Table for AZD6738 
Dose Level 
AZD6738 
0 
160 mg daily Days 1-7 
-1 (Hematologic toxicity) 
160 mg daily Days 1-4 
-1 (Non-hematologic toxicity) 
120 mg daily Days 1-7 
-2 
120 mg daily Days 1-4 
 
TABLE 2  Dose Modification Table for Olaparib 
Dose Level 
Olaparib 
0 
300 mg BID Days 1-28 
-1 
250 mg BID Days 1-28 
-2 
200 mg BID Days 1-28 
 
 
Hematologic Day 1 dosing requirement 
Hematologic toxicity is anticipated to be the biggest challenge.  To minimize this risk, there 
are clear Day 1 criteria (for any cycle) for both ANC and platelets.  Both an ANC over 
1000/µL and platelets over 75,000/µL are required to start each cycle. If either parameter is 
not met, treatment is delayed. If the patient has not recovered after 28 days, they are removed 
from protocol and please see section 5.13 for further hematologic workup.   
 
TABLE 3 Day 1 minimum hematologic criteria 
Treatment day blood counts and toxicity 
ANC 
 
Platelets 
Action 
≥ 1000/µL 
AND 
≥ 75,000/µL 
No dose modification 
or interruption 
< 1000/µL 
OR 
<75,000/µL 
Delay by 1 week 
intervals until 
recovery 
 
 
Management of anemia 
 Olaparib has shown the most suppression of red blood cells in prior studies, such that it is first 
reduced in lower risk anemia scenarios.  At development of anemia, appropriate supportive 
treatment should be considered (per local guidelines) and alternate cause evaluation considered 
(e.g. iron, vitamin B12, folate, hypothyroidism). Investigator judgement to continue study 
treatment with or without supportive treatment (e.g. transfusion) or interrupt dose for a 
maximum of 4 weeks per guidance below.  The use of erythropoietin is not allowed. 
For cases where patients develop prolonged hematologic toxicity causing >2-week 
interruption/delay in study treatment for CTCAE Grade 3 or worse anemia and/or blood 
transfusion dependence, refer to Section 5.4.14 for workup to consider.  

35 of 80 
 
Note, if at any time a dose reduction for a drug is required and the patient is already at dose 
level -2 for that drug, the patient must be removed from study. 
Symptoms related to the Anemia (e.g. fatigue, shortness of breath) are designated by treating 
provider. 
ASYMPTOMATIC Grade 2 Anemia (Hgb<10 and Hgb≥8 g/dL): 
Asymptomatic Grade 2 anemia may be monitored and treatment continued without required 
delay or dose reduction.  Delay, dose reduction and transfusions may be done at provider’s 
discretion.   
SYMPTOMATIC Grade 2 Anemia (Hgb<10 and Hgb≥8 g/dL) or ANY Grade 3 Anemia 
(Hgb<8 g/dL): 
First episode: 
1. Symptomatic Grade 2:  
A treatment delay up to 28 days maximum (with or without blood transfusion) 
to allow resolution to asymptomatic Grade 2, Grade 1 or lower. Olaparib may 
be dose reduced or continued at current dose level. 
2. Grade 3:  
Treatment is delayed to allow resolution to asymptomatic Grade 2, Grade 1 or 
lower (up to 28 days maximum). Transfusions may be done at provider’s 
discretion. Upon recovery, olaparib is reduced by one dose level (if possible). 
Second episode: 
3. Symptomatic Grade 2:  
A treatment delay up to 28 days maximum (with or without transfusion) to 
allow resolution to asymptomatic Grade 2, Grade 1 or lower. Upon recovery, 
Olaparib is dose reduced by one level (if possible).  
1. 
If olaparib was at full dose, AZD6738 dose/schedule is unchanged.  
2. 
If olaparib was at dose level -1, AZD6738 is moved down one dose 
level.  Either from dose level 0 to dose level -1 (hematologic toxicity, 
which is 160 mg daily Days 1-4) OR from dose level -1 (hematologic or 
non-hematologic) to dose level -2. 
4. Grade 3:  
Treatment is delayed to allow resolution to asymptomatic Grade 2, Grade 1 or 
lower (up to 28 days maximum). Transfusions may be done at provider’s 
discretion. Upon recovery, olaparib is reduced by one dose level (if possible). 
1. 
AZD6738 is moved down one dose level.  Either from dose level 0 to 
dose level -1 (hematologic toxicity, which is 160 mg daily Days 1-4) OR 
from dose level -1 (hematologic or non-hematologic) to dose level -2.  

36 of 80 
 
Third episode:  
5. Symptomatic Grade 2 or Grade 3:  
A treatment delay up to 28 days maximum (with or without transfusion) to 
allow resolution to asymptomatic Grade 2, Grade 1 or lower. Upon recovery, 
Olaparib is dose reduced by one level (if possible).   
1. 
AZD6738 is moved down one dose level to dose level -2 (if possible). 
If no further reductions are possible because olaparib or AZD6738 are already at 
dose level -2, the patient should be removed from the study. 
Fourth episode: 
6. Symptomatic Grade 2: Patient is removed from study 
7. Grade 3:  Patient is removed from study 
Any episode of Symptomatic Grade 2 or Grade 3 anemia in conjunction with Grade 2 or 
higher neutropenia, leukopenia or thrombocytopenia 
Treatment is delayed to allow resolution of anemia to asymptomatic Grade 2, Grade 1 or lower 
and thrombocytopenia/leukopenia/neutropenia to Grade 2 or lower (up to 28 days maximum). 
Provider may do transfusions at their discretion.  Upon resumption of therapy, olaparib is dose 
reduced by one level.  AZD6738 is dose reduced by one dose level.  Either from dose level 0 to 
dose level -1 (hematologic toxicity, which is 160 mg daily Days 1-4) OR from dose level -1 
(hematologic or non-hematologic) to dose level -2.  
 
Management of neutropenia, leukopenia and thrombocytopenia 
Adverse events of neutropenia and leukopenia should be managed as deemed appropriate by 
the Investigator with close follow up and interruption of study drug if CTCAE Grade 3 or 
higher occurs. For toxicity of Grades 1-2, especially if more than one toxicity is present, drug 
can be interrupted at Investigator discretion. Interruption can be up to a maximum of 4 weeks.  
Appropriate supportive treatment and causality should be considered. For CTCAE grade 3-4 
toxicities, dose interruption until recovered to grade 1 or 2 or better (up to a maximum of 4 
weeks) should be done.  If repeat occurrences, then dose reduce olaparib to dose level -1 and 
AZD6738 to dose level -1 (hematologic) per above.  If a second event happens, dose reduction 
of olaparib to dose level -2 and AZD6738 to dose level -2 should be done.  If either dose does 
not have another dose level below, they should be removed from study.   
 
G-CSF should be given according to local hospital guidelines for febrile neutropenia but not 
within 24 hours of the last dose of study treatment unless absolutely necessary.  Primary 
prophylaxis with GCSF is not allowed.   After G-CSF, treatment can resume at the earliest 24 
hours after last G-CSF dose OR 7 days for pegylated G-CSF.   
 
 

37 of 80 
 
For cases where patients develop prolonged hematological toxicity (>2-week 
interruption/delay in study treatment due to CTCAE Grade 3 or worse), refer to 
Section 5.4.14. 
 
Management of non-hematologic toxicity 
Acute toxicities should be managed as medically indicated, with temporary suspension of IP 
and initiation of supportive care as clinically indicated by the treating physician. Treatment and 
study participation must be stopped for Grade 4 non-hematologic toxicity excluding; a) Grade 
4 nausea, vomiting, diarrhea that resolves to Grade 3 in less than 72 hours in patients who have 
not received optimal anti-emetic or anti-diarrheal therapy and b) Grade 4 laboratory 
abnormalities that can be readily corrected within 72 hours and do not result in hospitalization. 
At the first occurrence of CTCAE grade 3 or 4 non-hematologic toxicity that resolves to 
CTCAE grade 1 or 2 with supportive measures and treatment hold under 28 days, treatment 
may be resumed.  At the resolution of the first occurrence of a toxicity, a change to dose is not 
automatically required unless indicated by the specific nature of the AE in severy or recurrence 
in view of provider.  At the second occurrence, upon resolution of toxicity, it is suggested that 
olaparib AND AZD6738 should be dose reduced by one dose level (if possible). If no dose 
reduction is possible (e.g. either drug already at dose level -2), the patient is removed from 
study.   If the required interruption is longer than 28 days due to toxicity, the patient must be 
removed from the study treatment unless approved by the Principal Investigator. 
 
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in all study treatment dosing is recommended 
and further diagnostic workup (including a high-resolution CT scan) should be performed to 
exclude pneumonitis. In cases of confirmed pneumonitis (as known toxicity with olaparib), 
treatment is to discontinue.   
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 
• Physical examination; Signs and symptoms (cough, shortness of breath, pyrexia, etc.) 
including auscultation for lung field will be assessed. 
• SpO2; Saturation of peripheral oxygen (SpO2) 
• Other items; When pneumonitis (interstitial lung disease [ILD]) is suspected during 
study treatment, the following markers should be measured where possible: 
o ILD markers (KL-6, SP-D) and β-D-glucan 
o PSA 
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study treatment can be restarted at the same dosing, if deemed 
appropriate by the Investigator.  If significant pulmonary abnormalities are identified, these 
need to be discussed with the Study Physician. 

38 of 80 
 
 
Management of nausea and vomiting 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally 
a single agent antiemetic should be considered (e.g. dopamine receptor antagonist, 
antihistamines or dexamethasone). 
 
Events of nausea and vomiting are known to be associated with olaparib treatment. These 
events are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and 
manageable on continued treatment. The first onset generally occurs in the first month of 
treatment for nausea and within the first 6 months of treatment for vomiting. For nausea, the 
incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines.  
Alternatively, olaparib tablets can be taken with a light meal/snack (i.e. 2 pieces of toast or 
biscuits). See section 5.4.6 for exclusion criteria to Grade 4 trial discontinuation. 
 
 
Management of diarrhea 
Vigorous anti-diarrheal treatment loperamide (Imodium) is required at the first onset of 
diarrhea according to American Society of Clinical Oncology (ASCO) guidelines unless 
systemic infection is suspected and requires rule out per treating physician.  Oral loperamide 
(Imodium) should be used first and with repeat episodes per package guidelines.  The first dose 
of loperamide may be lowered to 2 mg if the diarrhea is recurrent and if in the opinion of the 
treating physician, the diarrhea is not severe.   
 
Patients should be instructed to notify the Investigator or research staff of the occurrence of 
bloody or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, and 
inability to control diarrhea within 24 hours of using loperamide or other prescribed 
anti-diarrheal medications. 
 
If diarrhea is severe (i.e. requiring intravenous [IV] rehydration) and/or associated with fever 
or severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed.  Patients 
with severe diarrhea or any diarrhea associated with severe nausea or vomiting should be 
hospitalized for IV hydration and correction of electrolyte imbalances per provider discretion.  
Doses should be held for Grade 3 or 4 toxicity. See section 5.4.6 for exclusion to Grade 4 trial 
discontinuation regarding diarrhea. 
 
Renal toxicity 
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls 
below the threshold for study inclusion (≥51 mL/min), retesting should be performed promptly. 
 
A one step dose reduction is recommended for patients who develop moderate renal 
impairment (calculated CrCl by Cockcroft-Gault equation of between 31 and 50 mL/min) for 
any reason during the course of the study: the dose of olaparib should be reduced to 200 mg 
BID, see Table 2. 

39 of 80 
 
 
Olaparib has not been studied in patients with severe renal impairment (CrCl ≤30 mL/min) or 
end-stage renal disease; if patients develop severe impairment or end stage disease is it 
recommended that olaparib be discontinued. 
 
Management of hepatic toxicity 
Drug should be stopped if 
• 
ALT or AST or ALP* > 5 × ULN   
• 
ALT or AST or ALP* > 3 × ULN with the appearance of symptoms associated 
with a clinical diagnosis of hepatitis including right upper quadrant pain or 
tenderness, fever, rash or eosinophilia (>5%) 
• 
[ALT or AST > 3 × ULN] and [total bilirubin > 2 × ULN or INR >1.5 (unless 
patient is receiving warfarin) or other evidence of impairment to the synthesis 
function of the liver] 
* In the presence of bone metastasis, assess bone specific isoform of raised ALP in 
the presence of a raised gamma-GT (to ensure the ALP change is specific to the 
liver). 
Please refer to Appendix A “Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law”. 
 
Management of cardiovascular abnormalities 
Cardiovascular toxicity is potentially associated with AZD6738. Either clinically significant 
hypotension (defined as an asymptomatic decrease of more than 20 mmHg in systolic blood 
pressure to below 70 mmHg persisting for at least 10 minutes) or symptomatic orthostatic fall 
in systolic blood pressure (of more than 20 mmHg compared to resting supine systolic blood 
pressure) should be managed with drug interruptions or reductions as per investigator’s 
discretion.  
 
Drug interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible.  If a patient cannot restart study treatment within 28 days for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the Study Physician. All dose reductions and interruptions (including any 
missed doses), and the reasons for the reductions/interruptions are to be recorded in the eCRF.  
 
Study treatment should be stopped at least 3 days prior to planned surgery and restarted 10 
days post-surgery if the wound has healed.  If the wound has not healed well, a further 7 days 
may be allowed and the patient can recommence study drug(s) if there is no evidence of 
disease progression. No stoppage of study treatment is required for any needle biopsy 
procedure. Study treatment should be discontinued for a minimum of 3 days before a patient 
undergoes palliative radiation treatment.  Study treatment should be restarted within 4 weeks as 
long as any bone marrow toxicity has recovered. 
 

40 of 80 
 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
TABLE 4 
Dose interruption and stopping criteria  
Event  
Action  
Surgery  
Interrupt both drugs (maximum 28 days) and resume at full dose.  Both 
drugs should be stopped 3 days prior to surgery and resumed 
approximately 10 days later.  If the wound has not healed a further 7 days 
are permitted prior to restarting combination.  
No stoppage is required for biopsy procedures.  
Vomiting  
If vomiting occurs shortly after study medication is swallowed, the dose 
should only be replaced if all of the intact tablets can be counted. Resume 
with the following scheduled dose. 
Missed dose  
Allowed to take the scheduled dose up to 2 hours after the scheduled dose 
time. If greater than 2 hours, the missed dose should not be taken and 
patient should continue with next dose at allotted time.  
 
 
Management of prolonged hematologic toxicities while on study treatment 
If a patient develops prolonged hematological toxicities (due to either AZD6738 or olaparib or 
both drugs) such as: 
• ≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
anemia and/or development of blood transfusion dependence 
• ≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
neutropenia (ANC < 1 x 109/L). 
• ≥2-week interruption/delay in study treatment due to CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 
50 x 109/L). 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear for 
prolonged hematologic toxicities requiring delays.  If any blood parameters remain clinically 
abnormal after 4 weeks of dose interruption, the patient should be referred to hematologist for 
further investigations.  Bone marrow analysis and/or blood cytogenetic analysis should be 
considered at this stage according to standard hematological practice.  Study treatment should 
be discontinued if blood counts do not recover to CTCAE Grade 1 or better within 4 weeks of 
dose interruption. 
 
Development of a confirmed MDS or other clonal blood disorder should be reported as an SAE 
and full reports must be provided by the Investigator to AstraZeneca Patient Safety.  Study 
treatment should be discontinued if patient’s diagnosis of MDS and/or AML is confirmed.  The 
effect if any of AZD6738 on the bone marrow in terms of prolonged suppression is unknown.  
 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section above.  Bone marrow analysis should include an 
aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy 
for bone marrow cellularity. If it is not possible to conduct cytogenetic analysis or flow 

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cytometry on the bone marrow aspirate, then attempts should be made to carry out the tests on 
a blood sample. Full reports must be provided by the investigator for documentation on the 
Patient Safety database. These data are not required to be entered into CRF. 
 
Treatment Compliance 
To safely participate in a clinical study, all patients should complete pill diaries and planned 
laboratory studies.  Unused drug will be returned to the study team who will contact the 
sponsor for instruction or follow local standard operating practices.   
 
Discontinuation of Investigational Product 
Subjects may be discontinued from protocol treatment in the following situations: 
• Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment 
• Adverse Event 
• Severe non-compliance with the study protocol  
• Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) 
• Disease Progression (as defined by Section 7.6.7).  In the absence of other indicators of 
disease progression, therapy should not be discontinued based on PSA rise alone.  
 
Procedures for discontinuation of a subject from investigational product  
A subject that discontinues will always be asked about the reason(s) for discontinuation and the 
presence of any adverse events. The Principal Investigator/Investigator will perform the best 
possible observation(s), test(s) and evaluation(s) as well as give appropriate medication and all 
possible measures for the safety of the subject. They should also immediately inform Sponsor 
of the withdrawal. Adverse events will be followed up for 30 days post last dose and all unused 
study drug should be returned by the subject.  
 
If a subject is withdrawn from study, see Section 5.7. 
 
Duration of follow-up  
Patients will be followed for 30 days after removal from treatment or until death, whichever 
occurs first.  Patients removed from treatment for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. 
 
All patients should be followed for MDS/AML and new primary malignancy assessment for up 
to 5 years after the patient completes the study per Section 7.7.1. 
 
Patient Removal from Study 
 
Screen failures  
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore will not be treated.  Screen failures should be documented on the Screening and 
Enrollment Log.  These patients will not have a study identification number assigned to them 
and will not receive study treatment.  

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 Off study criteria 
Patients can be taken off study at any time at their own request, or they may be withdrawn at 
the discretion of the investigator for safety, behavioral, administrative reasons or progression. 
The reason(s) for discontinuation from study will be documented and may include: 
• Patient withdraws consent (termination of treatment and follow-up); 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
• Patient is unable to comply with protocol requirements; 
• Treating physician views continuation on the study would not be in the patient’s best 
interest; 
• Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
• Lost to Follow-up. If a research subject cannot be located to document survival after a 
period of 2 years, the subject may be considered “lost to follow-up.” All attempts to 
contact the subject during the two years must be documented; 
Termination of the study by The University of MichiganPatient completes protocol treatment 
and follow-up criteria  
5.8        Patient Replacement  
Patients who are enrolled in the study but do not start treatment with Olaparib, will be replaced 
and not included in analyses.  
 
6. 
DRUG INFORMATION 
 
Olaparib 
Other names for the drug: AZD2281 
 
Description: Olaparib is a potent PARP inhibitor (PARP-1, -2 and -3) that is being developed 
as an oral therapy, both as a monotherapy (including maintenance) and for combination with 
chemotherapy and other anti-cancer agents. 
 
Mechanism of Action: Olaparib inhibits PARP enzymes (including PARP1, PARP2, and 
PARP3. PARP enzymes), which are involved in normal cellular homeostasis, such as DNA 
transcription, cell cycle regulation, and DNA repair.  
 
Absorption:  Following oral administration of olaparib tablets, absorption is rapid with peak 
plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing 
there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with 
steady state exposures achieved within 3 to 4 days. 
 
Limited data suggest that the systemic exposure (AUC) of olaparib increases less than 
proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable 
across trials. 

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Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of 
absorption, but did not significantly alter the extent of olaparib absorption (mean AUC 
increased by approximately 20%) 
 
Distribution: Olaparib had a mean (± standard deviation) apparent volume of distribution at 
steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding 
of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is 
approximately 82%.   
 
Metabolism: In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the 
metabolism of olaparib. 
 
Excretion: A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and 
apparent plasma clearance of 8.6 ± 7.1L/h were observed after a single 400 mg dose of 
olaparib.   
Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 
7-day collection period, 44% via the urine and 42% via the feces. The majority of the material 
was excreted as metabolites.   
Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax 
of olaparib increased by 1.5and 1.2-fold, respectively, when olaparib was dosed in patients 
with mild renal impairment (CLcr = 50-80 mL/min; N=14) compared to those with normal 
renal function (CLcr >80 mL/min; N=8). There are no data in patients with CLcr < 50 mL/min 
or in patients on dialysis.   
 
Side effects: The most common adverse reactions include GI distress (constipation, decreased 
appetite, diarrhea, indigestion, nausea, vomiting), dysgeusia, hematologic effects (anemia, 
leukopenia, neutropenia), headache, pneumonitis/cough/URI, arthralgias/myalgia and fatigue.  
Rare cases of myeloid leukemia have been observed also. 
 
Drug Interactions: In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at 
higher concentrations than are clinically achieved. Olaparib produced little/no inhibition of 
other CYP isozymes. In vitro studies have shown that olaparib is a substrate of CYP3A4.   
 
Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib 
increased by 2.7- and 1.4-fold, respectively, when olaparib was administered in combination 
with itraconazole, a strong CYP3A inhibitor. Simulations using physiologically-based 
pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole) 
may increase the AUC and Cmax of olaparib by 2- and 1.1-fold, respectively.   
 
Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib 
decreased by 87% and 71%, respectively, when olaparib was administered in combination 
with rifampicin, a strong CYP3A inducer. Simulations using PBPK models suggested that a 
moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 
60% and 20 - 30%, respectively. In vitro studies have shown that olaparib is a substrate of Pgp 
and an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The 

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clinical relevance of these findings is unknown.  See Appendix B for further discussion. 
 
Storage and stability: All study drugs should be kept in a secure place under appropriate 
storage conditions.  The investigational product label on the bottle and the IB specifies the 
appropriate storage.   
 
Preparation and Dispensing:  
Olaparib tablets (100 mg or 150 mg tablets) will be packed in high-density polyethylene 
(HDPE) bottles with child-resistant closures. Each dosing container will contain 60 tablets and 
desiccant. Multiple bottles of study treatment may be required for dispensing in order to make 
up the desired dose. Bottles will be labeled per local regulations. 
 
Administration:  
Tablets are to be swallowed whole (not broken, chewed, crushed, dissolved or divided) with 
water.  If given the same time as AZD6738, follow AZD6738 food instructions, otherwise 
olaparib may be taken with or without food. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time. 
 
Availability: Supplied by the Astra-Zeneca Pharmaceutical Development R&D Supply Chain 
 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the olaparib. The drug accountability records should 
capture drug receipt, drug dispensing, drug return and final disposition.   
 
The investigators will be instructed by the Coordinating Center on the return or destruction of 
unused olaparib. If any olaparib is lost or damaged, its disposition should be documented in 
the source documents. Olaparib supplies will be retained at the clinical site pending 
instructions for disposition by the Coordinating Center. 
 
AZD6738 
Description: AZD6738 is a potent ATR inhibitor that is being developed as an oral therapy, 
both as a monotherapy and in combination with chemotherapy and other anti-cancer agents.  
 
Mechanism of Action: AZD6738 inhibits ATR, which is involved in cell cycle checkpoint 
regulation, stalled replication fork resolution, single strand break repair (with Replication 
Protein A) and double strand break repair (with ATR Interacting Protein).   
 

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Distribution: AZD6738 has an estimated volume of distribution by modeling of 1 L/kg.   The 
in vitro protein binding of AZD6738 at plasma concentrations achieved following planned 
dosing is approximately 87%.   
 
Metabolism: In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the 
metabolism of AZD6738. 
 
Side effects: The most common adverse events are thrombocytopenia, anemia, neutropenia, 
nausea, vomiting and fatigue.   
 
Drug Interactions: AZD6738 is metabolized by CYP3A4 and potential inhibits organic anion 
transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (Pgp).  At clinically relevant 
doses, it is unlikely to induce CYP1A2, CYP2B6 or CYP3A4.  See Appendix B for discussion 
of management of potential drug interactions.   
 
Storage and stability: All study drugs should be kept in a secure place under appropriate 
storage conditions.  The investigational product label on the bottle and the IB specifies the 
appropriate storage.   
 
Preparation and Dispensing:  
AZD6738 will be supplied as tablets containing 20 mg, or 80 mg or of drug. AZD6738 tablets 
will be packed in HDPE bottles with child-resistant closures. Bottles will be labeled per local 
regulations. 
 
Administration:  
AZD6738 tablets are to be swallowed whole (not broken, chewed, crushed, dissolved or 
divided) with water at the same time as the morning dose of olaparib and with fasting 2 hours 
prior to dosing and 1 afterwards.  
   
If vomiting occurs shortly after the AZD6738 tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 
2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, 
the missed dose is not to be taken and the patient should take their allotted dose at the next 
scheduled time. 
 
Availability: Supplied by the Astra-Zeneca Pharmaceutical Development R&D Supply Chain. 
 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of AZD6738. The drug accountability records should 
capture drug receipt, drug dispensing, drug return and final disposition. 
The investigators will be instructed by the Coordinating Center on the return or destruction of 
unused AZD6738. If any AZD6738 is lost or damaged, its disposition should be documented in 

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the source documents. AZD6738 supplies will be retained at the clinical site pending 
instructions for disposition by the Coordinating Center.   
7. 
COLLECTION OF STUDY VARIABLES 
 
Recording of Data 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the 
web-based electronic data capture (EDC) system of the University of Michigan. Online access 
will be provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSPM during annual monitoring visits and 
prior to and between visits. Discrepant, unusual and incomplete data will be queried by the 
MSPM. The investigator or study coordinator will be responsible for providing resolutions to 
the data queries, as appropriate. The investigator must ensure that all data queries are dealt with 
promptly.  
 
The data submission schedule is as follows:  
• At the time of registration   
o Subject entry into EDC 
 Subject Status 
 Demographics 
• During study participation 
o All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 7.7 of the protocol.  
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
Record Retention 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  After study closure, the 
investigator will maintain all source documents and study-related documents.  Records are to 
be retained and securely stored until the later of: (a) two (2) years following the date a New 
Drug Application is approved for the Study Drug that is the patient of the Clinical Trial; of (b) 
two (2) years after the Investigational New Drug Application for such Study Drug is terminated 
or withdrawn, or such longer period of time as may be required by Participant policies, 
applicable laws, rule or regulations. 
 
Data and Safety Monitoring  
This study will be monitored in accordance with the NCI approved University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer 
Center Data and Safety Monitoring Committee (DSMC). 
 

47 of 80 
 
The Sponsor Investigator (S-I)/Study Principal Investigator and/or the Project 
Manager/Delegate will review data and patient safety issues with participating sites per a 
defined quarterly meeting cadence. Depending on the protocol activity, the meeting cadence 
may be more frequent. This data review meeting may be achieved via a teleconference or 
another similar mechanism to discuss matters related to: 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (SAE reporting, unanticipated problems) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion.  
Participating sites unable to participate in the data review meeting are required to provide 
written confirmation that their site has reviewed the relevant data and patient safety issues for 
the review period and their site’s data are in alignment with the data reported in the database. 
Written confirmation is to be provided to the Project Manager/Delegate within the timeline 
requested to retain compliance with monitoring timelines. 
Documentation of the teleconference or alternate mechanism utilized to review items above is 
to be retained in the Trial Master File. 
The Project Manager/Delegate is responsible for collating the data from all participating sites 
and completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to 
document the data review meeting discussion. 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a quarterly basis for independent 
review. 
 
Quality Assurance and Audits 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related 
issues.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 

48 of 80 
 
 
Clinical Monitoring Procedures 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of The University 
of Michigan Rogel Cancer Center. Monitoring visits will be made during the conduct of the 
study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo a site initiation meeting to be 
conducted by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and his/her 
study staff should make every effort in attending the site initiation meeting. Study–related 
questions or issues identified during the site initiation meeting will be followed-up by the 
appropriate The University of Michigan Rogel Cancer Center personnel until they have been 
answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source 
documents at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first 
‘Centralized’ visit should occur after the first subject enrolled completes Cycle 2.  The study 
site will send the de-identified source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment 
requires changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine 
monitoring visit will be done at least once a year, or once during the course of the study if the 
study duration is less than 12 months. The purpose of these visits is to verify: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Proper storage, dispensing and inventory of study medication 
• Compliance with regulations 
During a monitoring visit to a site, access to relevant hospital and clinical records must be 
given by the site investigator to the Coordinating Center representative conducting the 
monitoring visit to verify consistency of data collected on the CRFs with the original source 
data.  While most patient cases will be selected from patients accrued since the previous 
monitoring visit, any patient case has the potential for review.  At least one or more 
unannounced cases will be reviewed, if the total accruals warrant selection of unannounced 
cases.  
 

49 of 80 
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate 
the conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues 
identified during these visits will be communicated to the site and are expected to be resolved 
by the site in a timely manner.  For review of study-related documents at the Coordinating 
Center, the site will be required to ship or fax documents to be reviewed.    
 
Efficacy 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the RECIST Committee for measurable disease and the 
guidelines for prostate cancer endpoints developed by the Prostate Cancer Clinical Trials 
Working Group (PCWG3)[14] for bone metastasis. 
 
Patients will need to be reevaluated for response according to the guidelines below. 
 
 
PSA 
Perform PSA testing at a minimum of 4-weeks intervals with the threshold PSA level at 1.0 
ng/mL. To report PSA-based outcomes, PCWG3 recommends that the percent of change in 
PSA from baseline to 12 weeks (or earlier for those who discontinue therapy) and the 
maximum decline in PSA that occurs at any point after treatment be reported for each patient. 
PSA rise alone is insufficient to define progression within the study (see Section 7.6.7).  
 
 
Response evaluation criteria in solid tumors (RECIST) 
Response and progression will utilize the new international criteria proposed by the revised 
RECIST guideline (version 1.1) in combination with other metrics [15].  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria.  
 
 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with any drug. 
 
Evaluable for progression-free survival. Only patients who begin treatment will be evaluable 
for progression-free survival. 
 
Evaluable for objective response. A patient who receives at least one dose of treatment will be 
considered evaluable for objective response.  A patient who does not have an assessment for 
response after starting treatment will be considered a non-responder and will be censored for 
progression at the time of removal from the study.  
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, begin treatment, and have had 
their disease re-evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions. 

50 of 80 
 
 
 
Disease parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable.  
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in 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. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic 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 patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. 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. 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 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. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 

51 of 80 
 
 
 
Methods for evaluation of measurable disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 6 weeks before the beginning of the treatment. 
 
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 is 
preferred to evaluation by 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 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the same pulse 
sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques, 
if possible. 
 
 
Methods of evaluation of bone disease 
Bone disease will be evaluated using Radionuclide bone scan. 
 
 
Progression/response criteria 
Non-lethal disease progression (necessitating discontinuation from trial) is either clinical 
progression (see Section 7.6.7.5) or radiographic progression based on RECIST (see Section 
7.6.7.1, 7.6.7.2) or PCWG3 bone scan criteria (see Section 7.6.7.4). These are combined and 

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shown in graphical format in Section 7.6.8. Confirmatory bone scan ≥4 weeks after first bone 
scan progression per PCWG3 is required and must show ≥2 new lesions. 
PSA progression alone is NOT sufficient for removal from study. 
 
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 the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the 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 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. 
 
7.6.7.2      Evaluation of non-target lesions 
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).  
 
Note: If tumor markers are initially above the upper normal limit, 
they must normalize for a patient to be considered in complete 
clinical response. 
 
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):  
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should prevail 
in such circumstances, and the progression status should be 

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confirmed at a later time by the review panel (or Principal 
Investigator). 
 
7.6.7.3     Outcomes based on radionuclide bone scans 
The subjectivity in interpreting serial changes in a radionuclide bone scan is well recognized. 
Thus, the primary outcome will be whether the scan is stable or improved, vs. worse or 
progression. Changes in intensity will not be used as an outcome measure. 
 
Stable or Improved: A stable or improved classification requires that no new 
lesions appear at the 3rd cycle (12 weeks) ± 1 week assessments. 
 
Progression (Non-Response): Appearance of two or more new skeletal 
lesions. An increase in the size or intensity of known skeletal lesions will not be 
considered progression. This must be confirmed with another bone scan ≥4 
weeks after first bone scan progression per PCWG3 and must show ≥2 new 
lesions. 
 
7.6.7.4     Outcomes based on post-therapy PSA changes 
These definitions are intended to characterize the PSA changes on study for the purpose of 
reporting of results.  PSA progression is NOT criteria to remove from study. 
Complete Response (CR): Undetectable PSA (≤0.2 ng/ml) that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
Partial Response (PR): Decrease in PSA value by ≥ 50% that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
Stabilization (SD): Patients who do not meet the criteria for PR or PD for at 
least 90 days on study (2 cycles of treatment) will be considered stable 
 
Progression (PD): 25% increase over baseline or nadir whichever is lower and 
an increase in the absolute value of PSA level by 2 ng/ml that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
7.6.7.5     Definition of progression based on pain 
Progression by pain criteria is based on pain due to prostate cancer requiring one or more of the 
following palliative interventions:  
- 
Opioid Therapy: Intravenous, intramuscular or subcutaneous opioid therapy 
administered as a single dose; oral or transdermal opioid analgesic use administered for 
10 out of 14 consecutive days, and/or requiring Radionuclide or Radiation therapy. 
- 
Evidence of disease at the site of pain is required. Pain requiring only non-opioid 
analgesics will not be considered disease progression. 
 
7.6.7.6     Progression-free survival 
PFS is defined as the duration of time from date of assignment to treatment arm to time of 
objective progression or death, whichever occurs first (see Section 10.1). 
 

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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
TABLE 5 Best Overall Response For Patients with Measurable Disease (i.e. Target 
Disease) 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once ≥4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or 
CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*        See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**     In exceptional circumstances, unequivocal progression in non-target lesions may be    
           accepted as disease progression. 
Note:  Patients 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  
           the objective progression even after discontinuation of treatment. 
 
Table 6 Best Overall Response for Patients with Non -Measurable Disease (i.e., Non-
Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes of No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is confusing. 
 

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Duration of combined radiographic and PSA response 
Duration of combined radiographic and PSA response is measured from the time of first 
documented response (RECIST v1.1 CR/PR or PSA decline ≥50%) until death, recurrent or 
progressive disease (based on RECIST v1.1) or first PSA increase ≥25% and ≥ 2 ng/ml above 
the PSA nadir. 
 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
 
Adverse event reporting requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done 
to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Data on adverse events will be collected from the time of the 
initial study treatment administration through 30 days after the last dose of study treatment. 
Any serious adverse event that occurs more than 30 days after the last study treatment and is 
considered related to the study treatment will be reported to sponsor investigator. Serious 
Adverse Events (SAEs) will continue to be followed until: 
• Resolution or the symptoms or signs that constitute the serious adverse event return to 
baseline; 
• There is satisfactory explanation other than the study treatment for the changes 
observed; or  
• Death. 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of 
AEs and SAEs are given below. It is the responsibility of the principal investigator to ensure 
that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment is considered to be pre-existing in nature. Any known pre-existing conditions that are 
ongoing at time of study entry should be considered medical history. 
All events meeting the criteria and definition of an AE or SAE, as defined in this section, 
occurring from the initial study treatment through 30 days following the last dose of the study 
treatment must be recorded as an adverse event in the patient’s source documents and on the 
CRF regardless of frequency, severity (grade) or assessed relationship to the study treatment. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a 
pre-existing condition that occurs after the patient begins study treatment is also considered an 
adverse event. 
 
Adverse events after the 30 day follow up period 
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety regardless of investigator’s assessment of causality or knowledge of the 
treatment arm.  After study completion, vigilance will be maintained by either an a) annual 

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chart review for the diagnosis or b) phone call asking the patient whether they have been 
diagnosed with MDS/AML or a new malignancy (one of these should happen between months 
10-12 after discontinuation).  If a patient has been diagnosed with MDS/AML or another 
malignancy, a questionnaire may be sent to them for further information.  This will continue 
for 5 years after a patient completes study.  
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable 
possibility that the event is causally related to the investigational product, the investigator 
should notify the Principal Investigator who will notify AstraZeneca, Patient Safety. 
 
Definition of adverse events 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. An AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.  
• Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures will not 
be reported as adverse events. However, the medical condition for which the procedure 
was performed must be reported if it meets the definition of an adverse event unless it is 
a pre-existing (prior to protocol treatment) condition. 
• Symptoms of prostate cancer are not to be considered adverse events for this study. The 
following symptoms are indicative of underlying disease and will not be reported as 
adverse events (unless the event is considered serious): bone pain, urinary frequency, 
hesitancy or urgency. 
• Abnormal laboratory values or test results constitute adverse events if they induce 
clinical signs or symptoms or require therapy. They are to be captured under the signs, 
symptoms or diagnoses associated with them. 
 
AZD6738 adverse events of special interest 
There are no AESI for AZD6738 which require additional data collection. 
 
Olaparib adverse events of special interest: 
Adverse events of special interest [AESI] are events of scientific and medical interest specific 
to the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. Adverse Events of Special Interest for 
olaparib are the Important Potential Risks of MDS/AML, new primary  
malignancy (other than MDS/AML) and pneumonitis.   
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment. 

57 of 80 
 
 
Definitions of serious adverse event 
An adverse event is considered “serious” if, in the view of either the investigator or Sponsor-
Investigator, it results in any of the following outcomes: 
o Death 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
o A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the investigator 
[or sponsor], its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event that, had it occurred in a more severe form, might 
have caused death.  
o Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours. 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Adverse events for malignant tumors reported during a study should generally be 
assessed as serious AEs.  If no other seriousness criteria apply, the important medical 
event criterion should be used.  Medical judgment on an individual event basis should 
be applied to clarify if non-serious AE or not.  Please contact PI if this occurs for 
guidance.  
o Important medical event 
Any event that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition of “Serious Adverse Event”. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that do not result in inpatient hospitalization 
or the development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of 
the study. Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs. However, if the preexisting condition worsened 
during the course of the study, it should be reported as an SAE. The causality of SAEs (their 
relationship to all study treatment/procedures) will be assessed by the investigator(s) and 
communicated to AstraZeneca. 

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Expected adverse events 
An adverse event (AE) is considered “expected” if: 
• For approved and marketed drugs or devices, those adverse events are described in the 
approved Package Insert (Label).  
• For investigational new drugs or devices, those adverse events are described in the FDA 
Investigator’s Brochure.  
 
Unexpected adverse events 
An adverse event (AE) is considered “unexpected” if it is not described in the Package Insert, 
Investigator’s Brochure, in the protocol, or in the informed consent document 
 
Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction is when an SAE occurs that is unexpected in 
the nature and/or severity compared with the information set out in Investigators Brochures. 
 
Adverse event characteristics 
 
CTCAE term 
(AE description) and grade: The descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be down loaded from the CTEP web site. 
(http://ctep.cancer.gov) 
 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment]. 
Probable – The AE is likely related to the study treatment]. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Reporting of serious adverse events 
 Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality to 
study drug, will be reported to the Principal Investigator and also to the Coordinating Center.  
All SAEs and UPs must be reported to the Coordinating Center within 24 hours of first 
awareness of the event.  Events should be reported using the Coordinating Center’s SAE form 
as available in the study database.  A copy of the SAE form as available in the study database 
should be sent to the Coordinating Center via fax at 734-232-0744 or via email to CTSU-
Oncology-Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event.  
 
Follow-up information must also be reported within 24 hours of receipt of the information by 
the investigator. 

59 of 80 
 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating Center’s 
Principal Investigator (or designee in the event of extended absence) only in the case that the 
event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study drug.  
 Reporting procedures to AstraZeneca 
All Serious Adverse Events (SAEs) occurring from the initial study treatment administration 
through 30 days following the last dose of the study treatment will be reported by the 
Coordinating Center to AstraZeneca.  Any SAEs occurring after 30 days following the last 
dose of the study treatment that are believed to be related to study drug will also be reported to 
AstraZeneca.  
 
For pharmacovigilance purposes and characterization, any case of MDS/AML or new primary 
malignancy occurring after 30 day follow up period should be reported to AstraZeneca Patient 
Safety whether it is considered a non-serious AE [e.g. non-melanoma skin cancer] or SAE, and 
regardless of investigator’s assessment of causality or knowledge of the treatment arm.  
Investigators will be asked during the regular follow up for overall survival if the patient has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases.  If 
patients who are gaining clinical benefit are allowed to continue study treatment post data cut 
off and/or post study completion then all SAEs must continue to be collected and reported to 
Patient Safety within the usual timeframe.  Otherwise, after study treatment completion (i.e. 
after any scheduled post treatment follow-up period has ended) there is no obligation to 
actively report information on new AEs or SAEs occurring in former study patients. 
The Coordinating Center will send the initial completed SAE Form within 24 hours of receipt 
via email to AEMailboxClinicalTrialTCS@astrazeneca.com. 
   
If only limited information is initially available or an ongoing SAE changes in its intensity or 
relationship to the study drug, or if new information becomes available, a follow-up report will 
be generated and sent to AstraZeneca within 24 hours of receipt.   
 Reporting procedures to FDA 
In this trial, serious, unexpected adverse events believed to be definitely, probably or possibly 
related to the study treatment will be reported to the Food and Drug Administration via the 
MedWatch 3500A. The Michigan IND/IDE Assistance Program (MIAP) will be responsible 
for reporting SAEs to the FDA that meet the reporting requirements in 21 CFR 312.32. 
 
A copy of the MedWatch report must be faxed to AstraZeneca at the time the event is reported 
to the FDA.  It is the responsibility of the investigator to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines 
and to ensure that these reports are also submitted to AstraZeneca at the same time. 
* A cover page should accompany the MedWatch form indicating the following: 
• 
External Scientific Research (ESR) 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 

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• 
The trial name/title and AstraZeneca ESR reference number 
* Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
* Send SAE report and accompanying cover page by way of Email to 
AEMailboxClinicalTrialTCS@astrazeneca.com  
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the FDA 
 
 
Routine reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data submission. 
 
Reporting of unanticipated problems 
There are types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent unanticipated problems but are not considered adverse events. 
For example, some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) 
that may represent an unanticipated problem, the investigator should assess whether the 
incident, experience, or outcome represents an unanticipated problem. The incident, experience 
or outcomes is considered unanticipated if it meets all of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the Coordinating Center within 24 
hours of the study team becoming aware of the problem.  
 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
6 months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 6 months after 
the last dose should be followed up and documented. 
 

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Sites should notify the Coordinating Center for any patient partner pregnancies within 24 hours 
of knowledge of the pregnancy.  
 
Genetics  
As this study entails biopsy or circulating tumor genetic analysis at enrollment (unless already 
completed), genetic data will be analyzed and housed.  The exploratory correlatives also will 
capture similar information.   
 
Circulating correlative analytes 
These will be collected per study calendar and are encoded to protect privacy 
 
Specimen banking 
Patient excess samples collected within this study (peripheral blood and excess tissue from 
biopsy returned from TEMPUS) will be retained at University of Michigan if the patient 
consented to specimen banking. Specimens will be stored indefinitely or until they are used up. 
If future use is withdrawn by the patient, best efforts will be made to stop any additional 
studies and destroy the previously obtained specimens. 
Specimens being stored long-term for potential use not outlined in the protocol are subject to 
University of Michigan Policies Governing Tissue Sample Collection. 
If a patient consented to the analysis of prior obtained tissue (e.g. prior biopsies before 
enrolment in study), they may be requested and housed at the University of Michigan.  
 
7.7.17       Specimen management with AstraZeneca 
As rarer subgroups are being identified in prostate cancer, the need to combine anonymized 
results across studies using the same analytical process is important. To minimize genetic 
exposure risks, any tissue shared will NOT be allowed to undergo large-scale (>30 genes) next 
generation sequencing.  Again, patients may opt-out of sharing any tissue with AstraZeneca.  
8. 
ROLES AND RESPONSIBILITIES  
 
Sponsor Investigator 
The Sponsor Investigator is responsible for performing the following tasks: 
- 
Responsibility for the overall conduct of the study at all participating sites and for 
monitoring the progress of the study  
- 
Reviewing and ensuring reporting of SAEs  
- 
Reviewing data from all participating sites  
  
 
Participating Sites  
Participating sites are responsible for performing the following tasks:  
• Following the protocol as written, guidelines consistent with good clinical practice 
(GCP), and applicable Standard Operating Procedures (SOPs). Registering all patients 

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with the coordinating center by submitting the eligibility checklist, supporting source 
documentation, and signed informed consent promptly  
• Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol  
• Maintaining regulatory binders on site and providing copies of all required documents 
to the coordinating center  
• Collecting and submitting data according to the schedule specified by the protocol  
• Responding to queries in a timely manner  
 
Coordinating Center 
The Coordinating Center is responsible for performing the following tasks:  
• Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals and required 
regulatory documents from each site.  
• Managing patient registration  
• Developing and maintaining Clinical Data Management documents and procedures  
• EDC development, setup of study database, and subsequent design changes  
• Participating in review of content of the EDC against the protocol requirements  
• EDC system administration (user/site accounts setup, maintenance and revocation)  
• Data review, cleaning, query management and resolution  
• Establishing procedures for documentation, reporting and submitting of AEs and SAEs.  
• Reviewing SAEs  
• Training participating sites on EDC  
• Collecting and compiling data from each participating site  
• Data reviewing from all participating sites  
• Facilitating monitoring visits by securing selected source documents and research 
records from participating sites for review, or by monitoring at participating sites. 
9. 
ETHICAL AND REGULATORY REQUIREMENTS 
 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements  
 
Subject Data Protection 
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless required 
to do so by law. 
 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 

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identity and also have access to his or her genetic data. Also, Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate. 
 
Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the potential 
benefits of this program, the risks and the probability of their occurrence, and the procedures to 
minimize these risks. Should an AE occur, the provisions available to ensure medical 
intervention will also be reviewed. Why the risks are reasonable in relation to the anticipated 
benefits, incentives, or costs that will or may be incurred as a result of participating in the 
study, as well as the efforts to maintain confidentiality, will also be discussed with the patient.  
 
Patients will be required to sign and date an informed consent form that meets the requirements 
of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 
50) and the IRB. The medical record will include a statement that written informed consent 
was obtained (and document the date that it was obtained) before the patient is enrolled in the 
study. The original signed document will become part of the patient’s medical record, a copy 
will be forwarded to the lead site/sponsor pursuant to sponsor registration and a copy will be 
sent home with each patient.  
 
The consent form will include the following:  
- 
the nature and objectives, potential toxicities, and benefits of the intended study  
- 
the length of therapy and likely follow-up required  
- 
alternatives to the proposed therapy (including available standard and 
investigational therapies)  
- 
the name of the investigator(s) responsible for the protocol  
- 
the right of the patient to accept or refuse treatment and to withdraw from 
participation in this study  
 
Changes to the Protocol and Informed Consent Form 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics committee (IEC).  Amendments to the protocol may be made only with 
consent of the lead site/sponsor and are pending until approval by IRB before instating. 
 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. After this discussion, they will be asked to 
sign a Notice of Privacy Practice research authorization/HIPAA form. The original signed 
documents will become part of the patient’s medical records, and each patient will receive a 
copy of the signed documents. The use and disclosure of protected health information will be 
limited to the individuals described in the research authorization form. The research 
authorization form must be completed by the principal investigator and approved by the IRB. 

64 of 80 
 
 
Terminating or Modifying the Study 
AE and laboratory data from this trial will be assessed by the lead site on an ongoing basis. 
SAEs will be reviewed as they are reported to the lead site, and the medical monitor will make 
an assessment regarding the safety of continuing or modifying the study.  The futility 
evaluation after 17 patients as described.  This assessment will be shared with the investigators 
either in writing or as part of a teleconference. Should the assessment of either the lead 
site/sponsor or the principal investigator be that the study should be terminated, the study will 
be closed to further accrual. Patients who are receiving intervention will be assessed 
individually by the investigator to see if it is in the patients’ best interest to continue, which 
might be the case for a patient that is responding to the intervention. Follow-up safety 
assessments will be performed for all patients who are terminated from the study prematurely. 
10. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
 
Study Endpoints 
 
Analysis of the primary endpoint 
The primary endpoint of the study is the response rate of the DRPro cohort.  Response is 
defined as achieving a complete response (CR) or partial response (PR) by either radiographic 
response according to RECIST v 1.1 or PSA response.  The count of responses and 
corresponding response rate with the 95% binomial confidence interval will be reported in the 
DRPro patients.  
   
 
Analysis of the secondary endpoints 
- 
The response rate and 95% binomial confidence interval will be reported for DRDef 
patients. 
 
The following endpoints will be reported for DRDef and DRPro patients separately 
- 
Objective progression-free survival (combined radiographic and clinical progression-
free survival) will be reported using Kaplan-Meier methods.  This is measured from the 
date of treatment arm assignment until the specified tumor progression (assigned at the 
earliest observed time).  Patients whose disease has not progressed at follow-up will be 
censored at the date when the last tumor assessment determined a lack of progression.   
- 
Objective radiographic disease response rate is determined by the proportion of patients 
with measurable disease that have a response (CR+PR) according to RECIST v1.1.  
The proportion of responders will be reported with the corresponding 95% binomial 
confidence interval. 
- 
PSA progression-free survival (PSA-PFS) will be reported as the composite of survival 
and duration of PSA control as defined by after a start of therapy from baseline to time 
of first PSA increase ≥25% and ≥2 ng/mL above the nadir and confirmed by a second 
value at or beyond 4 weeks later.  Kaplan-Meier methods will be used to report PSA-
PFS. 

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- 
PSA response rate (≤ 0.2 ng/ml, 50% decline, 90% decline) proportions will be reported 
with corresponding 95% binomial confidence intervals.  A waterfall plot of the best 
PSA response decline will be reported. 
- 
Evaluate the qualitative and quantitative AE summaries will be reported by DNA repair 
status and organized by body system, frequency of occurrence, intensity (e.g. severity 
grade) and causality or attribution. Counts and proportions will be included. Treatment 
exposure will be summarized for all patients, including dose administration, number of 
cycles, dose modifications or delays and duration of therapy.  Categorical variables will 
be reported using counts and frequencies.  Continuous variables will be summarized 
using means or medians with the appropriate measure of variability. 
- 
Duration of combined radiographic and PSA response will be reported using Kaplan-
Meier methods. 
 
 
Correlative objectives 
To evaluate the predictive capacity of circulating analytes within both genetic cohorts 
circulating tumor DNA sequencing/quantification, circulating tumor cell number, circulating 
tumor cell composite gene expression by pooled RT-PCR will be measured.  Continuous 
biomarkers will be described using means and standard deviations or medians with percentile.  
Categorical covariates will be described with counts and frequencies.   
- 
The association of correlative biomarkers with response will be assessed using logistic 
models with response as outcome and the correlative covariates as the independent 
predictors.  The association of correlative biomarkers with failure will be assessed 
using Cox models with response rate as the outcome and correlative covariates as the 
independent predictors 
- 
Correlations between the metastatic biopsy and circulating analysis will be compared 
and the proportion of matches will be reported.  McNemar’s test may be used.  
- 
Correlations of liquid assays and tissue-based analyses will be reported using Pearson 
or Spearman correlation coefficients as is appropriate.  
 
Analysis Populations 
 
 
Response-to-treatment populations 
 
All patients who meet eligibility criteria and receive at least one dose of study medication will 
be included in the main analysis of the response rate, even if there are major protocol 
deviations (e.g., incorrect treatment schedule or drug administration). Each patient will be 
assigned to one of the following categories for each response outcome: 
TABLE 7: Categories for Response to Treatment 
Category 
Response 
1 
Complete response 
2 
Partial response 
3 
Stable disease 
4 
Progressive disease 
5 
Early death from malignant disease 
6 
Early death from toxicity 
7 
Early death from other causes 

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8 
Unknown (not assessable/insufficient data) 
NOTE: By arbitrary convention, category 8 designates unknown status in a clinical database.  
Patients in response categories 4 to 8 will be considered to have treatment failure (disease 
progression) 
 
Conclusions are to be based on the population of all eligible patients who receive at least one 
dose of study medication.  Subanalyses will be performed on various subsets of patients, such 
as those with no major protocol deviations, those who have at least one measure of response 
after starting treatment or those who continued in the study for the entire treatment period (i.e. 
did not withdraw prematurely).  Sub-analysis will not serve as the basis for drawing 
conclusions concerning treatment’s efficacy.  
 
 
Safety population 
All patients enrolled in the study who receive at least one dose of study treatment will be 
included in the safety analysis population and considered evaluable for toxicity and safety from 
the time of their first dose. Analysis will be completed by treatment received rather than 
treatment assigned. Demographic and baseline characteristics for the safety population will be 
summarized by number and percent for categorical data (e.g., race/ethnicity) and by descriptive 
statistics for continuous data (e.g., weight, vital signs, EKG readings, disease status). 
 
Safety Analysis 
 
Evaluation of adverse events 
Treatment-emergent AEs will be translated from investigator terms to a custom medical 
dictionary and summarized (number and percentage of patients) for each treatment arm for all 
patients who receive at least one dose. AE summaries will be reported by arm and organized by 
body system, frequency of occurrence, intensity (i.e., severity grade), and causality or 
attribution. Patients who experience an AE more than once will be counted only once. The 
occurrence with the maximum severity will be used to calculate intensity. 
 
 
Evaluation of serious adverse events and premature withdrawals 
AEs deemed serious and those resulting in treatment withdrawal or death will be summarized 
separately. Narrative paragraphs will be generated to describe the circumstances surrounding 
each SAE and death. 
 
 
Extent of exposure 
Treatment exposure will be summarized for all patients, including dose administration, number 
of cycles, dose modifications or delays, and duration of therapy. This will be reported 
separately by treatment arm. 
 
 
Early stopping 
Stopping rules for excessive toxicity will be incorporated for patients. Excessive toxicity will 
be defined as removal from treatment due to toxicity despite dose modification. We consider 
excessive toxicity if more than 25% of subjects have to stop the trial because of toxicity. Once 
10 subjects have been enrolled, we will continually monitor the rate of toxicity withdrawal and 
stop if we have evidence that the rate is above 25%. If the rate is >25% at any time after 10 

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patients are accrued, enrollment will be halted and re-evaluated for dose reduction or closed to 
accrual. 
 
 
Statistical procedures 
Summary statistics include the number of observations, mean, standard deviation, median, 
minimum, and maximum values. As this is not a comparative trial, p-values will be used 
sparingly. 
 
 
Sample size calculation 
The statistical design for DRPro will be an Optimal Simon 2-stage Phase II.  Based on the 
TOPARP-A study the null response rate for DRPro is 6% and a response rate of 6% or less 
would not be interesting.  Accrual of 35 DRPro patients will provide 80% power to detect a 
response rate of 20% or greater with 5% type I error.  Stage 1 will accrue 17 DRPro patients.  
If 1 or less DRPro patients have a preliminary response (CR/PR using radiographic by RECIST 
v.1.1 or PSA decline ≥50%) then the DRPro cohort will stop.  If 2 or more responses occur, 
then the 2nd stage will begin and another 18 DRPro patients will be accrued.  If 5 or more 
patient responses are seen out of the 35 DRPro patients, then the combination treatment will be 
deemed interesting for further study in the DRPro population.   
 
The statistical design for the DRDef is a Mini-Max Simon 2-stage Phase II. Based on a 
response rate of 45% within the first 12 weeks in TOPARP-A, a response rate of under 45% 
would not be interesting.  Stage 1 of this design requires 12 DRDef patients and if 5 or less 
patients have a preliminary response (CR/PR using radiographic by RECIST v.1.1. or PSA 
decline ≥50%), then the DRDef cohort would not be of interest.  If 6 or more patients do 
respond, this would support consideration to expand (with amendment or new protocol) with 
another 13 patients (to a total of 25 patients) or a completely separate trial.  Accrual of 25 
patients would provide 80% power to detect a response rate of 70% or greater with 5% type I 
error.  If 16 or more patient responses were seen in a 25 total DRDef patient cohort, then the 
combination treatment would be deemed interesting for further study  DRDef . Different RR 
are used for DRDef and DRPro as different expected baseline RR. 
 
 
Derived variables 
- 
Change from baseline will be calculated as the rating after baseline minus the rating at 
baseline 
- 
Percent change from baseline will be calculated as the rating after baseline minus the 
rating at baseline quantity divided by the baseline. 
- 
Duration of treatment will be defined as the number of days from the first day of 
protocol assigned intervention to the last day of protocol treatment. If the last day of 
protocol treatment is missing, the date of the last visit will be substituted for the missing 
value 
 
Data Monitoring Committee  
The trial will utilize the University of Michigan Rogel Cancer Center’s Data Monitoring 
Committee to monitor this study.  The University of Michigan Rogel Cancer Center will also 
compile the relevant data from participating sites.  

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11. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED   
 
Overdose  
There is currently no specific treatment in the event of overdose with AZD6738 and possible 
symptoms of overdose are not established. 
 
AZD6738 must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose. The Maximum Tolerated Dose is 160 mg by mouth daily 
for 7 out of 28 days for AZD6738 and 300 mg by mouth twice a day for olaparib. 
 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. Olaparib must only be used in accordance with the 
dosing recommendations in this protocol. Any dose or frequency of dosing that exceeds the 
dosing regimen specified in this protocol should be reported as an overdose. The Maximum 
Tolerated Dose is 300 mg twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose CRF module. 
 
An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel should inform the Coordinating Center within one day, 
i.e., immediately but no later than the end of the next business day of when he or she becomes 
aware of it.  The Coordinating Center will send the information within 24 hours of receipt to 
AstraZeneca Patient Safety.  
The designated AstraZeneca representative works with the Coordinating Center to ensure that 
all relevant information is provided to the AstraZeneca Patient Safety data entry site.  
 
For overdoses associated with SAE, standard reporting timelines apply, see Section 7.7.  For 
other overdoses, reporting should be done within 30 days.  
 
Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
6 months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should if possible be followed up and documented.  

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The outcome of any conception occurring from the date of the first dose until 6 months after 
the last dose should be followed up and documented. 
 
 
 
 
12. 
LIST OF REFERENCES 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 
2017. 67(1): p. 7-30. 
2. 
Robinson, D., et al., Integrative clinical genomics of advanced prostate cancer. Cell, 
2015. 161(5): p. 1215-28. 
3. 
Mateo, J., et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N 
Engl J Med, 2015. 373(18): p. 1697-708. 
4. 
Hussain, M., et al., Targeting Androgen Receptor and DNA Repair in Metastatic 
Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol, 2017: p. 
Jco2017757310. 
5. 
Cheng, H.H., et al., Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic 
Castration-resistant Prostate Cancer. Eur Urol, 2015. 
6. 
Balmana, J., et al., Phase I trial of olaparib in combination with cisplatin for the 
treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol, 
2014. 25(8): p. 1656-63. 
7. 
Rajan, A., et al., A phase I combination study of olaparib with cisplatin and 
gemcitabine in adults with solid tumors. Clin Cancer Res, 2012. 18(8): p. 2344-51. 
8. 
Oza, A.M., et al., Olaparib combined with chemotherapy for recurrent platinum-
sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol, 2015. 16(1): p. 87-
97. 
9. 
Wilson, R.H., et al., A phase I study of intravenous and oral rucaparib in combination 
with chemotherapy in patients with advanced solid tumours. Br J Cancer, 2017. 116(7): 
p. 884-892. 
10. 
Pujade-Lauraine, E., et al., Olaparib tablets as maintenance therapy in patients with 
platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation 
(SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 
trial. Lancet Oncol, 2017. 18(9): p. 1274-1284. 
11. 
Kaufman, B., et al., Olaparib monotherapy in patients with advanced cancer and a 
germline BRCA1/2 mutation. J Clin Oncol, 2015. 33(3): p. 244-50. 
12. 
Robson, M., et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline 
BRCA Mutation. N Engl J Med, 2017. 377(6): p. 523-533. 
13. 
Krebs, M.e.a., Phase I Study of AZD6738, an inhibitor of ataxia telangiectasia Rad3 
related (ATR), in combination with olaparib or durvalumab in patients with advanced 
solid cancer. AACR annual meeting 2018. Abstract CT026. 
14. 
Scher, H.I., et al., Trial Design and Objectives for Castration-Resistant Prostate 
Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working 
Group 3. J Clin Oncol, 2016. 34(12): p. 1402-18. 

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15. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
 

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13. 
APPENDICES  
Appendix A: Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law 
 
Appendix B: Guidelines Regarding Potential Interactions with Concomitant Medications 
 
Appendix C: Acceptable Birth Control Methods 
 
Appendix D: Genomics Research 
 
Appendix E: Study Management During COVID-19 
 
 
 

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Appendix A 
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can be 
found in Section 5.4.10 of the protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Sponsor clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the 
review and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 

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• 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before and 
After Starting Study Treatment  
• 
Notify the Company within 1 day of PHL criteria being met as SAE under serious 
criteria “important medical event” and causality according to CSP process for SAE 
reporting. 
• 
For patients meeting PHL criteria prior to starting investigational drugs, the investigator 
is not required to submit a PHL SAE unless there is a significant change in patient’s 
condition 
The Company contacts the Investigator, to provide guidance, discuss and agree an approach for 
the study patients’ follow-up and the continuous review of data.  Subsequent to this contact the 
Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Company. << For studies using a central laboratory add: This includes 
deciding which the tests available in the Hy’s law lab kit should be used>>  
• 
Complete the three Liver CRF Modules as information becomes available  
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Company 
contacts the Investigator in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  to ensure 
timely analysis and reporting to health authorities within 15 calendar days from date PHL 
criteria was met.  The Sponsor Physician will also be involved in this review together with 
other subject matter experts as appropriate.   

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According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly  
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to standard processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘ Hy’s Law Case’) ensuring causality assessment is medically 
important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the previously submitted PHL SAE report 
following CSP process for SAE reporting according to the outcome of the review 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined 
• 
 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment  
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 
• 
Determine if there has been a significant change in the patients’ condition# compared 
with the last visit where PHL criteria were met#  
− 
If there is no significant change no action is required 

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− 
If there is a significant change notify the Sponsor representative, who will 
inform the Company, then follow the subsequent process described in Potential 
Hy’s Law Criteria met of this Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Company if there is any uncertainty. 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.   
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study e.g. chronic or progressing malignant disease, severe 
infection or liver disease, or did the patient meet PHL criteria prior to starting study 
treatment and at their first on study treatment visit as described in Actions Required 
When Potential Hy’s Law Criteria are Met Before and After Starting Study Treatment? 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met 
• 
If there is no significant change no action is required 
• 
If there is a significant change follow the process described in Section 5.4.10 
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Company if there is any uncertainty. 
References 
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815 
 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
 

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Appendix B  
Guidelines Regarding Potential Interactions with 
Concomitant Medications 
AZD6738 is an investigational drug for which no data on in vivo interactions are currently 
available. Potential interaction is considered on the basis of preclinical in vitro data only.  
The lists of CYP and transporter inhibitors/inducers, and CYP and transporter substrates are 
available in this appendix. They are not exhaustive and the absence of a drug from these lists 
does not imply that its combination with AZD6738 is safe. If AZD6738 is being administered 
in combination, potential interactions of the combination partner should also be considered. 
 
Restrictions regarding drugs affection CYP3A metabolism  
There are currently no data confirming that there is a pharmacokinetic (PK) interaction 
between these agents and AZD6738; a potential interaction is considered on the basis of 
preclinical and in vitro data only. AZD6738 is predominantly eliminated via CYP3A 
metabolism (approximately 60%), therefore CYP3A inhibitors or inducers may increase or 
decrease exposure to AZD6738, respectively. Potent inhibitors or inducers of CYP3A should 
not be combined with AZD6738.  
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate CYP3A activity. Please contact AstraZeneca with any queries you 
have on this issue. Please refer to full prescribing information for all drugs prior to co-
administration with AZD6738. 
 
TABLE 8: Drugs Known to be Inhibitors and inducers of CYP3A 
- manage by stopping/not using these medications 
Potent CYP3A inhibitors 
Potent CYP3A inducers 
boceprevir 
clarithromycin 
conivaptan 
elvitegravir/ ritonavir 
fluconazole  
grapefruit juicea  
indinavir  
itraconazole  
ketoconazole  
lopinavir/ RIT  
mibefradil  
nefazodone  
nelfinavir  
posaconazole  
ritonavir  
saquinavir  
telaprevir  
telithromycin  
tipranavir/RIT 
troleandomycin  
voriconazole 
avasimibe  
carbamazepine  
enzalutamide  
mitotane  
phenobarbital  
phenytoin  
rifabutin  
rifampin 
St John's Wort 
List created using the University of Washington Drug-Drug Interaction Database January 2013.  
RIT = Ritonavir.  
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction, and the net pharmacokinetic 
outcome during chronic ritonavir therapy is inhibition of CYP3A activity 
a. Double-strength grapefruit juice 
Patients should abstain from eating grapefruit and Seville oranges (and other products containing these fruits 
eg, grapefruit juice or marmalade) while on olaparib and AZD6738 therapy.  
 
Drugs known to be inhibitors or inducers of Pgp and/or BCRP, undertake appropriate 
monitoring if co-administration is necessary  

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AZD6738 is a substrate of Pgp and BCRP. Co-administration of Pgp inhibitors/inducers or 
BCRP inhibitors/inducers may affect exposure to AZD6738 therefore it is recommended that 
these are not co-administered with AZD6738.  
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate Pgp activity or BCRP activity. Please contact AstraZeneca with 
any queries you have on this issue. Please refer to full prescribing information for all drugs 
prior to co-administration with AZD6738. 
 
Table 9: Drugs known to be inhibitors or inducers of Pgp 
- manage by stopping/not using these medications 
Drugs Known to be Inhibitors of Pgpa 
Drugs Known to be Inducers 
of Pgpb 
Amiodarone 
azithromycin  
captopril  
carvedilol  
clarithromycin  
conivaptan  
cremophor  
curcumin  
diltiazem  
dronedarone  
elacridar  
erythromycin  
felodipine  
fluvoxamine  
ginkgo  
indinavir  
itraconazole  
ketoconazole  
lapatinib 
lopinavir and ritonavir  
mibefradil 
milk thistle  
mirabegron  
nelfinavir 
nifedipine  
nitrendipine 
paroxetine  
quercetin 
quinidine  
ranolazine 
rifampin  
ritonavir  
saquinavir/ritonavir  
schisandra chinensis 
extract  
St Johns Wort 
talinolol  
telaprevir 
telmisartan  
ticagrelor 
tipranavir/ritonavir  
tolvaptan 
valspodar (PSC 833) 
verapamil 
avasimibe 
carbamazepine  
efavirenz  
genistein  
phenytoin  
rifampin 
St Johns Wort 
a. Inhibitors listed for Pgp are those that showed >25% increase in exposure to a Pgp substrate (e.g. digoxin). 
b. Inducers listed for Pgp are those that showed >20 % decrease in exposure to a Pgp substrate (e.g. digoxin) 
 
 
 

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Table 10: Drugs known to be inhibitors or inducers of BCRP 
- manage by stopping/not using these medications 
Drugs Known to be Inhibitors of BCRP 
Drugs Known to be inducers 
of BCRP 
Afatinib  
Aripiprazole  
Curcumin  
Cyclosporine  
Elacridar  
Erlotinib  
Fluvastatin  
Fumitremorgin  
Gefitinib  
Ivermectin  
Lapatinib  
Nilotinib  
Novobiocin  
Pantoprazole  
Pitavastatin  
Ponatinib  
Quercetin  
Quizartinib  
Rabeprazole  
Regorafenib  
Rilpivirine  
Sulfasalazine  
Sunitinib  
Tacrolimus  
Teriflunomide  
Trametinib  
Trifluoperazine  
Vismodegib 
eltrombopag 
Atazanavir 
Lopinavir 
Ritonavir 
Tipranavir 
Omeprazole 
Estrone 
17b-estradiol 
Imatinib mesylate 
Please check individual drugs 
on a case by case basis  
List created using http://dmd.aspetjournals.org/content/dmd/43/4/490.full.pdf 
Note: Although BCRP is involved in a number of clinically relevant DDIs, none of the cited inhibitors above 
is truly specific for this transporter 
 
Drugs known to be substrates of CYP3A4 and/or CYP2B6, undertake appropriate 
monitoring if co-administration is necessary  
AZD6738 is a potential inducer of CYP3A4 and CYP2B6. Therefore, caution should be 
applied with co administration of drugs that are either completely metabolized by CYP3A4 
and/or CYP2B6, or that are substrates of CYP3A4 and/or CYP2B6 and also have a narrow 
therapeutic index. Investigators should be aware that the exposure of other drugs metabolized 
by CYP3A4 and/or CYP2B6 may be reduced. 
 
Table 11: Drugs known to be metabolized by CYP3A4 and have a narrow therapeutic 
index 
- may co-administer, monitor toxicity/levels more frequently if possible 
Alfentanil  
Cyclosporine  
Dihydroergotamine  
Ergotamine  
Fentanyl 
Pimozide  
Quinidine  
Sirolimus  
Tacrolimus  
Astemizole  
Cisapride  
Terfenadine 
 

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Table 12: Drugs known to be metabolized by CYP2B6 and have a narrow therapeutic 
index 
- may co-administer, monitor for toxicity and check levels more frequently if possible 
Cyclophosphoamide 
Ifosfamide 
Efavirenz 
Bupropion 
Propofol 
Thiotepa 
Sorafenib 
alfentanil 
ketamine 
methadone 
methoxetamine 
nevirapine 
propofol 
selegiline 
sertraline 
sorafenib 
tamoxifen 
valproic acid 
From Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University 
School of Medicine  
 
Drugs known to be substrates of OATP1B1 and BCRP, undertake appropriate 
monitoring if co-administration is necessary  
AZD6738 is also an inhibitor of OATP1B1 and BCRP. Caution should be applied with co-
administration of substrates of OATP1B1 and/or BCRP as AZD6738 may increase their 
exposure. 
These lists are not intended to be exhaustive and appropriate medical judgment is required. 
Please contact AstraZeneca with any queries you have on this issue. Please refer to full 
prescribing information for all drugs prior to co-administration with AZD6738. 
 
Table 13: Drugs known to be substrates of OATP1B1 
- may co-administer, be aware of potential drug toxicity 
Atorvastatin  
Fluvastatin  
Lovastatin  
Pitavastatin  
Pravastatin  
Rosuvastatin  
Simvastatin  
Ezemibe  
Methotrexate  
Rifampin  
Bosentan  
Glyburide  
Repaglinide  
Valsartan  
Olmesartan  
Atrasentan 
List created using https://www.solvobiotech.com/transporters/OATP1B1 
 
 
 

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Table 14: Drugs known to be substrates of BCRP 
- may co-administer, be aware of potential drug toxicity 
Anthracyclines 
Daunorubicin 
Doxorubicin 
Topotecan 
SN-38 
Irinotecan 
Methotrexate 
Imatinib 
Irinotecan 
Mitoxantrone 
nucleoside analogs 
prazosin 
pantoprazole 
topotecan 
rosuvastatin and other statins 
teriflunomide 
chlorothiazide 
 List created using https://www.solvobiotech.com/transporters/bcrp 
Olaparib:  
This is guidance on management of olaparib on study when a strong or moderate CYP3A must 
be used for a short time.   
If a strong CYP3A inhibitor must be used, olaparib should be dose reduced to 100 mg daily for 
the duration of concomitant therapy and for 5 half-lives afterwards. If a moderate CYP3A 
inhibitor must be used, olaparib should be reduced to 150 mg po twice a day for the duration of 
concomitant therapy with the moderate inhibitor and for 3 half-lives afterwards.  After 
washout, olaparib may be increased to full prior dose. 
 
 
 
 
 

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Appendix C 
Acceptable Birth Control Methods 
Olaparib is regarded as a compound with medium/high fetal risk.  
Subjects who are sexually active, must agree to use TWO highly effective forms of 
contraception in combination (as listed below).  This should be started from the signing of the 
informed consent and continue throughout the period of taking study treatment and for at least 
6 months after last dose of study drug(s), or they must totally/truly abstain from any form of 
sexual intercourse (see below). 
Patients must use a condom during treatment and for 6 months after the last dose of study 
drug(s) when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly effective 
form of contraception if they are of childbearing potential (as listed below) with two forms of 
contraception.  Male patients should not donate sperm throughout the period of taking study 
drug(s) and for 6 months following the last dose of study drug(s). Men must not donate sperm 
throughout the period of taking study drug(s) and for 6 months after the last dose of study drug. 
Acceptable non-hormonal birth control methods include: 
• 
Total/True abstinence: When the patient refrains from any form of sexual intercourse 
and this is in line with their usual and/or preferred lifestyle; this must continue for the 
total duration of the study and for at least 6 months after the last dose of study drug (for 
6 months after last dose for male patients.  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods or declaration of abstinence solely for the 
duration of a study) and withdrawal are not acceptable methods of contraception. 
• 
Vasectomised sexual partner PLUS male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom 
• 
Intrauterine device PLUS male condom.  Provided coils are copper-banded 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom  
• 
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill. 
• 
Hormonal shot or injection (e.g. Depo-Provera) PLUS male condom 
• 
Etonogestrel implants (e.g. Implanon, Norplant) PLUS male condom  
• 
Norelgestromin / ethinyl estradiol transdermal system PLUS male condom  
• 
Intrauterine system (IUS) device (eg, levonorgestrel releasing IUS -Mirena®) PLUS 
male condom  
• 
Intravaginal device (e.g. ethinyl estradiol and etonogestrel) PLUS male condom 
 
 
 

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Appendix D:   Genomics Research  
Background and Rationale 
This trial requires analysis of the genetic content of cancer cells or circulating DNA.  This is 
imperative to the successful execution of the trial and is required.  Germline and tumoral 
analysis will be completed if possible to truly isolate the somatic vs inherited genetic 
components of each individual cancer.  These results will be shared with the patient and 
appropriate referrals completed if necessary.  See laboratory manual for how samples are 
collected and study calendar for when they are collected.     
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are important 
to maintain subject confidentiality.  Samples will be stored for a maximum of 25 years, from 
the date of last subject last visit, after which they will be destroyed.  DNA is a finite resource 
that is used up during analyses.  Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood, saliva or tissue.  The sample will utilize only the patient ID, which the master key is 
kept securely.  The samples and data for genetic analysis in this study will be single coded.  
The link between the subject enrollment/registration code and the DNA number will be 
maintained and stored in a secure environment, with restricted access.  The link will be used to 
identify the relevant DNA samples for analysis, facilitate correlation of genotypic results with 
clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent.