Clinical trial NCT02576444
Conditions: Cancer
Sponsor: Joseph Paul Eder
Start date: 2015-11-01; Completion date: 2019-11-18
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this phase II trial is to determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.

Detailed description:
This is a phase II signal-searching study in a range of tumor types with the potential to identify novel tumor indications for combination therapy with olaparib that can subsequently be explored in dedicated studies. Patients will be enrolled in this study based on molecular markers from genetic profiling performed on their tumors prior to study entry (outside of protocol). The trial will also identify genetic determinants of response and resistance.

Patients with tumors harboring damaging mutations in Homologous - DNA repair (HDR) genes or mutations such as ATM, CHK2, MRN (MRE11/NBS1/RAD50), CDKN2A/B and APOBEC will be treated with olaparib or olaparib and AZD6738. Enrollment to the olaparib monotherapy arm will be completed prior to commencement of enrollment to the olaparib and AZD6738 arm. Patients with tumors harboring IDH1/IDH2 mutations will be treated with olaparib. Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib.

Arms: arm 1: Patients with cholangiocarcinoma harboring IDH 1/2 tumors will be treated with olaparib. Patients with tumors harboring mutation in HDR genes will be treated with olaparib. arm 2: Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with AZD5363 plus olaparib. arm 3: Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus olaparib. TP53 mutations must be found on the TP53 mutation eligibility list. arm 4: Patients with tumors harboring mutations in HDR genes, including ATM, CHK2, APOBEC, MRE11 complex, will be treated with AZD6738 and olaparib.
Interventions: intervention 1: AZD2281 intervention 2: AZD5363 intervention 3: AZD1775 intervention 4: AZD6738
Intervention descriptions: intervention 1: Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 mL of water. intervention 2: Patients will be administered AZD5363 at 640 mg twice daily for two days on/five days off (2/7) schedule. Two (2) 200 mg tablets and three (3) 80 mg tablets should be taken twice daily. intervention 3: The recommended dose will be available no earlier than March 2016. intervention 4: Patients will be administered AZD6738 at 160 mg daily for days 1-7 of a 28-day cycle (7/28) schedule. AZD6738 is available as 100, 20, and 10 mg tablets. Tablets should be taken daily.

Protocol documents:
Prot_SAP_000.pdf: 
ClinicalTrials.gov ID: NCT02576444 
 
Title: OLAParib COmbinations 
ClinicalTrials.gov ID: NCT02576444 
Protocol Date: 2/7/2019 
 
 


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Abstract 
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Title: OLAParib COmbinations 
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Page 1 of 134 
Drug Substances 
Olaparib (AZD2281), 
AZD5363, AZD6738, 
AZD1775 
Version Number 
6.0 
Date 
07 February 2019 
Local Protocol # 
HIC#1508016363 
IND# 
128100 
A Phase II Study of the PARP Inhibitor Olaparib (AZD2281) Alone and in Combination with
AZD1775, AZD5363, or AZD6738 in Advanced Solid Tumors - OLAPCO (OLAParib
COmbinations) 


Page 2 of 134 
PROTOCOL SYNOPSIS 
TITLE: A Phase II Study of the PARP Inhibitor Olaparib (AZD2281) Alone and in Combination 
with AZD1775, AZD5363, or AZD6738 in Advanced Solid Tumors- OLAPCO (OLAParib 
COmbinations) 
Principal Investigator: 
Joseph Paul Eder, M.D. 
Professor of Medicine 
Director, Early Drug Development Program 
Yale University Cancer Center 
333 Cedar Street 
WWW211, PO Box 208028 
New Haven, CT 06520 
Direct: (203) 737-1906 
Cell: (203) 500-1019 
Email: joseph.eder@yale.edu 
Coordinating Center: 
Yale Cancer Center 
Participating Institutions:   Dana-Farber/Harvard Cancer Center (DF/HCC) 
Boston, MA 
Vanderbilt Ingram Cancer Center, Nashville, TN 
Cleveland Clinic, Cleveland, OH 


Page 3 of 134 
Objectives 
Primary Objective 
•
To determine tumor overall response rate (ORR) in molecularly selected patients with
measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors
(RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the
study (Note: there will be no formal comparison between arms)
Secondary Objectives 
•
To determine tumor overall response rate (ORR) in molecularly selected patients with
measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors
(RECIST), before versus after 16 weeks of treatment within tumor type in each arm of the
study (Note: there will be no formal comparison between arms)
•
To determine tumor clinical benefit rate (CBR) in molecularly selected patients with
measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors
(RECIST), before versus after 16 weeks of treatment across tumor types and within tumor
type in each arm of the study (Note: there will be no formal comparison between arms)
•
To determine progression free survival (PFS), duration of overall response, and duration of
stable disease in molecularly selected patients with measurable disease as assessed by the
Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of
treatment across tumor types and within tumor type in each arm of the study (Note: there will
be no formal comparison between arms)
•
To determine the safety and tolerability of oral administration of olaparib alone and in
combination of AZD1775, AZD5363, and AZD6738 in patients with advanced solid tumors
•
To collect and store molecular profiling data of all patients enrolled in this study, for the
purpose of correlating treatment response/clinical benefit with patterns of tumor genetic
abnormalities in tumors
Exploratory Objectives 
•
To correlate clinical benefit rate (CBR) associated with treatment at Week 16 (Overall
Response Rate (ORR), Complete Response (CR), and Partial Response (PR)) with additional
defects in DNA repair pathways as measured by genetic aberrations in the tumors
•
To compare genetic variants/mutations measured in tumor tissue in diagnostic archival
specimen at baseline and on progression (when samples available), and correlate with tumor
response and clinical benefit
•
To determine tumor mutations in ctDNA at baseline, on treatment, and at progression, and
evaluate the changes in ctDNA mutations and correlate with tumor response and clinical
benefit


Page 4 of 134
Study Design 
This is a phase II signal-searching study in a range of tumor types with the potential to identify novel 
tumor indications for combination therapy with olaparib that can subsequently be explored in 
dedicated studies. Patients will be enrolled in this study based on molecular markers from genetic 
profiling performed prior to study entry (outside of protocol). The trial will also identify genetic 
determinants of response and resistance. 
Patients with tumors harboring damaging mutations in Homologous – DNA repair (HDR) genes or 
mutations such as ATM, CHK2, MRN (MRE11/NBS1/RAD50), CDKN2A/B, and APOBEC will be 
treated with olaparib or olaparib and AZD6738. Enrollment to the olaparib monotherapy arm will be 
completed prior to commencement of enrollment to the olaparib and AZD6738 arm. Patients with 
tumors harboring IDH1/IDH2 mutations will be treated with olaparib. Patients with tumors harboring 
either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated with AZD1775 plus 
olaparib. Patients with tumors harboring PTEN, PIK3CA, AKT, or ARID1A mutations or other 
molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with 
AZD5363 plus olaparib. 
The recommended phase II doses of olaparib and the ATR inhibitor AZD6738 has recently been 
established. This combination will replace the combination of olaparib and AZD 2014 for 
programmatic reasons (a more homologous DNA repair/HDR focused agent in AZD6738 and re- 
ordered priorities within AstraZeneca). 
The doses for AZD1775 plus olaparib is not yet available. A Phase I clinical trial is currently under 
way to determine the recommended phase II doses for this combination. The AZD1775 plus olaparib 
will be added as a further addendum to the protocol and opened once the recommended phase II 
doses are available. 
A minimum of 80 subjects and a maximum of 125 subjects will be enrolled in this study, with each 
arm enrolling a minimum of 16 subjects and a maximum of 25 subjects depending on ORR in the first 
16  patients  treated  in  each  arm. Treatment  assignment  to  each  arm  is  non-randomized,  and 


Page 5 of 134 
dependent on the presence of molecular markers from genetic profiling. If a patient’s tumor is 
found to have multiple mutations (TP53 and PIK3CA, for example) meeting criteria for multiple 
arms, the decision of which arm to enroll the patient should be made by the treating physician. 
These decisions should also be made in conjunction with the PI. Treatment groups include 
olaparib, AZD1775 plus olaparib, AZD5363 plus olaparib, and AZD6738 plus olaparib. 
This protocol consists of the main protocol applicable across all arms, as well as appendices that 
are specific to the 4 treatment arms: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The AZD1775 plus olaparib and arm will be added as a further addendum to the protocol
and opened once the recommended phase II doses are available.
Investigational product, dosage and mode of administration 
Olaparib 
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply olaparib to the 
investigator as round or oval green film-coated tablets. 
Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg 
olaparib tablets should be taken at the same times each morning and evening of each day, 
approximately 12 hours apart with approximately 240 mL of water. The olaparib tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided. Combination drug should be 
given at least 1 hour after the patient has taken their olaparib. Dose reductions will be 
managed with 100 mg and 150 mg tablets. 
AZD5363 
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply AZD5363 to the 
investigator as beige film-coated tablets. 
Patients will be administered AZD5363 at 640 mg twice daily for two days on/five days off 
(2/7) schedule. Two (2) 200 mg tablets and three (3) 80 mg tablets should be taken twice 
daily. The AZD5363 tablets should be swallowed whole and not chewed, crushed, dissolved, or 
divided. Patients should fast for 2 hours before doing and for 1 hour after dosing. AZD5363 should 
be given at least 1 hour after the patient has taken their olaparib dose. Dose reductions will be 
managed with 80 mg tablets. 
AZD6738 
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply AZD6738 to the 
investigator as round white tablets. 
Patients will be administered AZD6738 at 160 mg daily  for days 1-7 of a 28-day cycle (7/28) 
schedule. AZD6738 is available as 100, 20 and 10 mg tablets. Tablets should be taken daily. 
The AZD6738 tablets should be swallowed whole and not chewed,  crushed,  dissolved,  or 
divided. When AZD6738 is administered in combination with olaparib, patients should fast for 2 
hours before dosing and for 1 hour after dosing. When olaparib is given on its own, the olaparib 
table3t formulation can be given without regard to food. Dose reductions will be managed with 


Page 6 of 134 
existing tablets. 
Duration of Treatment 
Treatment may continue indefinitely or until one of the following criteria applies: 
•
Objective disease progression according to RECIST v1.1 criteria
•
Unacceptable adverse event(s)
•
Significant treatment delays > 4 weeks due to adverse events determined to be
probably/definitely attributed to a study agent
•
Intercurrent illness that prevents further administration of treatment
•
Severe non-compliance to study protocol as judged by the investigator
•
Patient becomes pregnant
•
Patient is determined to no longer meet the required inclusion/exclusion criteria
for the study
•
Patient decided to withdraw from the study (the subject is at any time free to
discontinue
treatment, without further prejudice to further treatment)
•
General or specific changes in the patient’s condition render the patient
unacceptable for further treatment in the judgment of the investigator
Duration of Follow Up 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients will be followed every 12 weeks (+/- 1 week) thereafter by phone for survival status. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
Outcome Variable(s) 
Primary outcome variable: ORR by RECIST v1.1 at 16 weeks from starting study treatment 
Safety outcome variables: Adverse Events (AE), physical examination, vital signs including 
blood pressure (BP), pulse, electrocardiogram (ECG) and laboratory findings including clinical 
chemistry and hematology. 
Secondary outcome variables: 
•
CBR
•
PFS
•
Duration of overall response
•
Duration of stable disease
•
Collecting/storing molecular profiling data on all patients
Exploratory outcome variables: 
•
Correlating CBR with ORR, CR, and PR with additional defects in DNA repair
pathways in tumors
•
Comparing genetic variations/mutations at baseline and at progression and correlating
with response/clinical outcome
•
Measuring ctDNA mutations at baseline, on treatment, and at progression and
correlating changes in ctDNA mutations with response/clinical benefit
•
Potential retrospective biomarker research


Page 7 of 134 
Statistical Methods 
Sample Size Justification and Decision Rules 
The sample size estimation for each single arm of this phase II study is based on the objective 
response rate (ORR). A two-stage “minimax” accrual design described by Simon will minimize 
the maximum number of patients exposed to treatment for a set of assumed values of the 
design parameters [41]. These parameters are: (i) probability of response ≤ p0, where p0
defines the ineffective treatment response proportion, (ii) probability of response ≥ p1, where 
p1 defines the effective treatment response proportion, (iii) power = 1 - probability of Type II 
error, and (iv) α = probability of Type I error. For this study, the assumed design parameters 
are p0 = 0.10, p1 = 0.30, power = 0.90, α = 0.10. If there is evidence at the conclusion of stage 
1 or stage 2, that the true underlying ORR is at least 30% for a treatment arm, consideration 
will be given for further testing of that treatment. However, if the results at the conclusion of 
stage 1 provide evidence that the treatment is inactive in patients, i.e. ORR less than 10%, 
then the treatment arm will be terminated early. 
From the design parameters given above we derive the two-stage sample sizes and decision 
rules. Stage 1: Initially, 16 patients per arm will be enrolled into the study and treated at stage 
1. If there are less than 2 responses among these first 16 subjects, accrual to the treatment arm
will be terminated based on evidence that it is likely that ORR ≤ 10% and unlikely that ORR ≥ 
30%. If there are at least 5 responses among the first 16 patients, recruitment to 25 patients 
will continue in the treatment arm, but further development may be considered. If there are at 
least two but less than 5 responses in these first 16 patients, the trial will continue to stage 2 for 
the treatment arm until 25 patients have been treated. If there are at least 5 responses in these 
25 patients, then further development of the treatment will be considered. 
Some additional operating characteristics for this design are: expected number (i.e. frequentist 
mean number) of patients exposed when true ORR is 10% = 20.4; expected number of 
patients exposed when true ORR is 30% = 24.8; the probability of early termination for futility when 
true ORR is 10% = 0.515; the probability of early termination for futility when true ORR is 30% = 
0.026. 
This design provides 90% statistical power to detect a difference of 20% (successful treatment 
= 30% vs. futile treatment = 10%) with a type I error probability less than 0.10. 
Early Stopping Rule for Safety 
We will monitor the study for safety in the first 16 patients in each single arm. If we observe 4 or 
more patients with unacceptable toxicity in the first 16 patients, then the arm will be terminated 
early. Unacceptable toxicity is defined for this protocol as CTCAE Grade 4 hematological and CTCAE 
Grade 3 non- hematological toxicities that fail to resolve to Grade 1 despite appropriate supportive care. 
With this design, the probability of terminating any arm early is 0.07 if the true but unknown 
unacceptable toxicity rate is 10%, and 0.75 if the true toxicity rate is 30%. 
Analysis Sets 
Full Analysis Set: all enrolled patients. 
Safety Analysis Set: all patients who receive at least one treatment dose. 
Efficacy Analysis Set: all patients who receive at least one treatment dose and are evaluable for 
post- baseline response status. 


Page 8 of 134 
General Methods 
Analyses will be performed separately for each treatment arm, as if they are four parallel 
studies within one protocol. 
Descriptive statistics, including means, standard deviations, medians  and  ranges  for continuous 
scale parameters, as well as percent and frequencies for categorical parameters, will be 
presented. For time-to-event parameters, estimates of median  survival  with  95% confidence 
intervals will be calculated, and Kaplan Meier plots will be provided. Patients who are lost to follow-
up or who have not progressed at the time of data cut-off will be censored for PFS analysis at 
the time of their last study visit. 
No corrections for multiplicity will be performed. 
Disposition, Demographics, and Baseline Clinical Characteristics (Full Analysis Set) 
Patient disposition will be listed and tabulated by treatment arm. Demographic information 
including but not limited to age, gender and race, will be tabulated by treatment arm. Other 
baseline characteristics, such as medical history, concomitant medications, disease severity, time 
from diagnosis, physical exam and lab test results will be presented similarly. 
Safety and Toxicity (Safety Analysis Set) 
Adverse events (AEs) will be listed and tabulated by treatment arm. AEs will be classified 
based on the likelihood that they are treatment-related. NCI toxicity Grade 3 and Grade 4 
laboratory abnormalities will also be listed. PFS analysis will also be performed with patients in 
the safety analysis set. 
Efficacy (Efficacy Analysis Set) 
The efficacy of each treatment will be assessed by analysis of the primary endpoint using the 16- 
week response status. The exact Binomial method will be used to calculate two-sided 95% 
confidence intervals for ORR. Multivariate logistic regression will be used to predict the ORR by 
including patient characteristics variables and other clinically relevant factors as covariates. 
For time-to-event endpoints, Kaplan-Meier plots and estimates for median survival time with 95% 
confidence intervals will be provided for each treatment arm. 
Subgroup Analyses 
Due to the limitation of the sample size, we will not have sufficient power to perform official 
statistical tests to detect differences between patients with different tumor types or mutations. 
Descriptive statistics will be used to present ORR by tumor type and by specific mutation. Data 
permitting, survival function of patients in subgroups will also be summarized. 


Page 9 of 134
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................................... 2 
LIST OF ABBREVIATIONS ...................................................................................................................... 12 
1 OBJECTIVES ...................................................................................................................................... 14 
1.1 Primary Objectives ......................................................................................................................... 14 
 Secondary Objectives .....................................................................................................................  14 
 Exploratory Objectives ...................................................................................................................  14 
2 BACKGROUND .................................................................................................................................. 14 
 Background on cancer and molecular selection of patients ....................................................  14 
  DNA Damage Repair ......................................................................................................................  15 
2.3 Background on targeted agents .................................................................................................. 16 
2.3.1 Olaparib (AZD2281) .............................................................................................................. 16 
  AZD5363 ...................................................................................................................................  17 
 AZD1775 (MK1775) ................................................................................................................  18 
  AZD6738 ................................................................................................................................... 18 
3 STUDY DESIGN AND RATIONALE ................................................................................................ 21 
  Description of Study ....................................................................................................................... .  21 
3.2 Main Study Schema .................................................................................................................... 22 
3.3 Rationale for combinations with olaparib ................................................................................. 23 
  Combination of AZD1775 with olaparib ...............................................................................  23
 Combination of AZD5363 with olaparib ............................................................................. .23
3.3.3 Combination of AZD6738 and Olaparib .............................................................................. 24 
 Molecular Selection of Patients .................................................................................................... .25
4 PATIENT SELECTION ...................................................................................................................... 25 
  Inclusion Criteria ............................................................................................................................. ..25 
  Exclusion Criteria ........................................................................................................................... ..27 
5 REGISTRATION PROCEDURES .................................................................................................. 31 
 General Guidelines .......................................................................................................................... 31 
 Registration Process ....................................................................................................................... 31
6 TREATMENT PLAN ............................................................................................................................ 31 
 Agent Administration ........................................................................................................................ 31 
Definition of Toxicity ........................................................................................................................  32
Concomitant and Excluded Therapies .......................................................................................... 32
  Prohibited Therapy ........................................................................................................................... 33 
  Duration of Therapy ......................................................................................................................... 33 
 Duration of Follow Up ...................................................................................................................... 33
 Criteria for Removal from Study .................................................................................................... 34
7 DOSING DELAYS / MODIFICATIONS / DISCONTINUATION ................................................... 34 
8 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................................. 35 
9 PHARMACEUTICAL INFORMATION ................................................................................................ 41 
10 CORRELATIVE/SPECIAL STUDIES ............................................................................................ 41 
11 STUDY CALENDAR ........................................................................................................................... 43 
12 MEASUREMENT OF EFFECT ....................................................................................................... 43 
13 MULTICENTER MANAGEMENT AND COORDINATION ............................................................ 46 
14 ETHICAL AND REGULATORY REQUIREMENTS ................................................................. 50 
15 STATISTICAL CONSIDERATIONS ................................................................................................. 50 
APPENDIX A: Performance Status Criteria .......................................................................................... 53 
APPENDIX B: Olaparib in Patients with HDR Gene Mutations & IDH1/IDH2 Mutations .............. 54 
APPENDIX C: AZD5363 plus olaparib in patients with AKT, PIK3CA, or ARID1A mutations or 
other aberrations leading to dysregulation of the PI3K/AKT pathway .......................................... 70 


Page 10 of 134
APPENDIX D: AZD6738 plus Olaparib in Patients with DNA Damage Repair Gene Mutations 100 
APPENDIX E: AZD1775 plus olaparib in patients with either TP53 or KRAS mutations or 
mutations in both, TP53 and KRAS ........................................................................................................ 123 
APPENDIX F: Collection of plasma, preparation and shipment of ctDNA samples ..................... 124 
APPENDIX G: Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law ................................................................................................................... 125 
APPENDIX H: Acknowledgment of the Investigators ....................................................................... 129 
References .......................................................................................................................................................... 130 


Page 11 of 134
LIST OF ABBREVIATIONS 
Abbreviation 
Full text 
ADP 
Adenosine diphosphate ribose 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated 
AZ 
AstraZeneca 
BER 
base excision repair 
bid 
twice daily dosing 
bp 
base pair 
C 
Celsius 
ctDNA 
circulating tumor DNA 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CDK 
cyclin-dependent kinase 
CLIA 
Clinical Laboratory Improvement Amendment 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
d 
Day 
DDR 
DNA damage repair 
DF/HCC 
Dana-Farber/Harvard Cancer Center 
dL 
deciliter 
DNA 
deoxyribonucleic acid 
DSB 
double strand breaks 
DSMC 
Data and Safety Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
EKG 
electrocardiogram 
FDA 
Food and Drug Administration 
FH 
Fumarate Hydratase 
GBM 
Glioblastoma multiforme 
HCT 
hematocrit 
HER2 
human epidermal growth factor receptor 2 
Hgb 
hemoglobin 
HbgA1c 
glycated hemoglobin 
HIC 
Human Investigation Committee 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HDR 
Homologous DNA recombination 
HDRD 
Homologous DNA recombination deficient 
HDRR 
Homologous DNA recombination repair 
ICL 
interstrand crosslinks 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 


Page 12 of 134
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISS 
Investigator Sponsored Study 
kg 
kilogram 
L 
liter 
LVEF 
left ventricular ejection fraction 
m 
meters 
mcg 
microgram 
MDS 
Myelodysplastic syndrome 
mg 
milligram 
MI 
myocardial infarction 
miRNA 
micro ribonucleic acid 
mL 
milliliter 
mmol 
millimoles 
MMR 
mismatch repair 
MMTV 
mouse mammary tumor virus 
ms, msec 
milliseconds 
MTD 
maximum tolerated dose 
mTOR 
mammalian Target of Rapamycin 
MUGA 
multi-gated acquisition scan 
NAD 
Nicotinamide adenine dinucleotide 
NCI 
National Cancer Institute 
NER 
nucleotide excision repair 
NGS 
next-generation sequencing 
NHEJ 
non-homologous end joining 
NYHA 
New York Heart Association 
OAE 
other significant adverse event 
OLAPCO 
Olaparib Combinations 
ORR 
overall response rate 
PARP 
poly(ADP-ribose) polymerase 
PD 
progressive disease 
Ph 
phase 
PI 
principal investigator 
PI3K 
phosphotidylinositol 3-kinase 
PK 
protein kinase 
PO 
Orally 
PR 
partial response 
PRMC 
Protocol Review and Monitoring Committee 
PS 
performance status 
PTEN 
Phosphatase and tensin homolog 
PLT 
Platelet 
PTT 
partial thromboplastin time 
QD 
Once per day 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended phase II dose 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 


Page 13 of 134
SGPT 
serum glutamate pyruvate transaminase 
SOP 
standard operating procedures 
SSB 
single-strand breaks 
t1/2 
terminal half-life 
TBID 
to be determined 
TNBC 
triple negative breast cancer 
ul 
microliter 
ULN 
upper limit of normal 
US 
Ultrasound 
UV 
ultraviolet 
WBC 
white blood cells 
YCC 
Yale Cancer Center 


Page 14 of 134 
1 
OBJECTIVES 
1.1 Primary Objectives 
•
To determine tumor overall response rate (ORR) in molecularly selected patients with
measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors
(RECIST), before versus after 16 weeks of treatment across tumor types in each arm
of the study (Note: there will be no formal comparison between arms)
 Secondary Objectives 
•
To determine tumor overall response rate (ORR) in molecularly selected patients with
measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors
(RECIST), before versus after 16 weeks of treatment within tumor type in each arm of
the study (Note: there will be no formal comparison between arms)
•
To determine tumor clinical benefit rate (CBR) rate in molecularly selected patients
with measurable disease as assessed by the Response Evaluation Criteria in Solid
Tumors (RECIST), before versus after 16 weeks of treatment across tumor types and
within tumor type in each arm of the study (Note: there will be no formal comparison
between arms)
•
To determine progression free survival (PFS), duration of overall response, and
duration of stable disease in molecularly selected patients with measurable disease
as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before
versus after 16 weeks of treatment across tumor types and within tumor type in each
arm of the study (Note: there will be no formal comparison between arms)
•
To determine the safety and tolerability of oral administration of olaparib alone and in
combination of AZD1775, AZD5363, and AZD6738 in patients with advanced solid
tumors
•
To collect and store molecular profiling data of all patients enrolled in this study, for
correlating treatment response/clinical benefit with patterns of tumor genetic
abnormalities in tumors
 Exploratory Objectives 
•
To correlate clinical benefit rate (CBR) associated with treatment at Week 16, Overall
Response Rate (ORR), Complete Response (CR), and Partial Response (PR), with
additional defects in DNA repair pathways measured by genetic aberrations in the
tumors.
•
To compare genetic variants/mutations measured in tumor tissue in diagnostic archival
specimen, at baseline and on progression (when samples available), and correlate
with tumor response and clinical benefit
•
To determine tumor mutations in ctDNA at baseline, on treatment, and at progression,
and evaluate the changes in ctDNA mutations and correlate with tumor response and
clinical benefit
2 
BACKGROUND 
  Background on cancer and molecular selection of patients 
Over the last decade, the delineation of signaling pathways to understand tumor biology has laid 
the foundation for the discovery of novel targets and development of multiple therapies for cancer. 
The identification of driver mutations and critical pathway dependencies, as well as genomic 
sequencing and other large-scale “-omics” approaches, have facilitated the discovery and 
development of novel targeted anti-cancer therapeutics, or at least provide the scientific rationale 


Page 15 of 134 
for their development. This increased molecular understanding of tumors has led to a new era of 
personalized medicine that has begun to influence common practice for oncologists beyond 
academic institutions. 
Traditionally, the site of tumor origin, together with histology and clinical and/or pathological 
characteristics, especially stage, was used to make treatment decisions. This approach has been 
changed to include molecular tumor parameters. Markers presently used to guide decisions for 
personalized 
medicine 
treatment 
with 
targeted 
agents 
are 
either 
protein-based 
(immunohistochemistry (IHC)) or via detecting genetic aberrations. For genetic aberrations, a 
range of methodologies are used, nowadays often Next-Generation-Sequencing (NGS) of either 
multiple selected genes in parallel or whole exome sequencing, in particular in early clinical trials 
or for exploratory purposes. These large panels of genes offer the opportunity not only to detect 
aberrations, for which treatment options already exist, but also to generate data on additional 
driver mutations or resistance pathways [1,2]. Treatment decisions may be based on the data 
when tests have been performed in Clinical Laboratory Improvement Amendment (CLIA)-certified 
laboratories. 
Molecular profiling, including genomic profiling, is rapidly becoming commonplace for cancer 
patients. As such, a growing number of patients are being identified with potentially actionable 
mutations, translocations or pathway activation events, without availability of matched targeted 
treatments. Multiple so-called ” basket studies” are ongoing to investigate molecularly targeted 
agents, to explore if a similar molecular profile confers sensitivity to the same agents across tumor 
types. 
Experience at our institutions and through published literature shows, however, that patients’ 
tumors often bear multiple mutations and it is often not immediately obvious that one of these 
mutations would be the driving mutation. In addition, many targeted agents have shown efficacy, 
but are often more efficacious in combination with other anti-cancer treatments. The OLAPCO 
clinical trial therefore proposes to study combinations of agents in molecularly-defined patient 
populations across tumor types. Patients will be enrolled based on molecular profiling performed 
on tumor samples that has taken place prior to the study (the molecular profiling is not part of this 
study). The PARP inhibitor olaparib alone and combinations with olaparib will be tested based on 
the hypothesis that interfering with DNA damage repair in addition to targeting a specific signaling 
pathway by a second compound, would lead to increased cell death and tumor control. 
 DNA Damage Repair 
DNA damage repair (DDR) is an essential function to maintain viability in all cells. Several specific, 
mutually supporting and overlapping mechanisms exist in eukaryotic cells to process the type of 
DNA damage that results from environmental and cellular stress. Base excision repair (BER) 
mediates the removal and replacement of single damaged bases. Nucleotide excision repair 
(NER), classically associated with UV damage, removes helix distortions with excision of a longer 
(27-29 bp) tract of DNA. Mismatch repair (MMR) excises mismatched DNA base pairs. DNA 
double strand breaks (DSB) can be repaired by either an error-prone process of non-homologous 
end joining (NHEJ) or homologous DNA recombination repair (HDR), an error-free process with 
the greatest repair fidelity and lowest frequency of errors. HDR is a mechanism to repair several 
DNA lesions, including DSBs, single-strand DNA breaks (SSBs) and interstrand crosslinks (ICL)[3]. 
Several types of DNA repair mechanisms of DSBs and SSBs converge on HDR. The occurrence 
of SSB and DSB is increased in cancer cells because of the higher frequency of DNA replication 
in mitotically active cancer cells, the increased frequency of DDR defects in cancer cells, and the 
generalized cancer phenotype of genomic instability. 
PARP 1 and 2 (poly(ADP-ribose) polymerase) are nuclear proteins that act during the repair of 
SSBs, which are intermediates of base excision repair (BER)[4]. These catalyze the cleavage of 
NAD+ (nicotinamide adenine dinucleotide) and the formation of homopolymers of ADP-ribose on 


Page 16 of 134 
chromatin and also on proteins. The homopolymers present on the DNA act to recruit enzymes 
that function in the repair of SSBs. Inhibition of PARP 1 and 2 blocks repair of the SSBs and 
leads to formation of DSBs as a result of replication fork collapse [5]. PARP attracts SSB repair 
proteins like XRCC1 to the site of DNA damage to catalyze the repair of strand breaks. PARP 
also has roles in B-NHEJ and the restart of stalled replication forks[3]. Thus, cells in which PARP 
1 and 2 are inhibited rely on HDR to repair the DSBs. Inhibition of PARP activity in HDR-deficient 
BRCA mutant cells by genetic or pharmacological means is lethal and the magnitude of response 
is unprecedented[6,7]. Olaparib is a PARP1 & 2 inhibitor that demonstrates significant clinical 
activity in BRCA mutant breast and ovarian cancer [ 8, 9]. 
Recent work has identified a new class of genetic mutations that result in HDR defects not through 
disruption of DDR genes themselves but through epigenetic changes (A). The 2-Hydroxyglutarate 
(2HG) enantiomers, R-2HG and S-2HG are both implicated in tumor progression via their inhibitory 
effects on α-ketoglutarate (KG)-dependent dioxygenases. The former is an oncometabolite that 
is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) 
mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring 
IDH1/2 mutations are found in gliomas and acute myeloid leukemia (AML), and in multiple other 
tumor types. Many IDH1/2-mutant tumors are known to be chemo- and radiosensitive, although the 
mechanisms underlying this enhanced sensitivity have yet to be explained. 
Sulkowski et al (A) report that IDH1/2 mutations induce a homologous DNA recombination (HDR) 
defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) 
inhibitors, including olaparib. This “BRCAness” phenotype can be completely reversed by small 
molecule mutant IDH1/2 inhibitors, and it can be entirely restored by treatment with either 2HG 
enantiomer in cells with intact IDH1/2. A detailed series of studies implicate two KG-dependent 
dioxygenases, KDM4A and KDM4B, as key mediators of the observed HDR deficient repair 
phenotype. IDH1/2-dependent cells demonstrate olaparib and PARP inhibitor sensitivity in a range 
of clinically relevant models, including primary patient-derived glioma cells and AML bone marrow 
cultures in vitro, as well as genetically-matched tumor xenografts in vivo. These data indicate that 
the phenotype of 2HG-induced BRCAness is not tissue specific, suggesting that a diverse range of 
tumor types bearing these mutations can be exploited by PARP inhibitors. These observations have 
been extended to several structurally related and clinically relevant tricarboxylic acid (TCA) 
oncometabolites, such as fumarate and succinate, which demonstrate a marked synthetic lethality 
with olaparib/PARP inhibitors in tumors which produce these other oncometabolites, and the data 
suggest a similar mechanism of action via which HDR is suppressed. These findings uncover an 
unexpected link between oncometabolites, altered DNA repair and genetic instability but at the 
same time confer a collateral vulnerability to PARP inhibition that can be therapeutically exploited. 
 Background on targeted agents 
      Olaparib (AZD2281) 
Olaparib (AZD2281, KU-0059436) is a potent inhibitor of polyadenosine 5’diphosphoribose 
polymerase (PARP)[10]. PARP inhibition is a novel approach to targeting tumors that have 
homologous recombination deoxyribonucleic acid (DNA) repair (HRR) pathway deficiencies 
(HDR). In HDR tumors, single agent treatment with olaparib can lead to tumor regression 
by a process known as synthetic lethality- a result of the accumulation of un-repaired DNA 
double-strand breaks (DSBs) and an unsupportable increase in genomic instability. Olaparib 
may also enhance the DNA damaging effects of ionizing radiation and chemotherapy. Within 
the clinical development program, the focus is to assess tolerability and efficacy of olaparib 
in patients with advanced solid tumors containing HDR, such as breast cancer susceptibility 
gene (BRCA-1, -2 and BRCAness) mutated cancers (germline and somatic). 
Olaparib is currently being investigated in a range of Phase I, II, and III studies. 


Page 17 of 134 
Further details are provided in B and the Investigators’ Brochure. 
 AZD5363 
AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine 
AKT/PKB that is being developed as a potential treatment for solid and hematological 
malignancies. 
AKT is part of the AGC family of kinases (cAMP-dependent protein kinases A, cGMP 
dependent protein kinases G, and phospholipid-dependent protein kinases C). Mammalian 
cells express 3 closely related AKT isoforms: AKT1 (PKBα), AKT2 (PKBβ) and AKT3 
(PKBγ), all encoded by different genes. AKT is involved in multiple signaling pathways 
promoting tumorigenesis, inhibiting apoptosis, impacting on the cell cycle and promoting 
invasion and migration. 
The phosphatidylinositol 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) 
pathway is frequently deregulated in cancer and drives tumor growth and cell survival [15]. 
All 3 AKT isoforms are activated in different tumor types including breast, prostate, ovarian, 
pancreatic and gastric cancers. This activation is often associated with resistance to 
established cancer therapies as well as advanced disease and/or poor prognosis[16]. AKT 
activation in tumors is largely due to input from other signaling pathways upstream of AKT 
(e.g., mutation of oncogenes such as RAS, BCR-ABL, mutation of receptor tyrosine kinases 
such as epithelial growth factor receptor, amplification of human epidermal growth factor 
receptor 2 (HER2), loss of PTEN function, mutations of PI3K). 
Inhibitors of AKT are anticipated to have efficacy when dosed in combination with cytotoxic 
chemotherapies or in combination with other targeted or anti-hormonal agents. AZD5363 
inhibits all 3 AKT isoforms (AKT1, AKT2 and AKT3) and therefore has the potential to 
provide clinical benefit over a range of therapeutic indications. 
A recent phase I study with olaparib and AZD5363 presented at AACR 2015 determined a 
RP2D for the combination.  Dose escalation was completed in 7.5 months in 20 patients in 
1 center; with ≥6 evaluable patients treated at each of the 3 dose levels in two different 
intermittent schedules of AZD5363. Common (>15%) G1-2 toxicities were nausea, vomiting, 
fatigue, diarrhea and anemia. A DLT of G3 rash was seen at 480mg BID AZD 4 of 7 days + 
300mg BID Olaparib. Non DLT G3 anemia (n=2), diarrhea (n=2), fatigue (n=1) and vomiting 
(n=1) were seen in 4/7 arm; G3 hyperglycemia (n=1), transaminitis (n=1) and fatigue (n=2) 
in the AZD 5363 2 days of 7 arm. No significant PK interactions were seen. Intra-patient 
dose escalation of AZD5363 showed dose dependent increases in drug exposures. Platelet- 
rich plasma PD studies showed a significant decrease in pSer9 GSK3β post-therapy at all 
dose levels (mean ≥55% [p<0.002] in 4/7 arm and ≥70% [p<0.0001] in 2/7 arm). Confirmed 
partial responses were seen in a BRCA wild type PTEN LOH platinum resistant ovarian 
cancer patient for 6m and a BRCA1 mutant ovarian cancer patient for 5.5m+. An 
unconfirmed PR was seen in a BRCA1 mutated breast cancer patient (2.5m+ response 
duration). A BRCA1 mutated castration resistant prostate cancer patient had a response 
(PSA 14 to 0.7 µg/L) and tumor response (8m+). A PI3K/mTOR inhibitor resistant peritoneal 
mesothelioma patient had stable disease for 9m+ with 66% CA125 decline (202 to 69 U/mL). 
The RP2C was established at 640mg BID 2/7 AZD5363 + 300mg BID Olaparib based on 
tolerability. 
Phase I RP2D expansion and phase II trials with AZD5363 are ongoing. 
Further details are provided in C and the Investigators’ Brochure. 


Page 18 of 134 
 AZD1775 (MK1775) 
AZD1775 is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates 
and inhibits cyclin-dependent kinases 1 (CDK1) and 2 (CDK2), and is involved in 
regulation of the intra-S and G2 cell cycle checkpoints. Proper functioning of these  
checkpoints is essential for DNA metabolism and the DNA damage response [11]. 
CDK2 activity drives a cell into, and through, S-phase of the cell cycle where the genome 
is duplicated in preparation for cell division. CDK1 (also called cell division cycle 2, or 
CDC2) activity drives a cell from the G2 phase of the cell cycle into mitosis. In response 
to DNA damage, Wee1 inhibits CDK1 to prevent the cell from dividing until the 
damaged DNA is repaired (G2 checkpoint arrest). Inhibition of Wee1 is expected to 
release a tumor cell from chemotherapeutically-induced arrest of cell replication. 
Inhibition of Wee1 is expected to cause aberrantly high CDK2 activity in S-phase cells 
that, in turn, leads to unstable DNA replication structures and ultimately DNA damage. 
It is anticipated that AZD1775 will have independent anti-tumor activity in the absence 
of added chemotherapy. In vitro experiments demonstrate that AZD1775 has synergistic 
cytotoxic effects when administered in combination with various DNA damaging agents 
with divergent mechanisms of action. Therefore, the primary objective of the clinical 
development of AZD1775 is its use as a chemosensitizing drug in combination with a 
cytotoxic agent (or combination of agents) for treatment of advanced solid tumors. 
The tumor suppressor protein p53 regulates the G1 checkpoint. As the majority of 
human cancers harbor abnormalities in this pathway they become more dependent on 
S- and G2- phase checkpoints [12]. Thus, S- and G2-checkpoint abrogation caused 
by inhibition of Wee1 may selectively sensitize p53-deficient cells to anti-cancer agents 
[13]. In in vitro and in vivo preclinical models, AZD1775 selectively enhanced 
chemotherapy induced death of cells deficient in p53 signaling. Tumor context-specific 
sensitization to the DNA damaging agents gemcitabine and platinums was observed in 
TOV21G (ovarian carcinoma) cell lines matched for wild type and knock down of p53. 
Data from a phase I monotherapy trial of AZD1775 in solid tumors presented at ASCO 
2014 established the MTD at 225 mg bid for 5 doses/week, two out of every 3 
weeks [14]. Toxicities were myelosuppression and diarrhea.  PK exposure increased 2 
to 3-fold on day 3 compared to day 1, with a half-life of 9-12 hours. Additionally, 
phosphorylated Tyr15-Cdk levels were shown in three of five paired tumor biopsies. 
One partial response (PR) was seen in a BRCA mutant patient with squamous cell 
carcinoma of the head and neck [14]. This study defined the MTD, toxicities, 
pharmacokinetics, and pharmacodynamics of AZD1775, and concluded that DDR 
mutations may confer sensitivity across tumor cell of origin types. 
AZD1775 is currently tested in Phase I and Phase II clinical studies. 
Further details are provided in the Investigators’ Brochure. The AZD1775 plus olaparib 
arm will be added as an addendum to the protocol and opened once the recommended 
phase II dose is available. 
 AZD6738 
AZD6738 is an inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and 


Page 19 of 134 
Rad3 Related (ATR), a member of the phosphoinositide 3-kinase related kinase (PIKK) 
family. ATR is an atypical kinase in one of the DNA-damage induced checkpoint pathways, 
and during normal DNA replication is recruited at stalled replication forks, which can 
progress to double strand breaks if left unrepaired. Following resection of double strand 
breaks ATR is recruited to single strand DNA coated with Replication Protein A (RPA) 
following single strand DNA damage. Recruitment and activation of ATR leads to cell cycle 
arrest in the S phase while the DNA is repaired and the stalled replication fork resolved, or 
nuclear fragmentation and entry into programmed cell death (apoptosis). Loss of ATR 
function leads to the inability to resolve stalled replication forks, the accumulation of DNA 
damage and rapid cell death exemplified by nuclear fragmentation. ATR deletion is 
embryonic lethal in mice, however severe ATR hypomorphism is tolerated in humans 
leading to Seckel Syndrome. Normal cells from patients with Seckel Syndrome have 
reduced ATR function and show extensive DNA breaks when subjected to replication 
stress. 
Ataxia Telangiectasia Mutated (ATM) is a closely related kinase that is recruited to double 
strand breaks and like ATR, has both checkpoint and repair functions. In normal cells, there 
is a significant interplay between ATR and ATM as stalled replication forks can be 
converted into double strand breaks through fork collapse and the resection of double 
strand breaks generates single stranded DNA. During tumorigenesis, ATM can be 
inactivated or lost providing a selection advantage for the tumor cell through the increased 
potential for genome alteration, and an increased dependence on ATR function. Similarly, 
oncogene activation such as that of c-Myc leads to increased replication stress, an 
accumulation of stalled replication forks and dependence on ATR function. 
Sporadic ATM deficiency is reported in many malignant diseases (Stankovic et al 2002, 
Grønbæk et al 2002, Ambatipudi et al 2011, Bolt et al 2005, Mazumder et al 2011, Grabsch 
et al 2006), and ATM deficiency is expected to sensitize malignant cells to ATR inhibition 
through their complimentary roles in DNA damage repair. Patients with ATM deficient 
malignancies can be clinically identified and, in most cases, are known to have a poor 
prognosis with current therapies. 
Although ATM-deficient cells have a greater sensitivity to AZD6738, AZD6738 is cytotoxic 
in cell line panels of ATM-proficient hematological malignancies in vitro. In vivo 
combinations of AZD6738 with radiation induces a dose-dependent anti-tumor response, 
with regressions in ATM-deficient models and growth inhibition in ATM-proficient models. 
Anti-tumor activity of AZD6738 may, therefore, also be seen more broadly. 
There are other molecular features that could be envisaged to affect clinical response to 
ATR inhibition, and these would include: defects in additional genes/proteins that regulate 
ATM-function: MRE11A (NBS, RAD50 as part of M-R-N complex), TIP60 and CHK2; 
defects  in  G1/S  checkpoint  control  (in  addition  to  ATM/p53)  and  (ATR-dependent) 


Page 20 of 134
replicative stress. Molecular surrogates would be loss of tumor suppressors (e.g. 
CDKN2A/B (p15/p16) deletions) and/or coupled with hypoxia; and increased G1/S 
progression-proliferation and (ATR-dependent) replicative stress. Molecular surrogates 
would be oncogene driven and dependent tumors (e.g. Myc, Cyclin D/E, CDK4 amplified) 
and/or coupled with hypoxia. 
The ATR-Chk1 checkpoint pathway serves to ensure cell survival after replication stress, 
therefore a normal and robust checkpoint is thought to be a mechanism of resistance to 
chemotherapy. As a result, ATR-Chk1 pathway components are considered promising 
therapeutic targets, and preclinical data generated to date supports this hypothesis 
(Mukhopadhyay et al 2005, Pan et al 2009, Powell et al 1995, Strunz et al 2002, Tao et al 
2009, Parikh et al 2007). 
Increasing the exogenous replication stress with approaches that generate DNA strand 
breaks or DNA lesions which stall DNA replication forks in the tumor cell, for example 
through radiation, chemotherapy or inhibition of other DNA repair proteins e.g. PARP, 
should also lead to increased sensitivity to ATR inhibition. Thus, UV radiation, cisplatin 
and hydroxyurea are more efficacious in tumor cells where kinase-dead ATR has been 
expressed, and over expression of a mutated form of ATR observed in Seckel cells 
increases their sensitivity to alkylating agents. 
In patients with malignant disease, an ATR inhibitor has the potential to have monotherapy 
activity, through synthetic lethality (synthetic lethality arises when a combination of 
mutations in two or more genes, or inhibition of the production thereof, leads to cell death, 
whereas a mutation in only one of these genes does not, and by itself is said to be viable 
(Tucker and Fields 2003), e.g. ATM loss-of-function) or by exploiting on-going aberrant 
DNA replication. structures leading to dependency on ATR through replication stress (DNA 
replication stress is defined as inefficient DNA replication that causes DNA replication forks 
to progress slowly or stall (Burhans and Weinberger 2007)), to act synergistically in 
combination with DNA damaging radiotherapy, chemotherapy or novel DNA repair inhibitors 
such as ionising radiation, carboplatin or PARP inhibitors (e.g. olaparib) respectively which 
increase the threshold level of replication stress or induce DNA strand breaks; thus the 
potential for increased efficacy at the tumor with more manageable symptoms for normal 
tissues and to act as a maintenance therapeutic after either of the above 
The AstraZeneca sponsored study D5330C0004 is investigating AZD6738 administered 
orally in combination with olaparib, in patients with advanced malignancies. The purpose of 
this module is to establish the Recommended Phase 2 Dose (RP2D) of AZD6738 given in 
combination with olaparib (Part A), and assess preliminary efficacy in a subsequent 
expansion(s) in patients with advanced ATM-deficient gastric adenocarcinoma (Part B1), 
ATM-proficient gastric adenocarcinoma (Part B2), breast cancer patients with BRCA 
mutations (somatic or germline) excluding HER2-positive breast cancer patients (Part B3) 
and TNBC patients with no known BRCA mutations (Part B4). As of 1st June 2017, 64 
patients have received treatment in Module 2, the RP2D has been established and patients 
with gastric cancer are being recruited to expansions in Parts B1 and B2. Amendment 8, 
which adds Parts B3 and B4 to the study, has been submitted to the regulatory authorities 
for approval. 
Gr3-4 events occurring in ≥ 1 subject include anaemia, neutropenia, thrombocytopenia, 
ascites, anorexia, abdominal pain, large intestinal obstruction, leucopenia, dehydration and 
syncope. Very common adverse events (≥1/10 according to CIOMS III frequency 
classification) considered possibly related to AZD6738 and / or olaparib by the investigator 
include anaemia and fatigue. Common adverse events (≥1/1000 to <1/10) considered 


Page 21 of 134
possibly related, include nausea, neutropenia, thromobocytopenia, vomiting,  anorexia, 
dizziness, diarrhoea, thrombocytopenia, leucopenia, increase in blood creatinine and 
asthenia. 
A number of potential safety signals have been identified on the basis of general toxicology, 
safety pharmacology, genotoxicity and clinical studies. Most of these signals have not been 
confirmed to be causally related to AZD6738; some are considered potential risks which are 
being monitored in ongoing clinical trials e.g. gastrointestinal toxicity, hepatic toxicity, etc.; 
bone marrow toxicity is the only signal considered causally related to AZD6738, and is 
considered an ADR or identified risk for the product. In addition, some clinical toxicities from 
AZD6738 overlap with those seen with olaparib use in humans e.g. anemia, neutropenia, 
leukopenia, thrombocytopenia of potential prolonged duration. 
The Recommended Phase 2 Dose for expansion has been declared as AZD6738 OD D1- 
7 with olaparib 300 mg BD continuously. The dosing schedule of 7 days on, 21 days off 
within each treatment cycle was supported by the PK-PD model of thrombocytopenia, 
predicting a period of 21 days free of drug to achieve a full platelet recovery. The 
recommended dose 160 mg OD was predicted to maintain AZD6738 mean steady state 
concentrations above the estimated IC90 threshold (based on ATR enzyme inhibition assay 
in LoVo cells) and the GI90 threshold (based on the cellular growth inhibition activity in LoVo 
cells) across the full dosing interval i.e 24 h. Please refer to AZD6738 IB for further 
information around the in-vitro threshold values. In addition, this daily dose level was 
associated with a decrease in peripheral monocytes in most of the patients and the 
preliminary blood cell count data from D5330C00004 and D5330C00002 studies suggested 
this decrease to be AZD6738 specific and dose dependent (monocyte decrease was not 
observed with either single agent olaparib or durvalumab). Monocytes have been 
characterized as being deficient in DNA base excision repair and PARP1 expression [71], 
suggesting an on-target synthetic lethal effect of AZD6738 mediated ATR inhibition in this 
cell type. Utilizing the monocyte decrease as a quantitative measure of AZD6738 
pharmacological activity, the recommended Phase 2 dose of 160mg OD D1-7 was driven 
by maintaining maximally active exposure consistent with manageable safety. 
In summary, AZD6738 is a potent, selective inhibitor of the serine/threonine-specific 
protein kinase, ataxia telangiectasia and Rad3-related protein (ATR), with good selectivity 
against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. This 
compound is being developed as an oral anti-tumor agent with an initial focus on patients 
with ATM-deficient disease, although there is preclinical evidence for activity in broader 
malignant disease types. AZD6738 has the potential to provide benefit as a monotherapy 
or in combination with DNA damaging agents, including PARP inhibitors, in patients with 
both hematological and solid malignancies. 
Further details are provided in the Investigators’ Brochure. The AZD6738 plus olaparib 
3 
STUDY DESIGN AND RATIONALE 
     Description of Study 
This is a phase II signal-searching study in a range of tumor types with the potential to 
identify novel tumor indications for combination therapy with olaparib that can subsequently 
be explored in dedicated studies. Patients will be enrolled in this study based on molecular 


Page 22 of 134
markers from genetic profiling performed on their tumors prior to study entry (outside of 
protocol). The trial will  also identify genetic determinants of response and resistance. 
Patients with tumors harboring mutations in DNA damage repair genes will be treated 
with olaparib and as accrual goals are achieved, olaparib and AZD6738. Patients with tumors 
harboring either TP53 or KRAS mutations or mutations in KRAS and TP53 will be treated 
with AZD1775 plus olaparib. Patients with tumors harboring PIK3CA, AKT, or ARID1A 
mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway 
will be treated with AZD5363 plus olaparib. Patients with mutations in IDH1 or IDH2 will be 
treated with olaparib alone. 
The recommended phase II dose of AZD1775 plus olaparib is not yet available. Phase I 
clinical trials are currently either under way to determine the recommended phase II doses 
for this combination. The AZD1775 plus olaparib will be added as an addendum to the 
protocol and opened once the recommended phase II doses are available. 
For more detail on the molecular selection in the olaparib, AZD5363 plus olaparib and 
AZD6738 and olaparib treatment arms, please see Molecular selection of patients, B, C and 
D. 
 Main Study Schema 


Page 23 of 134
  Rationale for combinations with olaparib 
 Combination of AZD1775 with Olaparib 
TP53 mutations are one of the most common mutations across cancer types, but direct 
therapeutic targeting of p53 to restore the function of the tumor suppressor so far has had 
very limited success [22]. p53-deficient cells are more dependent on the S or G2 cell cycle 
checkpoint and may therefore, when treated with a G2 checkpoint inhibitor, be more 
sensitive to DNA damage [23, 24]. Inhibition of WEE1, a tyrosine kinase that phosphorylates 
CDK1 and thereby inactivates it, causes G2 checkpoint abrogation. AZD1775 (MK-1775) is 
a small molecule WEE1 inhibitor, that has been shown to sensitize p53-deficient tumor cells 
to DNA-damaging agents and radiotherapy [25-27]. In p53-deficient tumors, a combination 
of AZD1775 and the DNA-damage repair inhibitor olaparib may therefore be hypothesized 
to have synergistic anti-tumor efficacy. We are not aware of preclinical data combining 
AZD1775 and olaparib. However, WEE1 inhibition will lead to inappropriately high levels of 
CDK1 activation (and therefore checkpoint bypass). CDK1 can also phosphorylate BRCA2; 
this phosphorylation actually disrupts the interaction of BRCA2 and RAD51. Therefore, 
inappropriately high, unregulated CDK1 activity will reduce RAD51 loading and impair HR. 
Therefore, WEE1 inhibition should sensitize cells to PARP inhibition [28]. Mutant KRAS in 
cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways, and the 
phosphorylation of Chk1 at an inhibitory site. The resulting inhibition of ATR/Chk1 signaling 
abrogates the activation of the G2 DNA damage checkpoint and confers specific 
sensitization of mutant KRAS cancer cells to DNA damage [29]. Patients  with KRAS 
mutations and mutations in KRAS and TP53 will also be included in the study. 
 Combination of AZD5363 with Olaparib 
AZD5363 is  an AKT inhibitor, likely to be most active  in patients  with defects in the 
PI3K/PTEN pathway. PTEN-deficiencies, PIK3CA and AKT mutations are common events 
in multiple cancer types, with breast cancer as one of the examples with very high frequency, 
perhaps up to 50% in metastatic breast cancer [30]. 
Another PARP-inhibitor, BMN673, has shown anti-tumor activity in tumor xenografts that 
carried BRCA mutations or had PTEN- deficiency. Olaparib was used as a comparator and 
also showed efficacy in PTEN deficient cell lines [32]. A case report from a Phase I study 
using olaparib as monotherapy discussed a patient with a response to olaparib, who had a 
significant reduction in the size of brain metastases without steroid treatment or radiotherapy 
with patient-reported improvement. Upon progression after 8 months of treatment, the tumor 
biopsy displayed no somatic BRCA mutations, but showed PTEN loss [33]. 
Inhibition of the PI3K pathway by BKM120 in TNBC cell lines resulted in down regulation of 
BRCA and activation of PARP and sensitization to PARP inhibition by olaparib. The 
combination of both agents was more efficacious in some TNBC xenografts than each agent 
alone. These data therefore generated a rationale for combination of olaparib with PI3K 
inhibitors outside of the gBRCA setting and based on these data a clinical study combining 
olaparib with BKM120 is ongoing [34]. Synergy of the PI3K inhibitor with olaparib was also 
reported in the MMTV breast cancer model and two human BRCA1-related breast cancer 
models, suggesting that combined PI3K and PARP inhibition may be an effective treatment 
in certain breast cancers [35]. A recent PhI study reported at ASCO 2014 that combining 
olaparib with BKM120 was feasible with evidence of clinical benefit at all evaluated 
doselevels  [36].  Therefore,  combinations  with  an  AKT-  inhibitor,  targeting  the  same 


Page 24 of 134
signaling pathway may also be effective. 
Increased AKT phosphorylation has been shown to occur in tumors with ARID1A deficiency 
and these tumors have been shown to be sensitive to treatment with the AKT inhibitor MK- 
2206 [37-39] Patients with ARID1A mutations can therefore be included in the AZD5363 
plus olaparib combination arm. 
3.3.3 Combination of AZD6738 and Olaparib 
ATR is an atypical kinase in one of the DNA-damage induced checkpoint pathways, and 
during normal DNA replication is recruited at stalled replication forks, which can progress to 
double strand breaks if left unrepaired. Following resection of double strand breaks ATR is 
recruited to single strand DNA coated with Replication Protein A (RPA) following single 
strand DNA damage. Recruitment and activation of ATR leads to cell cycle arrest in the S 
phase while the DNA is repaired and the stalled replication fork resolved, or nuclear 
fragmentation and entry into programmed cell death (apoptosis). Loss of ATR function leads 
to the inability to resolve stalled replication forks, the accumulation of DNA damage and 
rapid cell death exemplified by nuclear fragmentation. ATR deletion is embryonic lethal in 
mice, however severe ATR hypomorphism is tolerated in humans leading to Seckel 
Syndrome. Normal cells from patients with Seckel Syndrome have reduced ATR function 
and show extensive DNA breaks when subjected to replication stress. 
Ataxia Telangiectasia Mutated (ATM) is a closely related kinase that is recruited to double 
strand breaks and like ATR, has both checkpoint and repair functions. In normal cells, there 
is a significant interplay between ATR and ATM as stalled replication forks can be converted 
into double strand breaks through fork collapse and the resection of double strand breaks 
generates single stranded DNA. During tumorigenesis, ATM can be inactivated or lost 
providing a selection advantage for the tumor cell through the increased potential for genome 
alteration, and an increased dependence on ATR function. Similarly, oncogene activation 
such as that of c-Myc leads to increased replication stress, an accumulation of stalled 
replication forks and dependence on ATR function. 
Sporadic ATM deficiency is reported in many malignant diseases (Stankovic et al 2002, 
Grønbæk et al 2002, Ambatipudi et al 2011, Bolt et al 2005, Mazumder et al 2011, Grabsch 
et al 2006), and ATM deficiency is expected to sensitize malignant cells to ATR inhibition 
through their complimentary roles in DNA damage repair. Patients with ATM deficient 
malignancies can be clinically identified and, in most cases, are known to have a poor 
prognosis with current therapies. 
Although ATM-deficient cells have a greater sensitivity to AZD6738, AZD6738 is cytotoxic 
in cell line panels of ATM-proficient hematological malignancies in vitro. In vivo combinations 
of AZD6738 with radiation induces a dose-dependent anti-tumor response, with regressions 
in ATM-deficient models and growth inhibition in ATM-proficient models. Anti-tumor activity 
of AZD6738 may, therefore, also be seen more broadly. 
There are other molecular features that could be envisaged to affect clinical response to 
ATR inhibition, and these would include: defects in additional genes/proteins that regulate 
ATM-function: MRE11A (NBS, RAD50 as part of M-R-N complex), TIP60 and CHK2; defects 
in G1/S checkpoint control (in addition to ATM/p53) and (ATR-dependent) replicative 
stress. Molecular surrogates would be loss of tumor suppressors (e.g. CDKN2A/B (p15/
p16) deletions) and/or coupled with hypoxia; and increased G1/S progression-
proliferation and (ATR-dependent) replicative stress. Molecular surrogates would be 
oncogene driven and dependent tumors (e.g. Myc, Cyclin D/E, CDK4 amplified) and/or 
coupled with hypoxia. 


Page 25 of 134
The combination of AZD6738 and olaparib are synergistically cytotoxic in HDR ovarian 
cancer cell lines in vitro and in vivo in a BRCA2-/- PDX model. PARP inhibition activates 
ATR/CHK1 as a survival mechanism and concurrent inhibition of this pathway permits the 
BRCA -/- cells to enter into mitotic catastrophe and apoptosis (B). The ATR-Chk1 checkpoint 
pathway serves to ensure cell survival after replication stress of many types, therefore a 
normal and robust checkpoint is thought to be a mechanism of resistance to chemotherapy. 
 Molecular Selection of Patients 
Patients with appropriate tumor profiles will be consented for enrollment in a specific arm of the 
clinical study prior to screening for further eligibility. 
Mutations, translocations, amplifications or other pathway activations inhibited by the listed agents 
will be identified by tests performed in a CLIA-certified laboratory, either locally, at one of the other 
participating sites or at a commercial testing facility, prior to participation in the trial. This process 
will not formally be part of this clinical protocol. 
Patients will be selected and treated as follows: 
a.
Patients with tumors harboring mutations in HDR genes will be treated with olaparib.
b.
Patients with tumors harboring P T E N , PIK3CA, AKT, or ARID1A mutations or other
molecular aberrations leading to dysregulation of the PI3K/AKT pathway will be treated with
AZD5363 plus olaparib.
c.
Patients with tumors harboring either TP53 or KRAS mutations or mutations in KRAS and
TP53 will be treated with AZD1775 plus olaparib. TP53 mutations must be found on the TP53
mutation eligibility list.
d.
Patients with tumors harboring mutations in HDR genes, including ATM, CHK2, APOBEC,
MRE11 complex, will be treated with AZD6738 and olaparib. The apparent overlap between
the olaparib alone and the AZD6738 plus olaparib is not present since accrual to the olaparib
alone arm will be completed prior to accrual to olaparib and AZD6738 arm.
e.
Patients with cholangiocarcinoma harboring IDH 1/ 2 tumors will be treated with olaparib.
If a patient’s tumor is found to have multiple mutations (TP53 and PIK3CA, for example) meeting 
criteria for multiple arms, the decision of which arm to enroll the patient should be made by the 
treating physician.  These decisions should also be made in conjunction with the Study PI. 
For details on patient selection specific to the study drugs to be used please see the following 
appendices: 
•
Olaparib (B)
•
AZD5363 plus Olaparib C)
•
AZD6738 plus Olaparib (D).
4 
PATIENT SELECTION 
      Inclusion Criteria 
Patients must meet the following criteria for study entry: 
•
Histologically documented metastatic cancer (solid tumors, not  including  hematologic
malignancies)
•
Patients who have received standard first-line therapy for metastatic cancer (except for the
tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is
considered the best available treatment option. Eligible patients should not have available


Page 26 of 134
therapies that will convey clinical benefit. 
•
Progressive cancer at the time of study entry
•
Measurable disease by RECIST v1.1
•
Age ≥ 18 years
•
Life expectancy ≥ 16 weeks
•
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1
(APPENDIX A: Performance Status Criteria)
•
Able to understand the nature of this trial and provide written informed consent
•
Patient is willing and able to comply with the protocol for the duration of the study including
undergoing treatment and scheduled visits and examinations including follow up.
•
Molecular testing or appropriate IHC results from CLIA-certified laboratories used for patient
eligibility should be obtained from the most recent tumor biopsy (baseline tumor biopsies
and on-progression tumor biopsies are optional)
•
No previous treatment with olaparib or any other drug sharing the same target.  Prior treatment
with PARP inhibitor monotherapy is allowed in the combination arms.
•
Prior radiation therapy is allowed.  Patients must not have received radiation therapy within
21 days prior to the initiation of study treatment.
•
Other therapies: Prior experimental (non-FDA approved) therapies and immunotherapies
are allowed. Patients must not have received these therapies for 21 days or five half-lives of
the drug (whichever is less) prior to the initiation of study treatment and must have full recovery
from any acute clinically significant effects of these therapies.
•
Adequate hematologic function defined as:
− 
Absolute neutrophil count (ANC) ≥  1500/μL 
− 
White blood cells (WBC) > 3 x109/L 
− 
Hemoglobin (Hgb) ≥  10 g/dL (may be achieved with erythropoietin agents; no blood 
transfusions in the 28 days prior to entry) 
− 
Platelets ≥  100,000/μL 
− 
No features suggestive of MDS/AML on peripheral blood smear 
•
Adequate renal and liver function defined as:
− 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the 
upper limit of normal (ULN) (≤ 5 × ULN if considered due to primary or metastatic 
liver involvement) 
− 
Total bilirubin ≤ 1.5 ×ULN’ Alkaline phosphatase ≤ 2× ULN (≤ 5 × ULN if 
considered due to tumor) 
− 
Serum creatinine ≤ 1.5 ULN 
•
At least one lesion, not previously irradiated, that can be accurately measured at baseline as
≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm)
with computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm with
calipers by clinical exam
OR
At least one lesion (measurable and/or non-measurable) that can be accurately assessed by
CT/MRI/plain x-ray/clinical exam at baseline and follow up visits.
•
Women of child-bearing potential must have a negative pregnancy test (urine or serum)
within 28 days prior to starting the study drug.  Both males and females must agree to
adequate birth control if conception is possible during the study and for 6 months after the
last dose.  Female patients are considered to not be of child-bearing potential if they have a
history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 1 year
without menses.
Additional inclusion criteria specific to the study drug to be used are as follows: 


Page 27 of 134
•
Olaparib → Olaparib and AZD6738
− 
Patients with solid tumors that harbor homologous DNA repair (HDR) gene mutations 
as exemplified below detected by next-generation sequencing (NGS) or real-time- 
polymerase chain reaction (RT-PCR) in assays performed at a Clinical Laboratory 
Improvement Amendments (CLIA)- certified laboratory: 
− 
Examples of Homologous DNA repair deficiency/HDR (germline/somatic 
mutations in tumors), but not limited to, are: BRCA 1, BRCA2/FANCD1, PALB2, 
RAD51, RAD 52, FANCN, FANCJ, FANCD2, DSS1, FANCC1, MRE11, RAD50, 
NSB1, BLM, ATM, ATR, CHK1, CHK2, FANC A,-B,-C, -E, -F, -G,-L, M, D2 
•
AZD5363 plus Olaparib
− 
Patients with solid tumors with PIK3CA or AKT mutations or other molecular 
aberrations leading to dysregulation  of the PI3K/AKT pathway detected by next- 
generation sequencing (NGS) or real-time-polymerase chain reaction (RT-PCR) in 
assays performed at a Clinical Laboratory Improvement Amendments (CLIA)- certified 
laboratory: 
− 
activating mutations in PIK3CA, AKT1, AKT2, AKT3, ARID1A; 
− 
other molecular aberrations leading to dysregulation of the PI3K/AKT pathway, 
for example PIK3R1and PTEN; 
− 
if new information emerges relating to molecular aberrations that dysregulate 
the PI3K/AKT pathway, patients whose tumors bear these aberrations can be 
included in the study. 
•
Olaparib for neomorphic oncometabolites, such as 2-HG, in patients harboring mutations in
IDH1/IDH2 mutant tumors or TCA/tricarboxylic acid cycle mutations such as FH and/or SDH.
•
The AZD1775 plus Olaparib additional inclusion criteria will be added as an addendum to
the protocol and opened once the recommended phase II doses are available.
     Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
•
Patients with known germline BRCA mutations in breast cancers will be excluded from
the study, however testing is not required for inclusion in the study.
•
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff
and/or staff at the study site)
•
Prior standard of care cancer chemotherapy, immunotherapy or radiotherapy < 21 days prior
to first dose of study agent(s).
•
Patients 
with 
hematologic 
malignancies
(includes 
patients 
with 
myelodysplastic 
syndrome/ acute myeloid leukemia).
•
Patients with primary CNS malignancies
•
Patients must not have received allogeneic stem cell transplant
•
Concurrent administration of any other anti-cancer therapy
− 
Bisphosphonates and Denosumab for bone metastases are allowed if started at least 
4 weeks prior to treatment with study agent(s). 
− 
Octreotide is allowed if dose is stable for >3 months with no worsening of carcinoid 
syndrome 
− 
Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for 
medical castration in patients with castrate-resistant prostate cancer is permitted 
•
Patients who have not demonstrated stable recovery (28 days or greater) from ≤ CTCAE
grade 2 non-hematological toxicities related to prior therapy, such as peripheral neuropathy or
alopecia, or incomplete recovery from previous surgery, unless agreed by the Principal
Investigator (PI) and documented, are not eligible to participate in this study.
•
Active or untreated brain metastases or spinal cord compression
− 
A scan to confirm the absence of brain metastases is not required. 


Page 28 of 134
− 
Patients with treated brain metastases or spinal cord compression are eligible if they 
have minimal neurologic symptoms and evidence of stable disease (for at least 1 
month) or response on follow-up scan. The patient can receive a stable dose of 
corticosteroids before and during the study if started at least 28 days prior to initiating 
the study agent(s). 
•
History of carcinomatous meningitis
•
Patients with second primary cancer, except: adequately treated non-melanoma skin cancer,
curatively treated stage I cancers (cervix, breast, colon, lung or prostate as examples) or other
advanced (> Stage I) solid tumors curatively treated with no evidence of disease for ≥ 5
years.
•
Patient must not have a co-morbid condition(s) that, in the opinion of the investigator, prevent
safe treatment.
•
Immunocompromised patients, e.g., patients who are known to be serologically positive for
human immunodeficiency virus (HIV) and are receiving antiviral therapy (testing is not part of
the protocol).
•
Patients with known (testing is not part of the protocol) active hepatic disease (i.e., Hepatitis
B or C) due to risk of drug interactions with anti-viral therapy.
•
Any of the following cardiovascular events within 6 months prior to study entry: myocardial
infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart
failure, cerebral vascular accident, or transient ischemic attack
•
History or presence of clinically significant ventricular or atrial dysrhythmia >  Grade 2 (NCI
CTCAE v4.0)
− 
Patients with chronic, rate-controlled atrial arrhythmias who do not have other cardiac 
abnormalities are eligible. 
•
Major surgery within 3 weeks prior to first dose of study treatment, and patients must have
recovered from the effects of surgery
•
Patients unable to swallow orally administered medication and patients with gastrointestinal
disorders likely to interfere with absorption of the study medication
•
Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel
disease) or significant bowel resection that would preclude adequate absorption
•
Patients with uncontrolled seizures
•
Inadequate bone marrow reserve within past 28 days prior to study treatment, excluding
clinically documented therapy related toxicity that have recovered at time of screening, as
exemplified by:
− 
Absolute neutrophil count (ANC) < 1500/µl, 
− 
WBC ≤ 3 x 109/L 
− 
Platelet count (PLT) < 100,000/µl, or 
− 
Hemoglobin (Hgb) < 10 g/dL 
•
Blood (packed red blood cells, platelets) transfusions within 1 month prior to study start
•
Whole blood transfusion in the last 120 days prior to entry to the study
•
Patients with concomitant use of drugs, herbal supplements and/or ingestion of foods known
to strongly modulate CYP3A4 enzyme activity as specified in the drug specific appendix.
•
Women who are pregnant or lactating (breastfeeding)
•
Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
•
Patients with a known hypersensitivity to the combination/comparator agent
•
Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality
that may increase the risk  associated with study participation or may interfere with the
interpretation of study results
− 
Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples 
include, but are not limited to, uncontrolled ventricular arrhythmia, superior vena cava 


Page 29 of 134
syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder 
that prohibits obtaining informed consent 
•
Psychological, familial, sociological, or geographical conditions that do not permit compliance
with the protocol
All patients must also meet the specific criteria for individual study drugs as follows: 
•
Olaparib
− 
No additional exclusion criteria 
•
AZD5363 plus olaparib
− 
Clinically significant abnormalities of glucose metabolism as defined by any of the 
following: 
− 
Diabetes mellitus type I- Fasting plasma glucose [fasting is defined as no 
calorific intake for at least 8 hours]: ≥ 7.0mmol/L (126 mg/dL) for those patients 
without a pre-existing diagnosis of  Type 2 diabetes mellitus≥  9.3 mmol/L 
(167mg/dL) for those patients with a pre-existing diagnosis of Type 2 diabetes 
mellitus 
− 
Glycosylated hemoglobin (HbA1C) ≥ 8.0% (63.9 mmol/mol) 
− 
Requirement for insulin for routine diabetic management and control 
− 
Requirement for more than two oral hypoglycemic medications for routine diabetic 
Patient must have no evidence of clinically significant troponin elevation (any CTC 
grade) 
− 
Patient must not have > Stage II NYHA classification cardiac status; recent history 
(i.e., within 6 months) of coronary artery disease or arteriosclerotic cardiovascular 
disease (angina, myocardial infarction [MI]) 
− 
Patient must not have PR interval greater than 200 msec 
− 
Patient must not have clinically significant PR (PQ) interval prolongation 
− 
Patient must not have resting LVEF < 55% measured by echocardiogram or MUGA, 
regional wall abnormality on ECHO, or any clinically significant structural 
abnormalities on echocardiogram such as left ventricular hypertrophy or diastolic 
dysfunction or valvular  disease 
− 
Patient must not have QTcF > 480 msec or b) family history of long QT Syndrome or 
c) evidence of recent myocardial infarction e.g. within 6 months prior to start of study
treatment) or risk of having a re-infarction, or d) history of torsade de pointes or e) 
QTcF < 350 msec (short QT syndrome) 
− 
Patient must not have intermittent second or third-degree AV block (Second degree 
AV block (Mobitz Type I and II). Third Degree AV block (Complete Heart Block). 
Incomplete, full or intermittent bundle branch block (QRS 110-120ms with normal QRS 
and T wave morphology is permitted if there is no evidence of left ventricular 
hypertrophy. Mobitz type 1, Wenckebach while asleep is permitted 
− 
Patient must not have clinically significant abnormalities in T wave or ST-T changes 
that can be indicative or be suggestive of acute ischemic changes or acute injury 
pattern 
− 
Use of any of the following potent negative inotropic drugs: 
- calcium channel blockers: verapamil or diltiazem; beta-blockers (pending discussion 
with cardiac SKG): metoprolol, propranolol, atenolol, bisoprolol, carvedilol, timolol, 
sotalol, esmolol; anti- arrhythmics (Class I): disopyramide, procainamide, mexiletine; 
(Class III): amiodarone 
− 
patients with uncontrolled hypotension (systolic blood pressure <90 mmHg and/or 
diastolic blood pressure <50 mmHg) 
− 
Patients with potassium or sodium levels outside the normal range for the site 


Page 30 of 134
− 
Patients with proteinuria (3+ on dipstick analysis or >500 mg/24 hours) 
•
AZD6738 plus olaparib
− 
A diagnosis of ataxia telangiectasia 
− 
Receiving, or having received during the four weeks prior to first dose, corticosteroids 
(at a dose > 10 mg prednisolone / day or equivalent) for any reasons 
− 
Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks 
before the dosing 
− 
Treatment with any biological IMP e.g. immune check point blockers, antibodies, 
nanoparticles, experimental) within 42 days prior to the first dose 
− 
Known hypersensitivity to AZD6738 or any excipient of the product 
− 
Patients with myelodysplastic syndrome / acute myeloid leukemia or with features 
suggestive of MDS / AML 
− 
Patient must not have impaired hepatic or renal function as demonstrated by the 
following laboratory value, in addition to those values previously delineated: 
▪
Total bilirubin > 1.5 ×ULN (or likely to be in 3 weeks)
▪
AST or ALT > 2.5 ULN (unless lever metastases are present in which case they
must be > 5x ULN)
▪
Albumin < 33 g/L (or outside of local laboratory reference range)
▪
INR ≥ 1.5 or other evidence of impaired hepatic synthesis function
▪
Alkaline phosphatase > 2.5 ×ULN (≤ 5 × ULN if considered due to tumor)
▪
Serum creatinine > 1.5 ULN
▪
Glomerular filtration rate (GFR) < 51 mL/min, as assessed using the standard
methodology at the investigating center (e.g. Cockcroft-Gault, MDRD or CKD-
EPI formulae, EDTA clearance or 24 hr urine collection)
▪
Hematuria: +++ on microscopy or dipstick
− 
Patient must not have > Class II NYHA classification cardiac status, recent history (i.e., 
within 6 months) of coronary artery disease or arteriosclerotic cardiovascular disease 
(unstable angina, myocardial infarction), or unstable cardiac arrhythmias 
− 
Patient must not have resting LVEF < 55% measured by ECHO/MUGA 
− 
Patient must not have mean resting corrected QT interval (QTc) >470 msec obtained 
from 3 electrocardiograms (ECGs) in 24 hours using the Fredericia formula. 
− 
Patient must not have any clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g., complete left bundle branch block, third degree heart 
block). 
− 
Patient must not have any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, 
immediate family history of long QT syndrome or unexplained sudden death under 40 
years of age. 
− 
Patient must not be at risk of brain perfusion problems, e.g., carotid stenosis 
− 
Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic 
hypotension, including a fall in blood pressure of >20mm Hg. 
− 
Patient must not have uncontrolled hypertension requiring clinical intervention. 
− 
Subjects receiving, or having received, concomitant medications, herbal supplements 
and/or foods that strongly modulate CYP3A4 or P-glycoprotein activity (wash out periods 
of two weeks, but three weeks for St. John’s Wort). 
− 
Concomitant use of known strong CYP3A4 inhibitors (e.g. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevit) or moderate CYP3A inhibitors (e.g. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting study treatment is 2 weeks. 


Page 31 of 134
− 
Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout 
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 
weeks for other agents. 
•
The AZD1775 plus olaparib additional exclusion criteria will be added as an addendum to
the protocol and opened once the recommended phase II doses are available.
5 
REGISTRATION PROCEDURES 
      General Guidelines 
Eligible patients will be entered on study centrally at Yale (YCCI). Prior to obtaining signed 
informed consent from a patient, the site principal investigator or designee must contact the YCCI 
Project Manager to inquire about study slot availability. If available, the potential study participant will 
be consented and all required screening procedures will be completed, as outlined in the 
appendices for each treatment arm. The site principal investigator (or other approved investigator) 
must document that the participant has met all inclusion/exclusion criteria. 
Following completion of eligibility testing, the participating site must provide documentation verifying 
eligibility of the patient to the YCCI Project Manager (refer to Study Procedure Manual for 
acceptable documentation). Upon review and approval by the YCCI Project Manager, the patient 
will be registered into Yale’s web-based clinical database (OnCore). Confirmation of registration 
and treatment arm, in addition to a unique patient ID number, will then be communicated to the 
participating site. 
Following registration, patients should begin protocol treatment within 72 hours (if a spot is 
available). Issues that would cause treatment delays should be discussed with the Study Principal 
Investigator. If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled. The YCCI Project Manager should be notified of 
cancellations as soon as possible. 
 Registration Process 
Detailed information regarding the patient registration process is located in the Study Procedure 
Manual. 
6 
TREATMENT PLAN 
  Agent Administration 
Dose Schedule 
Drug Combination 
Dose* 
Olaparib 
Combination Drug 
Olaparib 
300mg BID 
None 
Olaparib + AZD5363 
300mg BID 
640mg BID D1-2/weekly 
Olaparib + AZD6738 
300mg BID 
160 mg daily D1-7/Q 28 D 


Page 32 of 134
Olaparib + AZD1775** 
300mg BID 
TBD 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a
percentage. 
** The AZD1775 plus olaparib arm doses will be added as an addendum to the protocol 
once the recommended phase II doses are available. 
Please refer to the appendices for the specifics of agent administration for each agent as follows: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The AZD1775 plus olaparib arm agent administration will be added as an addendum
to the protocol once the recommended phase II doses are available.
 Definition of Toxicity 
If toxicities occur, they will be defined based on toxicities observed following the administration of 
olaparib or the combination administration (C1D1) of olaparib and AZD1775, AZD5363, and 
AZD6738. Toxicities will be graded using the descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the following web site: (http://ctep.cancer.gov). 
Management and dose modifications associated with the above adverse events are outlined 
In the following appendices: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The AZD1775 plus olaparib arm agent administration will be added as an addendum to
the protocol once the recommended phase II doses are available.
Assessment of tumor response will be performed at 8 week intervals. Assessment for full 
expansion from 16 to 25 patients will be made at 16 weeks. Patients with an objective response 
or stable disease may receive additional treatment cycles until disease progression or withdrawal 
criteria are met. Ongoing evaluation of response will be conducted every 8 weeks, and safety 
will be evaluated weekly. 
Other Modalities or Procedures 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
 Concomitant and Excluded Therapies 
 Permitted Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient from ≤ 7 days prior to the first dose of study drug to the end of treatment visit. 
All concomitant medications should be reported to the investigator. 
Patients who use oral contraceptives or hormone-replacement therapy and do  not  have 
breast cancer may continue these medications under the  supervision  of  their  physician. 
Other medications may be continued unless otherwise indicated in the specific study drug 


Page 33 of 134
appendix. 
Supportive care, including certain antiemetic medications, may be administered at the 
discretion of the investigator unless otherwise indicated in the specific study drug appendix. 
 Prohibited Therapy 
No other investigational therapy should be given to patients. 
No concomitant cancer treatment of any type (including chemotherapy, biologic therapy, 
hormonal therapy, immunotherapy, radiation therapy) should be administered at any time while 
the patient is taking study treatment. If such treatment is required, then the patient  must first be 
withdrawn from the trial. 
•
Bisphosphonates and Denosumab for bone metastases are allowed as long as these
were started at least 4 weeks prior to treatment with study drug.
•
Octreotide is allowed if dose is stable for >3 months with no worsening of carcinoid syndrome.
•
Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for
medical castration in patients with castrate-resistant prostate cancer is permitted.
•
Palliative radiotherapy is allowed for pre-existing  small areas of painful metastases that
cannot be managed with local or systemic analgesics as long as no evidence of disease
progression is present. Study treatment should be discontinued for a minimum of 3 days
before the patient undergoes palliative radiation treatment. Study treatment should be
restarted within 4 weeks if bone marrow toxicity has resolved.
Additional excluded concomitant therapies are provided in the specific appendix for each 
study drug: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The AZD1775 plus olaparib arm agent administration will be added as an addendum
to the protocol once the recommended phase II doses are available.
 Duration of Therapy 
In the absence of significant treatment delays ≥4 weeks due to adverse events determined to 
be probably/definitely attributed to a study agent (as defined in Adverse Events 
Characteristics), treatment may continue indefinitely or until one of the following criteria applies: 
•
Objective disease progression according to RECIST criteria
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s) to include any drug toxicity considered related, probably
related, or possibly related to the drug. This excludes only toxicities clearly not related to the
drug, such as environmental, unrelated trauma, etc.
•
Severe non-compliance to study protocol as judged by the investigator
•
Patient becomes pregnant
•
Patient is determined to no longer meet the required inclusion/exclusion criteria for
the study
•
Patient decides to withdraw from the study (the subject is at any time free to
discontinue treatment, without prejudice to further treatment)
•
General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator
 Duration of Follow Up 


Page 34 of 134 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first. Patients will be followed every 12 weeks (+/- 1 week) thereafter by phone for survival status. 
Patients removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. 
     Criteria for Removal from Study 
Patients will be removed from study when appropriate criteria listed in Section 6 applies.  The 
reason for study removal and the date the patient was removed must be recorded. 
7 
DOSING DELAYS / MODIFICATIONS / DISCONTINUATION 
Toxicities will be graded using the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the following web site: (http://ctep.cancer.gov). 
•
Doses of olaparib and AZD5363 will be administered at the same dose level throughout a
cycle if no toxicities occur
•
If a toxicity is < Grade 3, the patient can continue the daily dosing at the same dose level if
the principal investigator deems it safe to proceed after evaluation of the toxicity
•
If an intolerable Grade 2 toxicity or Grade 3 or 4 toxicity is observed at any time during a
treatment cycle, the dose olaparib and/or AZD5363 for subsequent cycles will be reduced to
the next lower dose level as discussed in the following appendices:
− 
Olaparib (APPENDIX B) 
− 
AZD5363 plus olaparib (APPENDIX C) 
− 
AZD6738 plus olaparib (APPENDIX D) 
− 
The AZD1775 plus olaparib arm dosing delays/modifications/discontinuation will be 
added as an addendum to the protocol once the recommended phase II doses are 
available. 
•
All dose modifications will be based on toxicities that are determined to be definite/probably
or unlikely/unrelated attributed to a study agent (as defined in Adverse Events Characteristics)
and not attributable to disease or other causes.
The combination of olaparib and/or AZD5363 and/or AZD6738 will be treated as separate entities 
and any dose modification will occur as indicated in APPENDICES C and D. The AZD1775 plus 
olaparib arm will be added as an addendum to the protocol once the recommended phase II doses are 
available. 
If there is a < 4 week delay due to recovery of toxicity or if there is a report of grade 3 or grade 4 
toxicity thought to be due to olaparib and/or AZD5363 or AZD6738 therapy, then the patient will be 
re-treated at the specified dose modification. 
A new cycle of therapy should not begin until the treatment-related toxicity has recovered to baseline 
grade if baseline was grade 2 or NCI-CTCAE grade 1 or less. Treatment may be delayed 1 to 2 weeks 
to allow for recovery from treatment-related toxicity. If there is a ≥ 4 week delay of treatment due to 
drug-related toxicity, then the patient will discontinue the combination therapy and be removed from 
the study. The patient may continue to receive this investigative combination until any criteria defined in 
Duration of Therapy applies. Dose reductions may occur multiple times; as long as the participant 
continues to respond to therapy, reductions may occur down to the lowest protocol-specified dose 
level. Dose re-escalation will not be allowed. Every effort will be made to follow patients to 
progression/death regardless of future treatment once study treatment is discontinued and they are 
removed from the study. 


Page 35 of 134
An exception to the management of treatment-related toxicity is the occurrence of leukopenia and/or 
anemia. In this case, the AE should be managed as deemed appropriate by the investigator (growth 
factor, transfusions), without interruption in study drug or change in dose. However, growth factors 
must be discontinued once the AE has recovered to grade 1 or better. They may be resumed if 
leukopenia/anemia develops again. Treatment should be stopped before surgery and re-started 
following recovery. No stoppage of treatment is required for any biopsy procedures. Treatment 
should be discontinued for a minimum of 7 days before a patient undergoes therapeutic radiation 
treatment. This is not required where palliative doses are used. 
Any patient discontinuing investigational product should be seen at 30 days post discontinuation for 
the evaluations outlined in the study schedule or contacted at least 30 days after discontinuing study 
medication to collect and  /or complete AE information. The patient’s tumor status should be 
assessed clinically and, if appropriate, disease progression should be confirmed by radiological 
assessment. 
After discontinuation of the study medication at any point, all ongoing or new (within 30 days after 
discontinuation) AEs or SAEs must be followed until resolution unless, in the investigator’s opinion 
the condition is unlikely to resolve due to the patients underlying disease, or the patient is lost to 
follow up. 
8 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
      Definitions 
The definitions of adverse events (AEs), serious adverse events (SAEs) and other significant 
adverse events (OAEs) are listed below. Toxicities will be graded using the descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the following web site: 
(http://ctep.cancer.gov). 
Adverse event 
An adverse event (AE) is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal 
results of an investigation (eg, laboratory findings, electrocardiogram). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
Serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfills one or more of the following criteria: 
•
Results in death
•
Is immediately life-threatening
•
Requires in-patient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Results in a congenital abnormality or birth defect
•
Is an important medical event that may jeopardize the subject or may require medical
intervention to prevent one of the outcomes listed above


It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Definitions. An AE of severe intensity need not 
Page 36 of 134
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review the 
list of AEs that were not reported as SAEs. Based on the expert’s judgment, significant adverse 
events of particular clinical importance may, after consultation with the Global Patient Safety 
Physician, be considered OAEs and reported as such. 
Other Significant Adverse Events (OAE) 
OAEs will be identified by the Drug Safety Physician and if applicable also by the Study Team 
Physician during the evaluation of safety data for the CSR. Significant adverse events of particular 
clinical importance, other than SAEs and those AEs leading to discontinuation of the patient from 
study treatment, will be classified as OAEs. Examples of these are AEs of reduction in ejection 
fraction, marked hematological and other laboratory abnormalities, and certain events that lead 
to intervention (other than those already classified as serious), dose reduction or significant 
additional treatment. For each OAE, a narrative may be written and included in the CSR. 
 Recording of adverse events 
Non-serious adverse events and SAEs will be collected from the time the study drug is given, 
throughout the treatment period and up to and including the 30 day follow-up period. After 
withdrawal from treatment, subjects must be followed-up for all existing and new AEs for 30 
calendar days after the last dose of trial drug and/or until event resolution. All new AEs occurring during 
that period must be recorded (if SAEs they must be reported to the FDA and AstraZeneca per 
Reporting to the Food and Drug Administration and Reporting to AstraZeneca (AZ). SAEs 
determined to be related to study treatment occurring after the 30 day follow-up period must also be 
reported. 
The following variables will be collected for each AE: 
•
AE (verbatim)
•
The date when the AE started and stopped
•
Whether the AE is serious or not
•
Investigator causality rating against the Investigational Product (definite/probably or
unlikely/unrelated) and comparator/combination drug (definite/probably or unlikely/unrelated)
•
Action taken with regard to investigational product/comparator/combination agent
•
Outcome.
In addition, the following variables will be collected for SAEs: 
•
Date AE met criteria for serious AE
•
Date Investigator became aware of serious AE
•
AE is serious due to
•
Date of hospitalization
•
Date of discharge
•
Probable cause of death
•
Date of death
•
Autopsy performed
•
Description of AE
•
Causality assessment in relation to Study procedure(s)
•
Causality assessment in relation to Other medication
•
Causality assessment in relation to Additional Study Drug


Page 37 of 134
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke but would be a SAE. 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated parameters (eg laboratory values) should 
therefore only be reported as AEs if they fulfill any of the SAE criteria or are the reason for 
discontinuation of treatment with the investigational product. 
If deterioration in a parameter is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated laboratory result/vital sign will be considered 
as additional information. Wherever possible the reporting investigator uses the clinical, rather than 
the laboratory term (eg, anemia versus low hemoglobin value). In the absence of clinical signs or 
symptoms, clinically relevant deteriorations in non-mandated parameters should be reported as 
AE(s). 
Deterioration of a parameter, which is unequivocally due to disease progression, should not be 
reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE. 
NB. Cases where a subject shows an AST or ALT ≥3x ULN or total bilirubin ≥ 2x ULN may need to 
be reported as SAEs, please refer to G ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
New cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria (see Section 8.1). New primary cancers are those that are not the 
primary reason for the administration of the study treatment and have developed after the inclusion 
of the patient into the study. They do not include metastases of the original cancer. Symptoms of 
metastasis or the metastasis itself should not be reported as an AE/SAE, as they are considered to 
be disease progression. 
Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study follow-up 
period after the administration of the last dose of study treatment, must be reported as follows: 
•
Death clearly the result of disease progression should be reported to the study monitor at the
next monitoring visit and should be documented in the eCRF but should not be reported
as an SAE.
•
Where death is not due (or not clearly due) to progression of the disease under study, the AE
causing the death must be reported to the study monitor as a SAE within 24 hours. The
report should contain a comment regarding the co-involvement of progression of disease,
if appropriate, and should assign main and contributory causes of death. This information
can be captured in the ‘death eCRF’.
•
Deaths with an unknown cause should always be reported as a SAE. A post mortem
maybe helpful in the assessment of the cause of death, and if performed a copy of the post-


Page 38 of 134
mortem results should be forwarded to AstraZeneca within the usual timeframes. 
 Follow-up of unresolved adverse events 
All study-related toxicities/ SAEs must be followed until resolution, unless in the Investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease. 
 Causality collection 
The causality of SAEs  (their  relationship  to  all  study treatment)  will  be  assessed  by  the 
investigators and communicated to the FDA, AstraZeneca, and appropriate IRBs. 
 Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
cancer. It may be an increase in the severity of the cancer or an increase in the symptoms of the 
disease. Expected progression of the disease under study and /or expected progression of signs and 
symptoms of the disease under study, unless more severe in intensity or more frequent than expected 
for the patient’s condition should not be reported as an AE. The development of progression 
of existing metastasis to the primary cancer under study should be considered as disease 
progression and not an AE. Events that are unequivocally due to disease progression must not be 
reported as an AE/SAE. 
  Lack of Effect 
Where there is deterioration in the condition for which the study treatment is being used, there may 
be uncertainty as to whether this is lack of efficacy, disease progression or constitutes an AE. In 
such cases, unless the reporting physician considers that the study treatment contributed to the 
deterioration or local regulations state to the contrary, the deterioration should be considered to be 
lack of efficacy and not an AE. 
  Adverse Events Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the following web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting purposes 
only. 
Attribution of the AE: 
− 
Definite – The AE is clearly related to the study treatment 
− 
Probable – The AE is likely 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 
 Yale Principal Investigator Safety Reporting Requirements 
AEs classified as “serious” and 
“unexpected” that are probably/definitely attributed to drug 
administration, or SAEs whose frequency exceeds expectations, require expeditious handling and 
reporting. 
The PIs will promptly investigate all safety information related to an adverse experience. If the 
results of the PIs’ investigation show an adverse drug experience not initially determined to be 
reportable (based on whether the event is serious,  unexpected,  and associated with drug 


Page 39 of 134 
administration) is so reportable, the PIs will report such experience. Follow‐up information to a 
safety report shall be submitted as soon as the relevant information is available. 
All adverse events will be reported to AstraZeneca at the conclusion of the study. 
 Reporting to the Yale Human Investigation Committee 
All SAEs, whether originating at Yale or a collaborating center, meeting the criteria for 
prompt reporting will be reported to the Yale University Human Investigation Committee (HIC) 
as per Yale HRPP policy. 
The Yale University Human Investigation Committee prompt reporting criteria are: Unexpected (in 
terms of nature, specificity, severity, or frequency) AND related or possibly related to participation 
in the research AND the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized. 
 Reporting to the Food and Drug Administration 
This study will be conducted under an IND (Investigational New Drug application) that will be 
held by the PI. The Principal Investigator will report in an expedited manner all SAEs meeting 
the criteria of “serious”, “unexpected” and “related to study treatment”. Written safety reports 
will use a MedWatch Form 3500A. A “fillable pdf” version with instructions is available 
at:http://www.fda.gov/medwatch/safety/FDA‐3500A_Fillable_08‐16‐2006.pdf 
There are two types of expedited safety reports to the FDA: 
1.
7‐Calendar‐Day FDA Telephone or Fax Report: The sponsor‐investigator will
directly notify the FDA, within 7 calendar days after his initial receipt of the 
information, of any adverse event that is ALL of the following: 
Death or immediately life‐threatening 
Unexpected 
Associated with the use of the study drug 
Notification to the FDA will be made directly to the new drug review division in the 
Center for Drug Evaluation and Research or in the product review division for the 
Center for Biologics Evaluation and Research, whichever was responsible for the 
review of the IND. 
A written report of the event is to follow within 15 calendar days. 
2.
15‐Calendar‐Day FDA Written Report: The sponsor‐investigator will directly
notify the FDA within 15 calendar days of any adverse event that is ALL of the 
following: 
Serious (due to non‐fatal and non‐life threatening criteria 
Unexpected 
Associated with the use of the study drug 
Note: Serious Adverse Events which do not meet the criteria for expedited reporting will 
be reported to the FDA in the IND Annual Report. 
 Reporting to AstraZeneca (AZ) 


Page 40 of 134 
Investigators will concurrently forward all FDA-reported Serious or unexpected adverse 
events reports to AZ. A copy of the report must be faxed to AstraZeneca at the time the event 
is reported to the FDA. All SAEs should be reported to AstraZeneca within 24 hours of the 
Investigator becoming aware of the event. 
* A cover page should accompany the FDA Report form indicating the following:
•
OLAPCO Investigator Sponsored Study (ISS)
•
The investigator IND number assigned by the FDA
•
The investigator’s name and address
•
The trial name/title and AstraZeneca 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 fax (+46 31 776 37 34) 
or secure email to AstraZeneca using AEmailboxclinicaltrialTCS@astrazeneca.com. 
Fax is the preferred method. If a non-serious AE becomes serious, this and 
other relevant follow-up information must also be provided to AstraZeneca 
and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA need to 
be reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events. This information should be reported on a monthly basis and under no 
circumstance 
less frequently than quarterly. All SAEs have to be reported to 
AstraZeneca, whether or not considered causally related to the investigational product. 
All SAEs will be documented. 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided to AstraZeneca and the FDA. 
The investigator is responsible for informing the IRB and/or the Regulatory Authority of 
the SAE as per local requirements. 
Non-serious adverse events and SAEs will be collected from the time study drug is 
given, throughout the treatment period and up to and including the 30 day follow-up 
period. After withdrawal from treatment, subjects must be followed-up for all existing 
and new AEs for 30 calendar days after the last dose of trial drug and/or until event 
resolution. All new AEs occurring during that period must be recorded (if SAEs, then 
they must be reported to the FDA and AstraZeneca). All study-related toxicities/ SAEs 
must be followed until resolution, unless in the Investigator’s opinion, the condition is 
unlikely to resolve due to the patient’s underlying disease. 
New Cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers 
are those that are not the primary reason for the administration of the study treatment 
and have been identified after the patient’s inclusion in this study. 
Deaths 
All deaths that occur during the study, or within the protocol defined safety follow up 
period after the administration of the last dose of study treatment, as specified in 


Page 41 of 134 
section 8.2 above must be reported to AstraZeneca. 
 Duration of Reporting of SAEs 
From the administration of first treatment until 30 days (unless otherwise specified) 
after t h e last treatment or withdrawal of subject, new onset adverse events will be 
captured. Follow-up and reporting of these events will follow the same procedure as for 
AEs observed during the study period. In addition, any unexpected Serious Adverse 
Event that occurs 
more than 
30 days 
after 
drug 
administration but 
is 
probably/definitely attributed to drug administration . 
9 
PHARMACEUTICAL INFORMATION 
   Pharmaceutical Information 
Detailed Pharmaceutical information for each compound is provided in the following appendices: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The  AZD1775  plus  olaparib  arm  pharmaceutical information will be added as an
addendum to the protocol once the recommended phase II doses are available.
 Pharmaceutical/Drug Distribution 
Study drug will be supplied to each study site by AstraZeneca. Participating sites are responsible to 
ensure processes, procedures, and documentation  are in place for storage, distribution, inventory 
control, and disposition. 
 Accountability 
The study drug provided for this study is for use only as directed in the study protocol. It is the 
investigator/institution’s responsibility to establish a system for handling study treatments, including 
investigational medicinal products, so as to ensure that: 
1.
Deliveries of such products from AstraZeneca are correctly received by a responsible
person
2.
Such deliveries are recorded
3.
Study treatments are handled and stored safely and properly as stated on the label
4.
Study treatments are only dispensed to study patients in accordance with the protocol
The study personnel will account for all study medications dispensed and returned.
Certificates of delivery and return should be signed
At the end of the study, it must be possible to reconcile delivery records with records of
usage and destroyed/returned stock. Records of usage should include the identification
of the person to whom the study treatment was dispensed, the quantity and date of
dispensing and unused study treatment returned to the investigator. This record is in
addition to any drug accountability information recorded on the CRF. Any discrepancies
must be accounted for on the appropriate forms. Certificates of delivery and return must
be signed, preferably by the investigator or a pharmacist, and copies retained in the
investigator site file
10 CORRELATIVE/SPECIAL STUDIES 


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    Sample collection 
   Tumor samples 
The evaluation of patient eligibility based on mutation data (and FH status by IHC) will be 
done based on archival / new tumor biopsies prior to enrolment of the study. On the 
study, the following samples will be collected: 
•
Archival tumor sample
− 
If available, archival tissue will be requested by the enrolling site after 
consenting procedures are completed. The same sample that was used for the 
genetic profiling should be requested as a preference, if not available other 
samples are acceptable 
− 
Archival tissue should be provided from formalin-fixed and paraffin-embedded 
tissue. If possible, provide tissue blocks rather than cut sections. 
− 
Tumor sample collection and storage will be performed as outlined in the 
laboratory procedure manual 
•
Tumor sample at baseline if feasible (optional)
− 
The sample can be collected up to 4 weeks before the first dose. Therefore, 
any sample collected during this time period prior to study enrollment can be 
used as baseline sample 
− 
The tumor sample for use in genetic and protein analyses (see below) should 
be formalin-fixed and embedded in paraffin according to standard procedures 
at each institution 
− 
Additional tumor samples may also be collected and used fresh or frozen 
− 
Tumor sample collection and storage will be performed as outlined in the 
laboratory procedure manual 
•
Tumor sample at progression or discontinuation if feasible (optional)
− 
The sample can be collected at progression or discontinuation, or any time 
between progression and discontinuation from the study 
− 
The tumor sample for use in genetic and protein analyses (see below) should 
be formalin-fixed and embedded in paraffin according to standard procedures 
at each institution 
− 
Additional tumor samples may also be collected and used fresh or frozen 
− 
Tumor sample collection and storage will be performed as outlined in the 
laboratory procedure manual 
  Plasma samples 
Plasma samples (optional) will be collected at baseline, on treatment and at progression/ 
discontinuation on study to isolate cell-free circulating tumor DNA (ctDNA) to determine the 
mutational profile and changes thereof 
•
The plasma sample (optional) at baseline can be collected up to 2 weeks before the
first dose
•
Samples on study should be taken at the end of the first cycle (+/- 7 days), and at the
end of the cycles 4, 6 and 10 (+/- 7 days) and at progression or discontinuation or any
time between progression and discontinuation from the study
•
Additional samples after cycle 10 and before progression can be collected (optional),
if the investigator deems a particular time point of interest. However, samples should
not be collected more frequently than every 2 cycles


Page 43 of 134 
•
F describes the procedures for collection, processing, storage and shipment of plasma
   Analyses of samples 
   Analyses of tumor samples 
•
Genetic analyses of a sample prior to study enrollment is a requirement for enrollment
and not part of the study (see B and C for relevant mutations)
•
The tumor samples collected at baseline and on progression/ discontinuation, will be
used primarily for genetic testing to investigate if the mutational profile of the patients
has changed between diagnosis, the start of the study and progression/
discontinuation. Archival samples provided may be used for this purpose too as
enrollment is based on multiple accepted CLIA tests.
•
Genetic findings will be correlated with outcome and tumor markers, where available.
•
Where appropriate, protein- / RNA-analyses will complement the genetic findings on
the tumor samples (archival, baseline and progression/ discontinuation samples) to
further establish the functional consequence of mutations
•
Where possible, patients’ cells may also be cultured and retrospectively tested for
sensitivity to the relevant agents in exploratory laboratory experiments to study if
sensitivity to these agents could potentially be predicted (this will not be done
prospectively and not determine enrollment in the study)
•
Samples may also be used for additional exploratory endpoints to be defined
While defects in DNA-damage-repair pathways will only be used to select patients for the 
olaparib monotherapy arm, a focus of the biomarker analyses in the study will be to 
determine mutations in genes of the DNA-Damage-repair pathway. Mutational analyses of 
new tumor samples at baseline and on progression, were feasible, is planned, but archival 
tissue may be used as well. 
 Analysis of plasma samples 
•
The plasma samples collected optionally at baseline, on treatment and on progression/
discontinuation, will be used primarily for genetic testing to investigate if the mutational
profile of the patient that is detected in tumor samples can also be detected in ctDNA
•
Changes in the ctDNA genetic profile as well as quantitative changes in ctDNA levels
between the start of the study, on treatment samples and progression/ discontinuation
will be evaluated
•
Genetic findings will be correlated with outcome and tumor markers, where available.
•
Samples may also be used for additional exploratory endpoints to be defined
11 STUDY CALENDAR 
Please refer to the following appendices regarding the study calendar for each specific study drug: 
•
Olaparib (B)
•
AZD5363 plus olaparib (C)
•
AZD6738 plus olaparib (D)
•
The AZD1775 plus olaparib arm study calendar will be added as an addendum to
the protocol once the recommended phase II doses are available.
12 MEASUREMENT OF EFFECT 
Patients with measurable disease will be assessed by standard criteria. For the purposes of this 


Page 44 of 134 
study, patients should be re-evaluated every 8 weeks. In addition to a baseline scan, confirmatory 
scans will also be obtained at 4 weeks following initial documentation of a partial or complete 
response, which ever response is first. 
12.1 Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1)[43]. 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. 
12.1.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment. 
Evaluable for objective response. Patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease 
re- evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who 
exhibit objective disease progression prior to the end of cycle 1 or patients with therapy 
stopped due to toxicity prior to completion of one cycle of therapy will also be considered 
evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, 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. 
 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 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 might or might not be 
considered measurable. Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression by RECIST v1.1 in the lesion. 
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. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 


Page 45 of 134 
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. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated. 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. 
 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 4 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. 
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). 
 Response Criteria 
  Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes 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 also considered progressions). 
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. 
 Evaluation of Non-Target Lesions 


Page 46 of 134 
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 confirmed at a later time by the review panel (or Principal Investigator). 
 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. 
 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
Every effort will be made to follow patients  to progression/death  regardless of future 
treatment once study treatment is discontinued and they are removed from the study. 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
 Clinical Benefit 
Clinical Benefit is defined as the sum of CR, PR, or SD at 16 weeks from the start of 
treatment. 
13 MULTICENTER MANAGEMENT AND 
COORDINATION 
    Data Management 
   Data Submission 


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Data will be collected and managed in Yale’s web-based clinical trial management system, 
OnCore. The schedule for completion and submission of the electronic case report forms 
will be indicated within OnCore. 
  Data Monitoring 
The Yale Center for Clinical Investigation (YCCI) has been designated to monitor this trial. 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion. 
   Safety Evaluations 
Safety analysis will be conducted on all participants who have received at least one dose 
of therapy, and will include the frequency of all AEs  and laboratory abnormalities as  well 
as frequency of dose interruptions, dose reductions, and treatment discontinuation. Participants 
who receive one total cycle of treatment will be considered as having completed the evaluation 
for safety. Additional treatment cycles may be delivered if there are no safety concerns, there 
is no disease progression, and/or there is an indication of clinical benefit. Maintenance 
monitoring will occur on day 1 of every additional treatment cycle, unless indicated. 
Any safety concern or new information that might affect either the safety or the ethical conduct 
of this trial will be immediately forwarded to the principal investigator in written form. The 
principal investigator will be responsible for informing the IRB and Data and Safety Monitoring 
Committee (DSMC). If trends in toxicities are noted or stopping rules are met, the principal 
investigator will temporarily suspend enrollment while reviewing the episodes with the IRB and 
DSMC. Toxicity data must be submitted via OnCore at the end of each cycle of therapy. 
   Safety Monitoring 
   Data and Safety Monitoring Committee 
The Yale Cancer Center Data and Safety Monitoring Committee (DSMC) will provide the 
primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator. 
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to 
the committee includes: a study narrative by the PI, a summary DSMC report produced by 
OnCore (which includes participant accrual, response, trial status history, SAEs, Adverse 
Events, Deviations and survival); audit results, and monitoring reports as applicable. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
   Audit Plan 
The YCCI Office of Quality Assurance and Training will audit the trial at least annually or as 
determined by the DSMC. The overall principal investigator, project manager and/or monitor may 
request access to all source documents and other study documentation for on-site or remote 
monitoring, audit or inspection. 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator or Yale. The purpose of these audits or inspections is to examine study-related 


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activities and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, institutional policy, 
and any applicable regulatory requirements. 
   Study Site Monitoring 
The study principal investigator and YCCI are responsible for monitoring the performance of all 
of the participating sites. This will be performed by conducting a study site initiation visit, as well 
as regularly scheduled monitoring visits and/or remote monitoring throughout the life of the 
protocol. At the end of the trial, the monitor will then perform a study site close-out visit at all 
participating sites. 
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. Following each 
site visit, a visit report will be generated containing information on site activities, and a summary 
of pertinent points and action items together with a copy of the follow-up letter will be sent to each 
investigative site. 
During these monitoring visits, some of the items that will be reviewed are the following: 
•
Training of the sites
•
Site personnel qualifications to participate in the trial
•
That study related documents are current
•
That regulatory compliance is accomplished
•
That each subject has signed the informed consent
•
That the current and approved protocol is complied with (including reporting and logging
of all protocol deviations)
•
That all SAEs and AEs  have been reported to the local regulatory and Ethics/IRB
Committees, YCCI and Astra Zeneca, as appropriate
•
That source documentation matches CRFs
•
That required procedures for study drug accountability, distribution, and storage are
followed.
YCCI will document the required study monitoring activities in a Study Monitoring Plan. 
   Protocol Research Team Meetings 
Scheduled meetings will be held via teleconference monthly, or more frequently depending on 
the activity of the protocol. These meetings will include the protocol investigators and research 
staff involved with the conduct of the protocol. 
During these meetings the investigators will discuss: 
•
Safety of protocol participants (adverse events and reporting)
•
Validity and integrity of the data (data completeness on case report forms and complete
source documentation)
•
Enrollment rate relative to expectation of target accrual, (eligible and ineligible\participants)
•
Retention of participants, adherence to the protocol and protocol violations
•
Protocol amendments
   Tissue Donor Privacy and Confidentiality 
We recognize that the process of both contribution and access to human specimens needs to be 
transparent and governed by sound ethical and scientific principles so we can assure our patients 
that their free donations are put to as appropriate a use as possible. We feel confident that the 


Page 49 of 134 
studies performed with these specimens are important, are covered by the individuals’ initial 
consent, and pose no greater than minimal risk. 
It is the responsibility of the coordinating site-Principal Investigator to ensure that confidentiality 
for all patients participating in the trial and all of their medical information is maintained. Case 
report forms and other documents submitted must never contain the name of a trial participant. 
Each patient in the trial will be identified by a unique identifier that will be used on all CRF’s and 
any other material. All case report forms and any identifying information will be kept in a secure 
location with access limited to the study staff directly participating in the trial. 
Personal medical information may be reviewed by representatives of the coordinating site (Yale), 
of the IRB or of regulatory authorities in the course of monitoring the progress of the trial. Every 
reasonable effort will be made to maintain such information as confidential. Personal identifying 
information will only be released with the express written permission of the tissue/blood donor 
along with IRB approval. 
The results of the study may be presented in reports, published in scientific journals or presented 
at medical meetings; however, patient names will never be used in any reports about the study. 
13.7.1 Access to Biospecimens and Donor Information 
Only personnel authorized by the Principal Investigators will have direct access to the 
specimen storage facilities and samples, including records pertaining to the identity of 
participants. Authorized study personnel at Yale will keep a copy of the signed consent form 
and the key linking the unique identifiers to the patient PHI. The master list linking the patient 
PHI and unique study identifiers will be kept in the Yale OnCore computer system with 
electronic safeguards. The access is limited to the designated Yale study personnel. Other 
than elements of dates that will possibly be needed by the Clinical Tumor Board to identify 
potential appropriate treatments (i.e. dates of initial diagnosis or prior treatment dates), and 
the unique de-identified coded sample number, no PHI will be shared  with  entities outside 
of Yale. 
Standard Yale procedure is to train requested staff on OnCore’s Biospecimen Module (BSM) 
role and assign that to them. The scope of the role is limited to the protocol, in this case 
the Phase I program at Yale. Therefore, the assigned Data Manager with this role would 
be able to access the BSM Console for entry and management of specimens on the protocol. 
13.7.2 Biospecimen Banking 
Specimens will be collected and stored as per the laboratory procedure manual. 
  Future Use of Banked Samples: 
Patients will have the option during the consent process of allowing their specimens to be 
used for additional medical research beyond the scope of this study, provided the 
specimens are completely de-identified. Use of this material will require prior review and 
approval by the IRB or record at the recipient investigator’s site and approval from study 
Principal Investigators. Other than the de-identified sample number, no PHI will remain with 
the biobank-stored specimen. 
  Restrictions on Sample Usage 


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The intended use for these samples is to facilitate research. All investigators receiving 
samples will be reminded of their ethical and regulatory responsibilities concerning the use 
of such samples by providing them the following statement: 
The recipient of any human samples will acknowledge that the conditions for use of this 
research material are governed by their site IRB in accordance with Department of Health 
and Human Services regulations noted in 45 CFR 46. The recipient agrees to comply fully 
with all such conditions and to report promptly to their IRB any proposed changes in the 
research project and any unanticipated problems involving risks to subjects or others. The 
recipient remains subject to applicable State or local laws or regulations and institutional 
policies that provide additional protections for human subjects. This research material may 
only be used in accordance with the conditions stipulated by the IRB. 
  Incidental Findings 
During the course of data analysis, investigators may discover genetic information about the 
study participant that is not related to the current study (an incidental finding). We will follow 
the guidelines outlined by the American College of Medical Genetics and Genomics (ACMG) 
for incidental variants of known significance, when encountered (45). Investigators will 
consult with a genetic counselor if needed. 
14 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, applicable 
regulatory requirements. 
   Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written Informed Consent Form must include a subject authorization to release medical 
information to AstraZeneca and/or allow AstraZeneca, a regulatory authority, or Institutional 
Review Board access to subject’s medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
   Informed consent 
Provision of written Informed Consent must be obtained prior to any study-related 
procedures. The principal investigator will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. 
The subject should be given the opportunity to ask questions and allowed time to consider 
the information provided. 
The original, signed written Informed Consent Form must be stored. A copy of the signed 
written Informed Consent Form must be given to the subject. 
15 STATISTICAL CONSIDERATIONS 


Page 51 of 134 
    Sample Size Justification and Decision Rules 
The sample size estimation for each single arm of this phase II study is based on the objective 
response rate (ORR). A two-stage “minimax” accrual design described by Simon will 
minimize the maximum number of patients exposed to treatment for a set of assumed values 
of the design parameters [44]. These parameters are: (i) probability of response ≤ p0, where 
p0 defines the ineffective treatment response proportion, (ii) probability of response ≥ p1, 
where p1 defines the effective treatment response proportion, (iii) power = 1 - probability of 
Type II error, and (iv) α = probability of Type I error. For this study, the assumed design 
parameters are p0 = 0.10, p1 = 0.30, power = 0.90, α = 0.10. If there is evidence, at the 
conclusion of stage 1 or stage 2, that the true underlying ORR is at least 30% for a treatment 
arm, consideration will be given for further testing of that treatment. However, if the results at 
the conclusion of stage 1 provide evidence that the treatment is inactive in patients, i.e. ORR 
less than 10%, then the treatment arm will be terminated early. 
From the design parameters given above we derive the two-stage sample sizes and decision 
rules. Stage 1: Initially, 16 patients per arm will be enrolled into the study and treated at stage 
1. If there are less than 2 responses among these first 16 subjects, accrual to the treatment
arm will be terminated based on evidence that it is likely that ORR ≤ 10% and unlikely that 
ORR ≥ 30%. If there are at least 5 responses among the first 16 patients, recruitment to 25 
patients will continue in the treatment arm, but further development may be considered. If there 
are at least two but less than 5 responses in these first 16 patients, the trial will continue to 
stage 2 for the treatment arm until 25 patients have been treated. If there are at least 5 
responses in these 25 patients, then further development of the treatment will be considered. 
Some additional operating characteristics for this design are: expected number (i.e. frequentist 
mean number) of patients exposed when true ORR is 10% = 20.4; expected number of patients 
exposed when true ORR is 30% = 24.8; the probability of early termination for futility when true 
ORR is 10% = 0.515; the probability of early termination for futility when true ORR is 30% = 0.026. 
This design provides 90% statistical power to detect a difference of 20% (successful treatment = 
30% vs. futile treatment = 10%) with a type I error probability less than 0.10. 
   Early Stopping Rule for Safety 
We will monitor the study for safety in the first 16 patients in each single arm. If we observe 4 or 
more patients with unacceptable toxicity in the first 16 patients, then the arm will be terminated 
early. Unacceptable toxicity is defined for this protocol as CTCAE Grade 4 hematological and CTCAE 
Grade 3 non-hematological toxicities that fail to resolve to Grade 1 despite appropriate supportive care. 
With this design, the probability of terminating any arm early is 0.07 if the true but unknown 
unacceptable toxicity rate is 10%, and 0.75 if the true toxicity rate is 30%. 
   Statistical Analysis 
   Analysis Sets 
Full Analysis Set: all enrolled patients. 
Safety Analysis Set: all patients who receive at least one treatment dose. 
Efficacy Analysis  Set:  all  patients  who  receive  at  least  one  treatment  dose and are 
evaluable for post-baseline response status. 


Page 52 of 134
  General Methods 
Analyses will be performed separately for each treatment arm, as if they are four parallel 
studies within one protocol. 
Descriptive statistics, including means, standard deviations, medians and ranges for 
continuous scale parameters, as well as percent and frequencies for categorical 
parameters, will be presented. For time-to-event parameters, estimates of median survival 
with 95% confidence intervals will be calculated, and Kaplan Meier plots will be provided. 
Patients who are lost to follow-up or who have not progressed at the time of data cut-off will 
be censored for PFS analysis at the time of their last study visit. 
No corrections for multiplicity will be performed. 
  Disposition,  Demographics,   and  Baseline  Clinical   Characteristics   (Full 
Analysis Set) 
Patient disposition will be listed and tabulated by treatment arm. Demographic information 
including but not limited to age, gender and race, will be tabulated by treatment arm. Other 
baseline characteristics, such as medical history, concomitant medications, disease 
severity, time from diagnosis, physical exam and lab test results will be presented similarly. 
  Safety and Toxicity (Safety Analysis Set) 
Adverse events (AEs) will be listed and tabulated by treatment arm. AEs will be classified 
based on the likelihood that they are treatment-related. NCI toxicity Grade 3 and Grade 4 
laboratory abnormalities will also be listed. PFS analysis will also be performed with patients 
in the safety analysis set. 
  Efficacy (Efficacy Analysis Set) 
The efficacy of each treatment will be assessed by analysis of the primary endpoint using 
the 16 week response status. The exact Binomial method will be used to calculate two-sided 
95% confidence intervals for ORR. Multivariate logistic regression will be used to predict the 
ORR by including patient characteristics variables and other clinically relevant factors as 
covariates. 
For time-to-event endpoints, Kaplan-Meier plots and estimates for median survival time with 
95% confidence intervals will be provided for each treatment arm. 
  Subgroup Analyses 
Due to the limitation of the sample size, we will not have sufficient power to perform official 
statistical tests to detect differences between patients with different tumor types or 
mutations. Descriptive statistics will be used to present ORR by tumor type and by specific 
mutation. Data permitting, survival function of patients in subgroups will also be 
summarized. 


Page 53 of 134
OLAPCO APPENDIX A: Performance Status Criteria 
Date 07 Feb 2019 
APPENDIX A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry 
on normal activity or to do active 
work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
3 
In bed >50% of the time. 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled. Cannot carry on any 
self-care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


OLAPCO APPENDIX B: Olaparib Date 
07 Feb 2019 
Page 54 of 134
APPENDIX B: Olaparib in Patients with HDR Gene Mutations & IDH1/IDH2 Mutations 
Treatment of patients with solid tumors that harbor DNA damage repair gene mutations or neomorphic 
oncometabolites, such as 2-HG, in patients harboring mutations in IDH1/IDH2 mutant tumors or 
TCA/tricarboxylic acid cycle mutations such as FH and/or SDH is part of the clinical trial outlined in 
the main protocol. 
Defects in components of the HDR/DSB repair mechanism require affected cells to depend on 
alternative error-prone pathways of DNA repair, including BER and B-NHEJ. PARP1 hyperactivity 
has been demonstrated in HDR-defective cells and ought to confer a similar sensitivity to PARP 
inhibitors, which target the essential DDR pathway remaining intact in HDR deficient cells [45]. This 
has led to the concept of “BRCA-ness”, which proposes that somatic mutations in the BRCA 1 and 2 
genes, as well as other HDR genes as noted above, should confer a similar sensitivity to PARP 
inhibitors as gBRCA mutations. This expanded repertoire of mutations in HDR should be considered 
as potential clinical targets for DDR-focused therapies such as PARP inhibitors. This would include 
somatic mutations of BRCA 1 & 2, the BRCA interacting proteins of the MRN complex (MRE11, RAD 
50, NBS), RAD51, PALB2/FANCN, FANCD2, FANCC and DSS1. This grouping of BRCA-interacting 
proteins can be considered the HDR effector arm or RAD51 foci-forming proteins. Another grouping 
of DDR proteins includes the checkpoint controllers ATM, ATR, CHK1 and CHK2, which regulate cell 
cycle and the expression of the HR effector proteins such as BRCA1. Other DDR proteins comprise 
the FANCA/B/C/E/F/G/L/M complex core, which activates FANCD2, thus localizing the HDR repair 
effector complex to the site of DSB and SSB, plays a critical role in DDR such that loss of any of the 
components has a profound repair-defective phenotype. 
In fifty consecutive 50 tumors profiled at Yale, nonsense mutations and mutations considered to have major 
effects on DNA damage repair pathways at critical functional sites (COSMIC) were detected in 8   (16%). 
This incidence makes identifying appropriate patients for this study feasible. These  aberrations were 
detected in multiple different tumor types including GBM, H&N cancer, NSCLC,  prostate, breast, colorectal 
and other solid and hematological malignancies. 
This appendix contains details and study requirements that are specific to treatment with olaparib, 
including: 
Appendix B-1 
MATERIALS AND METHODS 
Appendix B-1.1 
PATIENTS 
Appendix B-1.2 
METHOD OF TREATMENT ASSIGNMENT 
Appendix B-1.3 
STUDY TREATMENT 
Appendix B-1.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Appendix B-1.5 
STUDY ASSESSMENTS 
AB-Figure 1 
Study Schema: Olaparib 
AB-Table 1 
Olaparib dosage form and strength 
AB-Table 2 
Dose Modifications for Hematologic Toxicity 
AB-Table 3 
Dose Modifications for Non-Hematologic Toxicity 
AB-1 
MATERIALS AND METHODS 
AB-1.1 PATIENTS 
Eligible patients must meet all of the eligibility requirements contained in the main study protocol. 
AB-1.1.1 Inclusion Criteria 
Refer to the main protocol Inclusion Criteria. 


OLAPCO APPENDIX B: Olaparib Date 
07 Feb 2019 
Page 55 of 134
AB-1.1.2 Additional Exclusion Criteria 
Refer to the main protocol Exclusion Criteria. 
AB-1.2 METHOD OF TREATMENT ASSIGNMENT 
Please refer to the main body of the protocol for the methods of treatment enrollment and study 
drug procurement (STUDY DESIGN AND RATIONALE). 
AB-1.3 STUDY TREATMENT 
All patients will receive treatment with olaparib, given at a bid daily dose of 300 mg orally (PO) in 
cycles of 28 days (4 weeks) duration. A schema of the study design is presented in Study Schema: 
Olaparib. 
All patients will receive: 
•
Olaparib 300 mg bid daily tablets.
•
No routine premedications are required.
AB-Figure 1: Study Schema: Olaparib 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 56 of 134
AB-1.3.1 Olaparib 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB) 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose] 
polymerization (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. 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair mechanisms. 
PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARPs leads 
to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks 
(DSBs) during the process of DNA replication. During the process of cell division, DSBs can be 
efficiently repaired in normal cells by homologous recombination repair (Tumors with HDR 
deficiencies, such as serous ovarian cancers, cannot accurately repair the DNA damage, which 
may become lethal to cells as it accumulates. In such tumor types, olaparib may offer a potentially 
efficacious and less toxic cancer treatment compared with currently available chemotherapy 
regimens. 
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment or 
in combination with established chemotherapies. Cells deficient in homologous recombination DNA 
repair factors, notably BRCA1/2, are particularly sensitive to olaparib treatment. 
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of chemotherapy. 
For further information, please refer to the current version of the olaparib IB. 
a. Formulation
Chemical Name: 4-[(3-[[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl]-4- 
fluorophenyl)methyl]phthalazin-1(2H)-one 
Laboratory Codes: AZD2281; KU-0059436; CO-CE 42 
CAS No.: 763113-22-0 
Molecular Formula:  C24H23FN4O3 
Molecular Weight: 434.46 
b. Dosage, Administration, and Storage
The AstraZeneca Pharmaceutical Development  R&D  Supply Chain  will supply olaparib to the 
investigator as round or oval green film coated tablets 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 57 of 134
AC-Table 1: Olaparib dosage form and strength 
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
For all centers, olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child- 
resistant closures. Each dosing container will contain 32 tablets and desiccant. Multiple bottles of 
study treatment may be required for dispensing in order to make up the desired dose. 
Olaparib will be dispensed to patients on Day 1 of each cycle until the patient completes the study, 
withdraws from the study or closure of the study. 
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 
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 (e.g. forgetting to take the tablets or vomiting) or need to modify the timing of a 
scheduled dose for any reason, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours before or after that scheduled dose time. The dose should not be taken more 
than 2 hours in advance of the scheduled dose time. If greater than 2 hours has passed 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. Doses should not be taken fewer than 10 hours apart. 
Food intake restrictions 
Olaparaib doses can be taken without regard to food. The olaparib tablets should be swallowed 
whole and not chewed, crushed, dissolved or divided 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions. The product 
should be stored in the pack provided and used according to the instructions on the label. 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label text will be translated 
into local language. 
Each bottle of 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 enrolment 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
•
enrolment code (E-code)
•
date of dispensing
•
Instructions stating that the olaparib tablets should be taken at approximately the same time
each morning and evening


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 58 of 134
c. Dosage Modification
Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.0 (NCI CTCAE v4.0). If toxicity occurs, the toxicity will be graded, and 
appropriate supportive care treatment will be administered to decrease the signs and symptoms 
thereof. 
The pre-clinical experience is fully described in the current version of the olaparib Investigator’s 
Brochure (IB). 
Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog cardiovascular 
and respiratory function tests, and the rat Irwin test. There were no noticeable  effects on the 
cardiovascular or respiratory parameters in the anaesthetized dog or any behavioral, autonomic or 
motor effects in the rat at the doses studied. 
The toxicology studies indicate that the target organ of toxicity is the bone marrow. 
Further information can be found in the current version of the olaparib Investigator’s Brochure 
Clinical experience with olaparib is fully described in the current version of the olaparib Investigator’s 
Brochure. 
The administration of olaparib may be delayed to assess or treat adverse events (AEs). Once a dose 
level reduction has occurred, the dose level may not be re-escalated. 
Any toxicity observed during the study could be managed by interruption and/ or dose reduction of 
the dose if deemed appropriate  by the Investigator. Repeat dose interruptions are allowed as 
required, for a maximum of 14 days on each occasion. If the interruption is any longer than this the 
AstraZeneca study team must be informed. Olaparib must be interrupted until the patientrecovers 
completely or the toxicity reverts to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (current version) grade 1 or less. If a dose is interrupted, drug should be 
resumed beginning the next cycle according to the schedule of assessments. 
Where toxicity reoccurs following re-challenge with olaparib, and where further dose interruptions are 
considered inadequate for management of toxicity, then the patient should be considered for dose 
reduction or must permanently discontinue treatment with olaparib. 
Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the 
Investigator considers to be related to administration of olaparib. 
Dose Modifications Due to Hematologic Toxicity 
Dose modifications on Day 1 of each cycle will be based on blood counts determined on the day of 
scheduled treatment. Nadir blood counts will not be used to determine dose modifications. Treatment 
on Day 1 of any cycle will proceed if blood counts demonstrate absolute neutrophil count (ANC) ≥ 
1500/μL, hemoglobin (Hgb) ≥  10 g/dL, and platelets ≥  100,000/μL. 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 59 of 134
AB-Table 2: Dose Modifications for Hematologic Toxicity 
Day 1 Blood Counts 
Olaparib 
ANC >1500/ul; Hgb >10 g/dl; Platelets >100,000/ul 
No dose modification 
ANC < 1500/ul or Hgb <10 g/dl or Platelets < 
100,000/ul 
1st incidence 
Hold until count recovery, then restart without 
dose modification 
ANC < 1500/ul or Hgb <10 g/dl or Platelets < 
100,000/ul 
2nd  incidence 
Reduce to 250 mg bid 
ANC < 1500/ul or Hgb <10 g/dl or Platelets < 
100,000/ul 
3rd    incidence 
Reduce to 200 mg bid 
ANC < 1500/ul or Hgb <10 g/dl or Platelets < 
100,000/ul 
4th    incidence 
Discontinue 
ANC = absolute neutrophil count; PO = orally. 
Note: olaparib should be discontinued if hematologic toxicity does not resolve (ANC ≥  1500/μL, Hgb ≥ 
10 g/dL, and platelets ≥ 100,000/μL) within 28 days. 
Management of anemia 
Adverse events of anemia CTCAE grade 1 or 2 (Hemoglobin (Hgb) > 8 g/dl) should be investigated 
and managed as deemed  appropriate by the investigator (This can include ESA/erythropoietin 
stimulating agents or PRBCs/packed red blood cell transfusions) with or without interruption of study 
drug or change in dose, in accordance with the table above and considering previous history of 
anemia. Common treatable causes  of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be excluded. In some cases, management of anemia may require blood 
transfusions. However, if a patient develops anemia CTCAE grade 3 (Hgb < 8g/dl) or worse, study 
treatment should be interrupted for up to maximum of 4 weeks to allow for bone marrow recovery 
and the patient should be managed appropriately. Study treatment can be restarted at the same dose 
if Hgb has recovered to > 10 g/dl. Any subsequently required  anemia related  interruptions, 
considered likely to be dose related, or coexistent with newly developed neutropenia, and or 
thrombocytopenia, will require study treatment dose reductions to 250 mg bid as a first step and to 
200 mg bid as a second step. 
If a patient has been treated for anemia with multiple blood transfusions without study treatment 
interruptions and becomes blood transfusion dependent as judged by investigator, study treatment 
should be permanently discontinued. 
Management of neutropenia and leukopenia 
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 CTC grade 3 or worse neutropenia 
occurs. Primary 
prophylaxis 
with 
Granulocyte 
colony-stimulating 
factor 
(G-CSF) 
is 
not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be stopped 
and appropriate management including G-CSF should be given according to local hospital guidelines. 
Please note that G-CSF should not be used within at least 24 h of the last dose of study treatment. 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 60 of 134
Study treatment can be restarted at the same dose if an adverse event of neutropenia or leukopenia 
have been recovered up to CTC AE grade >1 (ANC > 1.5 x 109/L). Growth factor support should be 
stopped at least 24h before restarting study drug (7 days for pegylated G-CSF). 
Any subsequent interruptions will require study treatment dose reductions to 250 mg bid as a first 
step and to 200 mg bid as a second step for a 300 mg monotherapy starting dose. 
Management of thrombocytopenia 
An adverse event of thrombocytopenia should be managed as deemed appropriate by the 
investigator. If a patient develops thrombocytopenia CTCAE grade 3 or worse study treatment should 
be interrupted for a maximum of 4 weeks. In some cases, management of thrombocytopenia may 
require platelet transfusions. Platelet transfusions should be done according to local hospital 
guidelines. 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
•
≥ 2-week interruption/delay in study treatment due to CTC grade 3 or worse anemia
and/or development of blood transfusion dependence
•
≥2-week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia (ANC
< 1 x 109/L)
•
≥2-week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia
(Platelets < 50 x 109/L)
Weekly differential blood counts including reticulocytes (calculate reticulocyte index (RI), RI = 
reticulocyte count x hematocrit (Hct)/normal Hct; a value of 45 is usually used for normal Hct) and 
peripheral blood smear should be performed. 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. 
Development of a confirmed myelodysplastic syndrome 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 diagnosis of myelodysplastic syndrome is 
confirmed. 
The dose of olaparib must not be adjusted under any other circumstances unless the AstraZeneca 
Study Physician gives prior agreement. 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019  
Page 61 of 134
Dose Modifications Due to Non-Hematologic Toxicity 
AB-Table 3: Dose Modifications for Non-Hematologic Toxicity 
CTCAE = Common Terminology Criteria for Adverse Events. Bid = twice daily. 
If Grade 3 or 4 non-hematologic toxicity (other than nausea, vomiting) occurs, treatment with olaparib 
should be held. Treatment with olaparib should be resumed according to Dose Modifications for Non- 
Hematologic Toxicity as soon as the toxicity resolves to < grade 1. 
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality occurs, an 
interruption in olaparib dosing is recommended and a diagnostic workup (including a high resolution 
CT scan) should be performed, to exclude pneumonitis. Following investigation, if no evidence of 
abnormality is observed on CT imaging and symptoms resolve, then olaparib treatment can be 
restarted, if deemed appropriate by the investigator. If significant pulmonary abnormalities are 
identified, these need to be discussed with the AstraZeneca 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. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the placebo 
treated patients and vomiting was reported in 34% of the olaparib treated patients and 14% in the 
placebo treated patients. They 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 with the incidence of nausea and vomiting not showing an increase over the 
treatment cycles. 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 62 of 134
No stoppage of olaparib is required for any biopsy procedures. 
Olaparib should be discontinued for a minimum of 7 days before a patient undergoes therapeutic 
palliative radiation treatment. 
Other Toxicities 
Olaparib dosing should be discontinued for any severe toxicity that does not respond to treatment. 
d. Olaparib Warnings and Precautions
MDS/AML 
 The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, including long-term 
survival follow-up, was <1.5% and the majority of events had a fatal outcome. All patients had potential 
contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum 
agents. Many had also received other DNA damaging treatments. The majority of reports were in gBRCA 
mutation carriers and some of the patients had a history of previous cancer or of bone marrow dysplasia. If MDS 
and/or AML are confirmed while on treatment with olaparib, it is recommended that olaparib should be 
discontinued and the patient be treated appropriately. 
New Primary Malignancies 
New primary malignancies have been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in all cases, 
including documented BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents.  
Pneumonitis 
Pneumonitis events have been reported in <1% of patients receiving olaparib. The reports of 
pneumonitis had no consistent clinical pattern and were confounded by a number of pre-disposing 
factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy).  When olaparib was used in clinical studies in combination 
with other therapies there have been events with a fatal outcome. If patients present with new or 
worsening respiratory symptoms such as dyspnea, cough and fever, or an abnormal chest radiologic 
finding is observed, olaparib treatment should be interrupted and prompt investigation initiated. If 
pneumonitis is confirmed, olaparib treatment should be discontinued and the patient treated 
appropriately. 
Pregnancy 
Pre-clinical data indicate that olaparib can have adverse effects on embryo-fetal survival and 
development and pregnancy is an Exclusion Criterion for the clinical studies with Olaparib. If any 
patient becomes pregnant during a study, olaparib must be discontinued and the patient followed 
up until birth or termination of pregnancy. The clinical protocol gives details on the requirements to 
report pregnancy and its outcome. Should pregnancy occur, the physician and patient should 
discuss the risks of continuing the pregnancy. 
Male patients should refrain from fathering a child or donating sperm during a study and for 6 months 
following the last dose of Olaparib. 
Contraception 
Patients of child bearing potential and their partners, who are sexually active, must agree to the use of 
two highly effective forms of contraception throughout their participation in the study and for 6 months 
after last dose of study drug(s). 
Condom with spermicide and one of the following: 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 63 of 134
•
Oral contraceptive or hormonal therapy (e.g. hormone implants)
•
Placement of an intra-uterine device
Acceptable non-hormonal birth control methods include: 
•
Total sexual abstinence.  Abstinence must be for the total duration of the study and the drug
washout period.
•
Vasectomised sexual partner plus male condom.  With participant assurance that partner
received post-vasectomy confirmation of azoospermia
•
Tubal occlusion plus male condom with spermicide
•
Intrauterine Device (IUD) plus male condom+spermicide.  Provided coils are copper-banded
Acceptable hormonal methods: 
•
Etonogestrel implants (e.g., Implanon, Norplan)+male condom with spermicide
•
Normal and low dose combined oral pills + male condom with spermicide
•
Hormonal shot or injection (eg, Depo-Provera) + male condom
•
Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®)
+ male condom
•
Norelgestromin/ethinyl estradiol (EE) transdermal system + male condom with spermicide
•
Intravaginal device + male condom with spermicide (e.g., EE and etonogestrel)
•
Cerazette (desogestrel)+male condom with spermicide. Cerazette is currently the only highly
efficacious progesterone based pill.
Lactation 
Lactation is an Exclusion Criterion within the study protocols for olaparib. It is not known whether 
olaparib is excreted in human milk. 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
Maternal exposure 
If a patient becomes pregnant during   the study olaparib should be discontinued immediately. 
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. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be reported 
and handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient was 
withdrawn from the study. 
If any pregnancy occurs in the course of the study, then Investigators or other site personnel must 
inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 days for SAEs, 
and within 30 days for all other pregnancies 


Page 64 of 134
OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
The same timelines apply when outcome information is available. 
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. 
Overdose 
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 bid (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 during the study, then investigators or other site 
personnel inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the investigator 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. For other overdoses, 
reporting should be done within 30 days. 
e. Metabolism and Drug Interactions
The use of any natural/herbal products or other “folk remedies” should be discouraged but use of 
these products, as well as use of all vitamins, nutritional supplements and all other concomitant 
medications must be recorded in the eCRF. 
Based on in vitro data and clinical exposure data, olaparib is considered unlikely to cause clinically 
significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. In 
vitro data have, however, also shown that the principal enzyme responsible for the formation of the 3 
main metabolites of olaparib is CYP3A4 and consequently, to ensure patient safety, the following 
strong inhibitors of CYP3A4 must not be used during this study for any patient receiving olaparib. 
While this is not an exhaustive list, it covers the known strong inhibitors, which have most often 
previously been reported to be associated with clinically significant drug interactions: 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 65 of 134
•
ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and
nelfinavir
For patients taking any of the above, the required wash-out period prior to starting olaparib is one 
week. 
In addition, to avoid potential reductions in exposure due to drug interactions and therefore a potential 
reduction in efficacy, the following strong CYP3A4 inducers should be avoided: 
•
Phenytoin, r i f a m p i c i n , rifapentine,  rifabutin,  carbamazepine,  phenobarbitol,
nevirapine, modafinil and St John’s Wort (Hypericum perforatum)
For patients taking any of the above, the required wash-out periods prior to starting olaparib are: 
•
phenobarbitol 5 weeks, and for any of the others, 3 weeks.
After randomization, if the use of any strong inducers or inhibitors of CYP3A4 are considered 
necessary for the patient’s safety and welfare, the Investigator must contact the AstraZeneca Study 
Physician. A decision to allow the patient to continue in the study will be made on a case-by-case 
basis. 
Other Concomitant Medications 
Any medications, other than those listed as excluded therapies, which are considered necessary for 
the patient's welfare, and which it is believed will not interfere with the study medication, may be given 
at the discretion of the Investigator, providing the medications, the doses, dates and reasons for 
administration are recorded in the eCRF. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the study 
period must be recorded in the eCRF. 
Anticoagulant Therapy: Patients who are taking warfarin may participate in this study; however, it 
is recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week 
for the first month, then monthly if the INR is stable.  Subcutaneous heparin is permitted. 
The reason(s) for the use, doses and dates of treatment should be recorded in the patient’s medical 
records and appropriate section of the eCRF. 
All medications (prescriptions or over-the-counter medications) continued at the start of the trial or 
started during the study or until 30 days from the end of the last protocol treatment and different from 
the study medication must be documented. 
For further detail, see the Investigator’s Brochure (IB). 
AB-1.4 CONCOMITANT AND EXCLUDED THERAPIES 
AB-1.4.1 Concomitant Therapy 
Refer to the main body of the protocol (Concomitant and Excluded Therapies) for concomitant 
therapies allowed. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that were 
present at baseline, provided the Investigator does not feel that these are indicative of clinical disease 
progression during the study period. Full details of these treatments must be recorded in the patient’s 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 66 of 134
notes and appropriate section of the eCRF. Study treatment should be discontinued for a minimum 
of 3 days before the patient undergoes palliative radiation treatment. Study treatment should be 
restarted within 4 weeks if bone marrow toxicity has resolved. 
AB-1.4.2 Excluded Therapy 
The following restrictions apply during the entire duration of study treatment: 
•
No other investigational therapy should be given to patients.
•
No concomitant cancer treatment of any type (including chemotherapy, biologic therapy,
hormonal therapy, immunotherapy, radiation therapy) should be administered at any time while
the patient is taking study treatment. If such treatment is required, then the patient must first
be withdrawn from the trial. The patient can receive a stable dose of corticosteroids during
the study if these were started at least 4 weeks prior to treatment, as per exclusion criteria.
Bisphosphonates and Denosumab for bone metastases are allowed if these were started at
least 4 weeks prior to treatment with study drug. Octreotide is allowed if dose is stable for >3
months with no worsening of carcinoid syndrome. Hormonal therapy with luteinizing hormone-
releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant
prostate cancer are permitted. Palliative radiotherapy is allowed for pre-existing small areas
of painful metastases that cannot be managed with local or systemic analgesics if no
evidence of disease progression is present.
•
Live virus and bacterial vaccines should not be administered whilst the patient is receiving
study medication and during the 30 day follow up period. An increased risk of infection by the
administration of live virus and bacterial vaccines has been observed with conventional
chemotherapy drugs and the effects with olaparib are unknown.
•
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods
known to modulate CYP3A4 enzyme activity from the time they enter the screening period
until 30 days after the last dose of study medication. In vitro data have shown that the principal
enzyme responsible for the formation of the 3 main metabolites of olaparib is CYP3A4 and
consequently, this restriction is required to ensure patient safety.


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 67 of 134
AB-1.5 STUDY ASSESSMENTS 
Screening Day 1 of 
Cycle 1 
Day 
1 of 
each 
cyclej 
Every 
8 
weeks 
End 
of 
Study 
30 Day 
Follow- 
up 
Long 
term 
Follow 
Up as 
per main 
protocol 
Visit window (days) 
28i 
+/- 3 
+/- 3 +/- 3 
+/- 3 
+/- 7 
+/- 7 
Informed consent 
X 
Inclusion/Exclusion Criteria 
X 
Pregnancy Testa 
X 
X 
Molecular Selection of Patients based on 
Archival Tumor Tissue (Paraffin embedded) 
X 
Medical History 
X 
Physical examination, weight and vital signs b 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
Laboratory tests (Clinical 
Chemistry/hematology/urinalysis/coagulation)c 
X 
Xh 
X 
Xd 
Concomitant medications 
X 
X 
X 
X 
Dosing compliance 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
RECIST Assessments e 
X 
X 
X 
X 
Tumor Tissue (Paraffin embedded) (optional)f 
X 
X 
Plasma Sampleg 
X 
X 
X 
Anti-cancer therapy follow-up 
X 
a Two pregnancy tests on blood or urine samples will be performed for pre-menopausal women of childbearing potential 
one within 28 days prior to the start of study treatment and the other on Day 1 of the study prior to commencing treatment. 
Tests will be performed by the hospital’s local laboratory. If results are positive the patient is ineligible/must be discontinued 
from the study.  In the event of a suspected pregnancy during the study, the test should be repeated. 
b A complete physical examination will be performed at the following timepoints (within 24 hours of visit): Screening Visit, 
Day 1 Every Cycle, Discontinuation Visit, Follow-up Visit. Constitutional symptoms will be collected during screening and 
pre-dose at all other visits. Constitutional symptoms will include the presence/absence of pruritus, night sweats, recurrent 
fever ≥38.0ºC, fatigue, weakness and nocturia (a history of weight loss is to be collected at screening visit only). Vital signs 
(heart rate, systolic and diastolic blood pressure, oxygen saturation (pulse oximetry), respiration rate, weight, height (at 
screening) and temperature) 
c Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell volume [MCV], mean cell 
hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white cell 
count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or segmented 
neutrophil count and Band forms should be performed at each visit and when clinically indicated. If absolute differentials 
not available please provide % differentials. Coagulation [activated partial thromboplastin time {APTT} and international 
normalized ratio {INR}] will be performed at baseline and if clinically indicated unless the patient is receiving warfarin. 
Patients taking warfarin may participate in this study; however, it is recommended that prothrombin time (INR and APTT) 
be monitored carefully at least once per week for the first month, then monthly if the INR is stable. If APTT testing is not 
locally available, Partial Thromboplastin Time (PTT) testing may be done along with INR. Any clinically significant results on 
PTT will be confirmed with APTT. 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 68 of 134
Bone marrow or blood cytogenetic analysis may be performed according to standard hematological practice for patients 
with prolonged hematological toxicities. 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 cytometry on the bone marrow aspirate, then attempts should be made to carry out the tests 
on a blood sample. If findings are consistent with MDS/AML, study drug should be discontinued and a full description of 
findings should be submitted with an SAE report by the investigator to AstraZeneca Patient Safety for documentation on 
the Patient Safety database. Presence or absence of blood cytogenetic abnormalities and flow cytometry will be 
documented on the clinical database. 
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, fasting glucose, creatinine, total bilirubin, 
gamma glutamyltransferase [GGT], alkaline phosphatase [ALP], aspartate transaminase [AST],  alanine  transaminase [ALT], 
urea or blood urea nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]). 
Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. Microscopic analysis should be 
performed by the hospital’s local laboratory if required. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged hematological toxicities. 
These tests will be performed by the hospital’s local laboratory. There is a 48 hr window for performance of lab testing for each 
visit. Additional analyses may be performed if clinically indicated. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to G ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
d All patients with clinically significant abnormal laboratory results at treatment completion or study drug discontinuation 
visit are to be followed until the results return to normal (or patient’s baseline), or until a valid reason, other than a drug- 
related effect, is identified 
Patients with an unresolved AE or SAE event at treatment completion or study drug discontinuation will be contacted by the 
investigator or his or her designee to determine the status of the event until the event is resolved or stabilized, the patient 
is lost to follow up, or it has been determined that the study treatment or participation is not the cause of the event. 
e Patients will be evaluated until objective disease progression by RECIST 1.1. If a chest CT scan at baseline (screening 
CT will be the baseline scan) is not performed as part of the RECIST assessment, the patient should undergo a chest CT 
scan in order to document the lung parenchyma status at baseline. High resolution CT should be performed if clinically 
indicated by pulmonary symptoms any time during the study. For any new respiratory symptoms (cough, dyspnea, lower 
respiratory infection) not clearly explained by other factors (eg, dyspnea associated with substantial drop in hemoglobin), 
patients should have oxygen saturation measured. If <92%, the high resolution CT scan of the chest should be repeated 
and pulmonary function tests should be performed. 
Scans will be performed every 8 weeks. If partial response (PR) or complete response (CR) is documented, a confirmatory 
scan will be performed 4 weeks later for PR/CR (whichever occurs first). 
f Tumor sample at baseline if feasible (optional). The sample can be collected up to 4 weeks before the first dose. Therefore, 
any sample collected during this time period prior to study enrollment can be used as baseline sample. The tumor sample 
for use in genetic and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures 
at each institution. Additional tumor samples may also be collected and used fresh or frozen. 
Tumor sample at progression or discontinuation if feasible (optional). The sample can be collected at progression or 
discontinuation, or any time between progression and discontinuation from the study. The tumor sample for use in genetic 
and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures at each 
institution. Additional tumor samples may also be collected and used fresh or frozen 
g Plasma samples (optional) will be collected at baseline, on treatment and at progression/ discontinuation on study to 
isolate ctDNA to determine the mutational profile and changes thereof. The plasma sample at baseline can be collected up 
to 2 weeks before the first dose. Samples on study should be taken at the end of the first cycle (+/- 7 days), and at the end 
of the cycles 4, 6 and 10 (+/- 7 days) and at progression or discontinuation or any time between progression and 
discontinuation from the study 
Additional samples (optional) after cycle 10 and before progression can be collected, if the investigator deems a particular 
time point of interest. However, samples should not be collected more frequent than every 2 cycles. F describes the 
procedures for collection, processing, storage and shipment of plasma 


OLAPCO APPENDIX B: Olaparib 
Date 07 Feb 2019 
Page 69 of 134
h. Results of all cycle 1 day 1 laboratory tests must re-meet eligibility criteria
i: Screening to be performed within 28 days unless otherwise specified 
j:  Continuous use of Olaparib is suitable during this window 


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OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
APPENDIX C: AZD5363 plus olaparib in patients with AKT, PIK3CA, or ARID1A mutations or 
other aberrations leading to dysregulation of the PI3K/AKT pathway 
Treatment of patients with solid tumors that harbor PTEN, PIK3CA, AKT, or ARID1A mutations 
or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway is part of the 
clinical trial outlined in the main protocol. 
AZD5363 is an inhibitor of AKT1, AKT2 and AKT3. Patients with tumors harboring PTEN, PIK3CA, 
AKT, or ARID1A mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT 
pathway are considered most likely to be sensitive  to AKT inhibition and will be treated with 
AZD5363 plus olaparib. 
Increased AKT phosphorylation has been shown to occur in tumors with ARID1A deficiency and these 
tumors have been shown to be sensitive to treatment with the AKT inhibitor MK-2206 [37-39] Patients 
with ARID1A mutations can therefore be included in the AZD5363 plus olaparib combination arm. 
Preclinical data suggest that PIK3CA mutations predict response to PI3K-, AKT-, or mTOR inhibitors, 
including AZD5363, whereas mutations in RAS genes predict resistance [46]. PIK3CA mutations 
have been detected in up to 10% of advanced tumors. Tumor types with high frequencies include 
breast cancer (>20%), endometrial cancer ((>20%), urinary tract cancers (>20%), cervical cancer 
(>10%), melanoma (>10%), colorectal cancer (>10%), ovarian cancer, gastric cancer, biliary tract 
tumors, and esophageal cancer, non-small cell lung cancer [NSCLC], and squamous cell head and 
neck cancer [47-51] (http://www.sanger.ac.uk/genetics/CGP/cosmic/). A retrospective  analysis of 
patients that were treated with different PI3K- or AKT- or mTOR inhibitors in multiple studies, PIK3CA 
or PTEN mutations were predictive of response, suggesting that tumors harboring PIK3CA or PTEN 
mutations are more sensitive to inhibition of this pathway by PI3K-, AKT-, or mTOR-inhibitors [47]. 
PIK3R1 and PIK3R2, which encode regulatory subunits of PI3K, have been identified in in >20% and 
5% of endometrial cancers with lower frequencies in other cancers. In addition to loss of function of 
the PI3K regulatory subunit, gain of function mutations were identified, that destabilize PTEN [48, 
52]. TCGA studies identified PIK3R1 mutations also in colorectal, gastric and bladder cancer, 
glioblastomas and other cancers (cBioPortal for Cancer Genomics, 2013). 
AKT1 mutations are found at low frequency in a number of tumor types. The most common mutation 
is E17K, which has been shown to be transforming and increases localization to the membrane where 
AKT is activated [53]. In a panel of tumor samples the occurrence of AKT1E17K mutation was 
detected in 5.9%, 1.1% and 0.6% of breast, colorectal and lung cancers, respectively [54]. AKT1E17K 
mutations have been characterized in 1–8% of breast carcinomas, both ductal and lobular histotypes 
and are mutually exclusive with respect to the PIK3CA E545K or H1047R alleles [53]. AKT1E17K 
mutations have also been detected in endometrial carcinomas, mainly limited to high grade, advanced 
stage tumors suggesting a link of this mutation with a more aggressive cancer disease, as well as in 
low frequency in NSCLC and SCC [55-60]. Shoji et al found that AKT1E17K mutant tumors do not 
harbor coexisting mutations in PTEN, PIK3CA or KRAS [56]. AKT1 mutations have also been found 
in meningeal, urinary tract, prostate, skin and other cancers [48]. 
Rare mutations in AKT2 and AKT3 have also been found in various cancers, although it is not known 
whether some of these are transforming. For example, AKT2 mutations were found in 1/51 gastric 
and 2/79 lung cancers, and in an independent study, in 2/43 non-small cell lung cancers (NSCLCs) 
[61, 62]. Mutations in AKT3 have been reported in melanoma at 1.5% frequency [63]. In endometrial 
cancer, rare mutations in AKT2 and AKT3 have been reported [64]. 


Page 71 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
This appendix contains details and study requirements that are specific to treatment with AZD5363 
plus olaparib, including: 
Appendix C-1 
MATERIALS AND METHODS 
Appendix C-1.1 
PATIENTS 
Appendix C-1.2 
METHOD OF TREATMENT ASSIGNMENT 
Appendix C-1.3 
STUDY TREATMENT 
Appendix C-1.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Appendix C-1.5 
STUDY ASSESSMENTS 
AC-Figure 1 
Study Schema: AZD5363 and olaparib 
AC-Figure 2 
AD-Figure 2: AZD5363 Glucose Management 
AC-Table 1 
AD-Table 1: Olaparib dosage form and strength 
AC-Table 2 
Dose Modifications for Hematologic Toxicity 
AC-Table 3 
Dose Modifications for Non-Hematologic Toxicity 
AC-Table 4 
AD-Table 4: Summary of guidance on dose adjustments of AZD5363 
for toxicity 
AC-Table 5 
AD-Table 5 CYP3A4 potential interactions with AZD5363 
AC-Table 6 
AD-Table 6: CYP2D6 potential interactions with AZD5363 
AC-Table 7 
AD-Table 7: Other potential interactions with AZD5363 
AC-1 
MATERIALS AND METHODS 
AC-1.1 
PATIENTS 
Eligible patients must meet all eligibility requirements contained in the main study protocol. Listed 
here are additional requirements specific to treatment with the combination of AZD5363 and olaparib. 
AC-1.1.1 Additional Inclusion Criteria Refer to the main protocol Inclusion Criteria. 
AC-1.1.2 Additional Exclusion Criteria Refer to the main protocol Exclusion Criteria. 
AC-1.2 METHOD OF TREATMENT ASSIGNMENT 
Please refer to the main body of the protocol for the methods of treatment enrollment and study drug 
procurement (STUDY DESIGN AND RATIONALE). 
AC-1.3 STUDY TREATMENT 
All patients will receive treatment with AZD5363, given at a dose of 640 mg bid for 2 days on 5 days 
off (2/7) in cycles of 28 days (4 weeks) duration. A schema of the study design is presented in 
Study  Schema: AZD5363 and olaparib. 
All patients will receive: 
•
Olaparib 300 mg bid and AZD5363 at a dose of 640 mg bid.
•
No routine premedications are required.


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OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
AC-Figure 1: Study Schema: AZD5363 and olaparib 
AC-1.3.1 Olaparib 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB) 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose] 
(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. 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair mechanisms. 
PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARPs leads 
to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks 
(DSBs) during the process of DNA replication. During the process of cell division, DSBs can be 
efficiently repaired in normal cells by homologous recombination repair (HR). polymerization Tumors 
with HDR deficiencies, such as serous ovarian cancers, cannot accurately repair the DNA 
damage, which may become lethal to cells as it accumulates. In such tumor types, olaparib may 
offer a potentially efficacious and less toxic cancer treatment compared with currently available 
chemotherapy regimens. 
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment or 
in combination with established chemotherapies. Cells deficient in homologous recombination DNA 
repair factors, notably BRCA1/2, are particularly sensitive to olaparib treatment. 


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OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of chemotherapy. 
For further information, please refer to the current version of the olaparib IB. 
a. Formulation
Chemical Name: 4-[(3-[[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl]-4- 
fluorophenyl)methyl]phthalazin-1(2H)-one 
Laboratory Codes: AZD2281; KU-0059436; CO-CE 42 
CAS No.: 763113-22-0 
Molecular Formula:  C24H23FN4O3 
Molecular Weight: 434.46 
b. Dosage, Administration, and Storage
The AstraZeneca Pharmaceutical Development  R&D  Supply Chain  will supply olaparib to the 
investigator as round or oval green film coated tablets 
AD-Table 1: Olaparib dosage form and strength  
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
For all centers, olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child- 
resistant closures. Each dosing container will contain 32 tablets and desiccant. Multiple bottles of 
study treatment may be required for dispensing in order to make up the desired dose. 
Olaparib will be dispensed to patients on Day 1 of each cycle until the patient completes the study, 
withdraws from the study or closure of the study. 
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be replaced 
if all the intact tablets can be seen and counted. Should any patient enrolled on the study miss a 
scheduled dose (e.g. forgetting to take the tablets or vomiting) or need to modify the timing of a 
scheduled dose for any reason, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours before or after that scheduled dose time. The dose should not be taken more 
than 2 hours in advance of the scheduled dose time. If greater than 2 hours has passed 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. Doses should not be taken fewer than 10 hours apart. 
Combination drug should be given at least 1 hour after the patient has taken their olaparib morning 
dose. 
Food intake restrictions 


Page 74 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Olaparib doses can be taken without regard to food. The olaparib tablets should be swallowed 
whole and not chewed, crushed, dissolved or divided 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions. The product 
should be stored in the pack provided and used according to the instructions on the label. 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label text will be translated 
into local language. 
Each bottle of 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 enrolment 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
•
enrolment code (E-code)
•
date of dispensing
•
Instructions stating that the olaparib tablets should be taken at approximately the same time
each morning and evening
c. Dosage Modification
Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.0 (NCI CTCAE v4.0). If toxicity occurs, the toxicity will be graded, and 
appropriate supportive care treatment will be administered to decrease the signs and symptoms 
thereof. 
The pre-clinical experience is fully described in the current version of the olaparib Investigator’s 
Brochure (IB). 
Olaparib has been tested in a standard range of safety pharmacology studies e.g. dog cardiovascular 
and respiratory function tests, and the rat Irwin test. There were no noticeable effects on the 
cardiovascular or respiratory parameters in the anaesthetized dog or any behavioral, autonomic or 
motor effects in the rat at the doses studied. 
The toxicology studies indicate that the target organ of toxicity is the bone marrow. 
Further information can be found in the current version of the olaparib Investigator’s Brochure 
Clinical experience with olaparib is fully described in the current version of the olaparib Investigator’s 
Brochure. 
The administration of olaparib may be delayed to assess or treat adverse events (AEs). Once a dose 
level reduction has occurred, the dose level may not be re-escalated. 
Any toxicity observed during the study could be managed by interruption and/ or dose reduction of 
the dose if deemed appropriate by the Investigator. Repeat dose interruptions are    allowed as 


Page 75 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
required, for a maximum of 14 days on each occasion. If the interruption is any longer than this the 
AstraZeneca study team must be informed. Olaparib must be interrupted until the patient recovers 
completely or the toxicity reverts to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (current version) grade 1 or less. If a dose is interrupted, drug should be 
resumed beginning the next cycle according to the schedule of assessments. 
Where toxicity reoccurs following re-challenge with olaparib, and where further dose interruptions are 
considered inadequate for management of toxicity, then the patient should be considered for dose 
reduction or must permanently discontinue treatment with olaparib. 
Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event occurs which the 
Investigator considers to be related to administration of olaparib. 
Dose Modifications Due to Hematologic Toxicity 
Dose modifications on Day 1 of each cycle will be based on blood counts determined on the day of 
scheduled treatment. Nadir blood counts will not be used to determine dose modifications. Treatment 
on Day 1 of any cycle will proceed if blood counts demonstrate absolute neutrophil count (ANC) ≥ 
1500/μL, hemoglobin (Hgb) ≥ 10 g/dL, and platelets ≥ 100,000/μL. 
Please see Dose Modifications for Hematologic Toxicity for dose modifications due to hematologic 
toxicity. 
Management of anemia 
Adverse events of anemia CTCAE grade 1 or 2 (Hemoglobin (Hgb) > 8 g/dl) should be investigated 
and managed as deemed appropriate by the investigator (including ESA/erythropoietin stimulating 
agents and PRBC/packed red blood cells) with or without interruption of study drug or change in 
dose, in accordance with the Table AB-2 and considering previous history of anemia. Common 
treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) 
should be excluded. In some cases, management of anemia may require blood transfusions. 
However, if a patient develops anemia CTCAE grade 3 (Hgb < 8g/dl) or worse, study treatment 
should be interrupted for up to maximum of 4 weeks to allow for bone marrow recovery and the 
patient should be managed appropriately. Study treatment can be restarted with dose reductions 
as outlined in Dose Modifications for Hematologic Toxicity. 
If a patient has been treated for anemia with multiple blood transfusions without study treatment 
interruptions and becomes blood transfusion dependent as judged by investigator, study treatment 
should be permanently discontinued. 
Management of neutropenia and leukopenia 
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 CTC grade 3 or worse neutropenia 
occurs. Primary prophylaxis 
with 
Granulocyte 
colony-stimulating factor 
(G-CSF) 
is 
not 
recommended, however, if a patient develops febrile neutropenia, study treatment should be stopped 
and appropriate management including G-CSF should be given according to local hospital guidelines. 
Please note that G-CSF should not be used within at least 24 h of the last dose of study treatment. 
Study treatment can be restarted as per Dose Modifications for Hematologic Toxicity if an adverse 
event of neutropenia or leukopenia have been recovered up to CTC AE grade >1 (ANC > 1.5 x 109/L). 
Growth factor support should be stopped at least 24h before restarting study drug (7 days for 
pegylated G-CSF). 
Any subsequent interruptions will require study treatment dose reductions found in Dose 


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OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Modifications for Hematologic Toxicity. 
Management of thrombocytopenia 
An adverse event of thrombocytopenia should be managed as deemed in Dose Modifications for 
Hematologic Toxicity. If a patient develops thrombocytopenia CTCAE grade 3 or worse study 
treatment should be interrupted for a maximum of 4 weeks. Management of thrombocytopenia 
may require platelet transfusions. Platelet transfusions. 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
•
≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or
development of blood transfusion dependence
•
≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia (ANC
< 1 x 109/L)
•
≥ 2 week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia
(Platelets < 50 x 109/L)
Weekly differential blood counts, including reticulocytes (calculate reticulocyte index (RI), RI = 
reticulocyte count x hematocrit (Hct)/normal Hct; a value of 45 is usually used for normal Hct) and 
peripheral blood smear should be performed. 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. 
Development of a confirmed myelodysplastic syndrome 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 diagnosis of myelodysplastic syndrome is 
confirmed. 
The dose of olaparib must not be adjusted under any other circumstances unless the AstraZeneca 
Study Physician gives prior agreement. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 77 of 134
Dose Modifications Due to Non-Hematologic Toxicity 
Management of new or worsening pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality occurs, an 
interruption in olaparib dosing is recommended and a diagnostic workup (including a high resolution 
CT scan) should be performed, to exclude pneumonitis. Following investigation, if no evidence of 
abnormality is observed on CT imaging and symptoms resolve, then olaparib treatment can be 
restarted, if  deemed  appropriate  by the  investigator. If significant pulmonary abnormalities are 
identified, these need to be discussed with the AstraZeneca 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. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib  treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the placebo 
treated patients and vomiting was reported in 34% of the olaparib treated patients and 14% in the 
placebo treated patients. They 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 with the incidence of nausea and vomiting not showing an increase over the 
treatment cycles. 
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 
Additional information for patients 
Olaparib should be stopped before surgery and re-started after wound has healed following recovery. 
No stoppage of olaparib is required for any biopsy procedures. 
Olaparib should be discontinued for a minimum of 7 days before a patient undergoes therapeutic 
palliative radiation treatment. 
Other Toxicities 
Olaparib dosing should be discontinued for any severe toxicity that does not respond to treatment. 
Please refer to Dose Modifications for Non-Hematologic Toxicity for dose modifications due to non- 
hematologic toxicities. 
d. Olaparib Warnings and precautions
MDS/AML 
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, including long-term 
survival follow-up, was <1.5% and the majority of events had a fatal outcome. All patients had potential 
contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum 
agents. Many had also received other DNA damaging treatments. The majority of reports were in gBRCA 
mutation carriers and some of the patients had a history of previous cancer or of bone marrow dysplasia. If MDS 
and/or AML are confirmed while on treatment with olaparib, it is recommended that olaparib should be 
discontinued and the patient be treated appropriately. 


Page 78 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
New Primary Malignancies 
New primary malignancies have been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in all cases, 
including documented BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents.  
Pneumonitis 
Pneumonitis events have been reported in <1% of patients receiving olaparib. The reports of 
pneumonitis had no consistent clinical pattern and were confounded by a number of pre-disposing 
factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy).  When olaparib was used in clinical studies in combination 
with other therapies there have been events with a fatal outcome. If patients present with new or 
worsening respiratory symptoms such as dyspnea, cough and fever, or an abnormal chest radiologic 
finding is observed, olaparib treatment should be interrupted and prompt investigation initiated. If 
pneumonitis is confirmed, olaparib treatment should be discontinued and the patient treated 
appropriately. 
Pregnancy 
Pre-clinical data indicate that olaparib can have adverse effects on embryo-fetal survival and 
development and pregnancy is an Exclusion Criterion for the clinical studies with Olaparib. If any 
patient becomes pregnant during a study, olaparib must be discontinued and the patient followed up 
until birth or termination of pregnancy. The clinical protocol gives details on the requirements to report 
pregnancy and its outcome. Should pregnancy occur, the physician and patient should discuss the 
risks of continuing the pregnancy. 
Male patients should refrain from fathering a child or donating sperm during a study and for 6 months 
following the last dose of Olaparib. 
Contraception 
Patients of child bearing potential and their partners, who are sexually active, must agree to the use 
of two highly effective forms of contraception throughout their participation in the study and for 6 
months after last dose of study drug(s). 
•
Condom with spermicide
and one of the following: 
•
Oral contraceptive or hormonal therapy (e.g. hormone implants)
•
Placement of an intra-uterine device
Acceptable non-hormonal birth control methods include: 
•
Total sexual abstinence.  Abstinence must be for the total duration of the study and the drug
washout period.
•
Vasectomized sexual partner plus male condom.  With participant assurance that partner
received post-vasectomy confirmation of azoospermia
•
Tubal occlusion plus male condom with spermicide
•
Intrauterine Device (IUD) plus male condom + spermicide.  Provided coils are copper-banded
Acceptable hormonal methods: 
•
Etonogestrel implants (e.g., Implanon, Norplan) + male condom with spermicide
•
Normal and low dose combined oral pills + male condom with spermicide
•
Hormonal shot or injection (eg, Depo-Provera) + male condom
•
Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®)
•
+ male condomNorelgestromin/ethinyl estradiol (EE) transdermal system + male condom with


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 79 of 134
spermicide 
•
Intravaginal device + male condom with spermicide (e.g., EE and etonogestrel)
•
Cerazette (desogestrel)+male condom with spermicide. Cerazette is currently the only highly
efficacious progesterone based pill.
Lactation 
Lactation is an Exclusion Criterion within the study protocols for olaparib. It is not known whether 
olaparib is excreted in human milk. 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
Maternal exposure 
If a patient becomes pregnant during the course of the study olaparib should be discontinued 
immediately. 
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. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be reported 
and handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient was 
withdrawn from the study. 
If any pregnancy occurs in the course of the study, then Investigators or other site personnel must 
inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 days for SAEs, 
and within 30 days for all other pregnancies 
The same timelines apply when outcome information is available. 
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. 
Overdose 
There is currently no specific treatment in the event of overdose with olaparib and possible symptoms 
of overdose are not established. 


Page 80 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
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 bid (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 inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the investigator 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. For other overdoses, 
reporting should be done within 30 days. 
e. Metabolism and Drug Interactions
The use of any natural/herbal products or other “folk remedies” should be discouraged but use of 
these products, as well as use of all vitamins, nutritional supplements and all other concomitant 
medications must be recorded in the eCRF. 
Based on in vitro data and clinical exposure data, olaparib is considered unlikely to cause clinically 
significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. In 
vitro data have, however, also shown that the principal enzyme responsible for the formation of the 3 
main metabolites of olaparib is CYP3A4 and consequently, to ensure patient safety, the following 
strong inhibitors of CYP3A4 must not be used during this study for any patient receiving olaparib. 
While this is not an exhaustive list, it covers the known strong inhibitors, which have most often 
previously been reported to be associated with clinically significant drug interactions: 
•
ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and
nelfinavir
For patients taking any of the above, the required wash-out period prior to starting olaparib is one 
week. 
In addition, to avoid potential reductions in exposure due to drug interactions and therefore a potential 
reduction in efficacy, the following strong CYP3A4 inducers should be avoided: 
•
Phenytoin,  rifampicin,  rifapentine,  rifabutin,  carbamazepine,  phenobarbitol,  nevirapine,
modafinil and St John’s Wort (Hypericum perforatum)
For patients taking any of the above, the required wash-out periods prior to starting olaparib are: 
•
phenobarbitol 5 weeks, and for any of the others, 3 weeks.
After randomization, if the use of any strong inducers or inhibitors of CYP3A4 are considered 
necessary for the patient’s safety and welfare, the Investigator must contact the AstraZeneca Study 
Physician. A decision to allow the patient to continue in the study will be made on a case-by-case 
basis. 


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OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Other Concomitant Medications 
Any medications, other than those listed as excluded therapies, which are considered necessary 
for the patient's welfare, and which it is believed will not interfere with the study medication, may be 
given at the discretion of the Investigator, providing the medications, the doses, dates and 
reasons for administration are recorded in the eCRF. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the study 
period must be recorded in the eCRF. 
The reason(s) for the use, doses and dates of treatment should be recorded in the patient’s medical 
records and appropriate section of the eCRF. 
All medications (prescriptions or over-the-counter medications) continued at the start of the trial or 
started during the study or until 30 days from the end of the last protocol treatment and different from 
the study medication must be documented. 
. 
Live virus and bacterial vaccines should not be administered while the patient is receiving study 
medication and during the 30 day follow up period. An increased risk of infection by the administration 
of live virus and bacterial vaccines has been observed with conventional chemotherapy drugs and 
the effects with olaparib are unknown. 
Anticoagulant Therapy: Patients who are taking warfarin may participate in this study; however, it 
is recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week 
for the first month, then monthly if the INR is stable.  Subcutaneous heparin is permitted. 
AC-1.3.2 AZD5363 
AZD5363 is a potent inhibitor of AKT 1, 2 and 3 (half maximal inhibitory concentration of the drug 
[IC50] <10 nM). Non-clinical in vitro and in vivo assays have demonstrated inhibition of 
phosphorylation of the AKT substrates GSK3β and PRAS40, tumor cell proliferation and xenograft 
tumor growth models. With treatment of nude mice bearing BT474c xenografts there was time- and 
dose-dependent inhibition of phosphorylation of the AKT substrates PRAS40 and GSK3β, and the 
downstream biomarker S6, after single oral doses of 100 and 300 mg/kg. Chronic oral treatment of 
nude mice bearing a variety of established and primary xenografts with AZD5363, resulted in dose- 
dependent tumor growth inhibition. 
Secondary and Safety Pharmacology studies have been carried out to investigate the effects of 
AZD5363 on related and unrelated receptors and enzymes, the cardiovascular, central and peripheral 
nervous, respiratory, gastrointestinal and renal systems. The key findings were that: 
•
In a panel of 333 in vitro radioligand binding and enzyme assays, there were 8 targets at which
there was significant activity.
•
AZD5363 produced motor-related effects (reduction in spontaneous activity and touch
response) at 4 hours post-dose. The no observed effect level (NOEL) was 30 mg/kg.
•
AZD5363 was active at the human Ether-a-go-go-related Gene (hERG)-encoded potassium
channel with an IC50 of 73 μM, and is classified as a low risk of triggering the QT-associated
arrhythmia of Torsades de Pointes (TdP).
•
In the dog telemetry study, heart rate was decreased for up to 8 hours following a single dose
of 5, 30 and 40 mg/kg. At 30 mg/kg and 40 mg/kg there were peak decreases in systolic and
diastolic blood pressure recovering within 4 hours, plus a sustained prolongation of QT interval
corrected for heart rate using an individual linear regression formula (QTcR) and increase in
integrated measure of left ventricular contractility (LVdP/dt+), along with elevation of both
glucose and insulin levels. Intravenous (IV) administration of atenolol or verapamil 4 hours


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
AZD5363 beige film-coated tablets contain AZD5363, microcrystalline cellulose, mannitol, 
croscarmellose cellulose and magnesium stearate. The tablet film-coat contains polyvinyl alcohol, 
Page 82 of 134
post administration of AZD5363 reversed the effect on QTcR and LVdp/dt+. The no observed 
adverse effect level (NOAEL) is considered to be 5 mg/kg. 
•
AZD5363 had no effects on respiratory parameters following a single dose. The NOEL was
150 mg/kg.
•
AZD5363 caused a dose-dependent, inhibition of gastric emptying at 100 mg/kg and 150
mg/kg. In addition, there was a decrease in intestinal transit at 150 mg/kg only. The NOEL
was 30 mg/kg.
•
In an assessment of renal function following a single oral dose, a marked glycosuria was seen
at 100 mg/kg and 150 mg/kg, with concurrent diuresis. There was an increase in the fractional
excretion of sodium and chloride at all doses, and of potassium and phosphate at 100 mg/kg
and 150 mg/kg. The plasma concentration of phosphorous was slightly increased after 150
mg/kg, while the potassium concentration was slightly decreased after 100 mg/kg and 150
mg/kg. A NOEL could not be determined.
Investigators should refer to the latest IB for AZD5363 for safety information and findings from on- 
going trials. 
Pharmacodynamics 
•
Platelet rich plasma (PRP) assays for GSK3β and PRAS40 phosphorylation showed a dose
dependent inhibition of AKT substrate phosphorylation in Phase 1 patients following an acute
dose of AZD5363.
•
Phosphorylated PRAS40 (pPRAS40) was measured in the epithelial cells of the eyebrow hair
root bulb and showed a trend for reduced PRAS40 phosphorylation with increasing AZD5363
exposure.
•
Results from tumor samples from patients showed target engagement and inhibition of AKT
substrate phosphorylation after exposure to AZD5363 at the recommended Phase 2 dose and
schedule (480mg bid 4d on 3d off).
Please refer to the Investigator’s Brochure (IB) for additional information regarding AZD5363. 
a. Formulation
Laboratory code: AZD5363 
CAS No.: 143532-39-1 
Molecular formula: C21H25ClN6O2 
Relative molecular mass: 428.92 
b. Dosage, Administration, and Storage
The drug product is presented for oral administration as a beige film-coated tablet containing 80 mg 
and 200 mg of AZD5363. AZD5363 tablets are packed in high-density polyethylene (HDPE) bottles. 
Bottles are secured with a child-resistant closure; induction-sealed membranes provide  tamper 
evidence. 


Page 83 of 134
OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
titanium dioxide, polyethylene glycol, talc, yellow iron oxide, red iron oxide and black iron oxide. 
The results of the effects of food on AZD5363 dosing indicate that the presence of food may reduce 
the rate of absorption of AZD5363, but the extent of absorption appeared to be comparable. The 
clinical relevance of this food effect is currently unknown, but a conservative approach has been taken 
to recommend that the existing food restrictions are maintained (ie, patients to fast from 2 h before 
dosing to 1 h after dosing, where possible) in ongoing clinical studies. 
AZD5363 tablets are swallowed, the dose should only be replaced if all of the intact tablets can be 
seen and counted. Should any patient enrolled in the study miss a scheduled dose or need to modify 
the timing of a scheduled dose for any reason, the patient will be allowed to take the scheduled dose 
up to a maximum of 2 hours before or after the scheduled dose time. The dose should not be taken 
more than 2 hours in advance of the scheduled dose time. If greater than 2 hours has passed after the 
scheduled dose time, the missed dose is not to be taken and the patient should take the allotted dose 
at the next time schedule. Doses should not be taken fewer than 10 hours apart. 
Storage 
The product should be stored in the pack provided and used according to the instructions on the label. 
c. Dosage Modification
Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.0 (NCI CTCAE v4.0). If toxicity occurs, the toxicity will be graded, and 
appropriate supportive care treatment will be administered to decrease the signs and symptoms 
thereof. 
The administration of AZD5363 may be delayed to assess or treat adverse events (AEs). Once a 
dose level reduction has occurred, the dose level may not be re-escalated. 
Dose Modifications Due to Hematologic Toxicity 
Dose modifications on Day 1 of each cycle will be based on blood counts determined on the day of 
scheduled treatment. Nadir blood counts will not be used to determine dose modifications. Treatment 
on Day 1 of any cycle will proceed if blood counts demonstrate absolute neutrophil count (ANC) ≥ 
1500/μL, hemoglobin (Hgb) ≥ 10 g/dL, and platelets ≥ 100,000/μL. 
AC-Table 2: Dose Modifications for Hematologic Toxicity 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 84 of 134
Day 1 Blood Counts 
Olaparib 
AZD5363 
ANC >1500/ul; Hgb > 10 g/dl; 
Platelets > 100,000ul 
No dose modification 
No dose modification 
ANC <1500/ul or Hgb < 10 g/dl 
or Platelets < 100,000ul 
1st incidence 
No dose modification 
560 mg bid 2/7 
ANC <1500/ul or Hgb < 10 g/dl 
or Platelets < 100,000ul 
2nd  incidence 
No dose modification 
480 mg bid 2/7 days 
ANC <1500/ul or Hgb < 10 g/dl 
or Platelets < 100,000ul 
3rd  incidence 
Discontinue treatment 
Discontinue treatment 
Neutropenic fever 
(ANC < 1,000/ul +Temperature 
> 101˚ F (38.5˚ C) 
1st incidence 
Delay until episode resolves 
with treatment. Resume at a 
dose of 300mg bid 
Delay until episode resolves 
with treatment. Resume at a 
dose of 560mg bid 2/7 days 
2nd incidence 
Discontinue treatment 
Discontinue treatment 
ANC = absolute neutrophil count; PO = orally. 
Note: AZD5363 and olaparib should be discontinued if hematologic toxicity does not resolve (ANC ≥ 
1500/μL, Hgb ≥ 10 g/dL, and platelets ≥ 100,000/μL) within 14 days. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 85 of 134
Dose Modifications Due to Non-Hematologic Toxicity 
AC-Table 3: Dose Modifications for Non-Hematologic Toxicity 
CTCAE = Common Terminology Criteria for Adverse Events. 
If Grade 3 or 4 non-hematologic toxicity (other than nausea, vomiting) occurs, treatment with 
AZD5363 and olaparib should be held.  Treatment with AZD5363 and olaparib should be resumed 
according to Dose Modifications for Non-Hematologic Toxicity as soon as the toxicity resolves. 
Glucose homeostasis 
Hyperglycemia (defined in the clinical studies as at least 1 post-baseline laboratory report of glucose 
> ULN) is a frequent clinical observation, but is transient and reversible on cessation of treatment. 
The overall incidence of hyperglycemia is 94.8% across all the clinical trials to date. The majority of 
cases occurred within the first week of study treatment (91.1% in patients treated with AZD5363 
monotherapy using intermittent dosing and 89.3% in patients treated with AZD5363 with paclitaxel). 
Approximately a third of patients with elevated glucose levels received metformin (given at the 
discretion of the investigator). A relationship between exposure to AZD5363 and HbA1c was 
investigated but no apparent linkage was seen between an individual’s maximum HbA1c value and 
their maximum observed blood glucose value (either for random/non-fasting or fasting glucose). 
Therefore, even though AZD5363 is known to affect pathways of glucose metabolism and insulin 
signaling, there is no evidence from the present clinical studies for these transient hyperglycemic 
episodes to have an effect on HbA1c levels. In the clinical studies to date patients with proven 
diabetes have been excluded. However, the option to include patients with diabetes managed by diet 
alone is currently under consideration for future studies. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 86 of 134
In order to reduce the potential risk of exacerbating abnormal glucose profiles, patients with Type I or 
Type II diabetes mellitus (irrespective of management) have been excluded from clinical studies with 
AZD5363 to date. However, given the apparent absence of clinical sequelae following AZD5363- 
induced hyperglycemia, 1 investigator sponsored study (A Phase 1b study of the oral PARP inhibitor 
olaparib with the oral mTORC1/2 inhibitor AZD2014 or the oral AKT inhibitor AZD5363 for recurrent 
endometrial, triple negative breast, and ovarian, primary peritoneal, or fallopian tube cancer), run by 
The University of Texas MD Anderson Cancer Center, Houston, USA, plans to include patients with 
Type II diabetes who are well controlled by diet alone. As our experience increases in this regard it 
may be that further modifications to the inclusion of such patients will become appropriate. Glucose 
profiles should be performed at the relevant time points in AZD5363 studies to adequately 
characterize emergent hyperglycemia and to allow appropriate clinical management of patients. A 
suggested algorithm for the management of hyperglycemia is provided. In addition, because of the 
pharmacological activity of AZD5363 on glycolysis and insulin signaling, fasting lipid profiles 
(triglycerides, high density lipoprotein, low density lipoprotein and cholesterol) will also be monitored 
at appropriate intervals. 
Guidance on metformin use is included in the suggested hyperglycemia management algorithm. 
AC-Figure 2: AZD5363 Glucose Management 
Diarrhea and Rash 
Rash is a frequent clinical observation, with 52.6% patients in all the clinical studies reporting rash. 
The occurrence of rash is less marked in terms of incidence and severity with intermittent dosing. 
9.8% of patients reported rash of Grade 3 or above (all cases considered by the investigator to be 
drug-related). Eight out of the 102 patients with rash (7.8%) had events that were considered serious 
and 8 patients discontinued AZD5363 treatment due to rash. Eight patients had a DLT of rash. Twelve 
patients (11.8%) had their dose of study medication interrupted and 10 patients (9.8%) had the dose 
reduced due to rash. In 57.8% of patients the rash resolved before cessation of study treatment, with 
treatment for the rash being required in 64.7% of cases. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 87 of 134
The onset of rash typically occurs after the first week of AZD5363 treatment and resolves with dose 
interruption. Grade 3 rash leading to discontinuation of AZD5363 occurred in 4.1% of patients. The 
vast majority of patients subjected to re-challenge following resolution of rash suffered a recurrence of 
the toxicity. There are no standard exclusion criteria for patients with rash. Clinical experience 
indicates that rash can be managed with treatment as outlined in the rash management algorithm 
(eg, use of oral or topical steroids, use of oral antihistamine), as well as by interruptions to AZD5363 
dosing. 
Diarrhea is a frequent clinical observation in studies with AZD5363, with most cases starting within 
the first week of treatment. Overall, 73.7% patients in all the clinical studies had diarrhea. Overall, 
14.9% of patients had diarrhea of Grade 3 or above (in all but 3 patients who had ≥Grade 3 diarrhea 
the events were considered by the investigator to be drug-related). Thirteen of the 145 patients with 
diarrhea (9.0%) had events that were considered serious, with 7 patients discontinuing study 
treatment as a result of diarrhea. Five patients had a DLT of diarrhea. Twenty patients (13.8%) had 
their dose of study medication interrupted and 9 patients (6.2%) had their dose reduced due to 
diarrhea. In 67.3% of patients the diarrhea  resolved  before cessation of study treatment, with 
treatment for the diarrhea being required in 71.7% of patients. 
Most patients report diarrhea within the first week following commencement of AZD5363 dosing. Most 
patients experience 1 or 2 episodes, however, patients receiving AZD5363 in combination with 
paclitaxel seemed to experience more episodes. There appeared to be a relationship between 
increasing dose and severity with continuous monotherapy of AZD5363, but this was not seen with 
the intermittent dosing schedules. Patient reports of diarrhea are to be evaluated and treated by 
investigators according to local practice (eg, use of medications such as loperamide). The need for 
an interruption in dosing with AZD5363 should be considered according to the clinical study protocol. 
Hypersensitivity 
Hypersensitivity has been  commonly (4 /301 patients) reported within the AZD5363 program. 
Symptoms of hypersensitivity included rash in association with 1 or more of events such as flushing, 
pruritus, urticaria, throat itchiness, pyrexia and facial and/or lip edema. Time to onset of event ranged 
from 11 to 120 days (median: 21 days) from start of therapy with AZD5363. In all patients 
hypersensitivity or related events were considered related to AZD5363 by the investigator and in 3 
patients the reported events were considered serious, leading to hospitalization or prolonged 
hospitalization. Three patients had positive re-challenge. One patient had a reported allergy to heat and 
cold. In all patients the symptoms resolved with study drug discontinuation and treatment with 
antihistamines and steroids. 
Patients with history of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a 
similar chemical structure or class to AZD5363 will be excluded from studies. Significant 
hypersensitivity reactions, as characterized by rash along with clinical features such as flushing, 
pruritus, urticaria, throat itchiness, pyrexia and facial and/or lip edema requiring treatment with 
antihistamines and steroids have occurred commonly (1-10%) in patients receiving AZD5363. In the 
case of hypersensitivity reactions, AZD5363 should be discontinued and symptomatic/supportive 
therapy should be initiated (including with antihistamines and/or steroids) as considered appropriate 
by the investigator/treating physician. Any subsequent decision on re-challenge with AZD5363 at the 
same or a lower dose, with its potential for recurrence of such or more severe events should be 
carefully considered against the potential benefits to the individual patient from continuation of 
AZD5363 therapy. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 88 of 134
AC-Table 4: Summary of guidance on dose adjustments of AZD5363 for toxicity 
Toxicity 
AZD5363 
Diarrhea of  
CTCAE Grade ≥3 
or that is clinically 
significant or 
intolerable and 
causally related to 
treatment with 
AZD5363/matching 
placebo. 
Institute appropriate anti-diarrheal treatment. (Refer to “Guidance for the 
Management of Adverse Events in Studies of AZD5363” for treatment 
guidance). If clinically appropriate or if toxicity does not improve to CTCAE 
Grade < 2 or remains clinically intolerable, despite optimal treatment, 
withhold AZD5363/matching placebo for up to 14 days. 
If toxicity improves to CTCAE Grade <2 or becomes clinically tolerable 
reinstate AZD5363/matching placebo, as clinically appropriate, at either the 
current dose or at a reduced dose (1 dose level) maintaining treatment for 
toxicity as necessary. 
Where a CTCAE Grade >3 or clinically significant or intolerable toxicity does 
not improve after 14 days of AZD5363/matching placebo dose interruption, 
AZD5363/matching placebo should be permanently discontinued. 
Recurrence: on recurrence of a CTCAE Grade >3 or clinically significant or 
intolerable toxicity, reinstate treatment as required. 
If toxicity improves to CTCAE Grade <2 or becomes clinically tolerable 
reinstate AZD5363/matching placebo, as clinically appropriate, at either the 
current dose or at a reduced dose (up to two dose level reductions) 
maintaining treatment for toxicity as necessary. 
If toxicity does not improve to CTCAE Grade <2 or remains clinically 
significant or intolerable, despite optimal treatment, withhold dose for up to 
14 days until improvement of toxicity. 
Any skin reaction 
of CTCAE Grade > 
3 or that is 
clinically significant 
or intolerable and 
causally related to 
treatment with 
AZD5363/matching 
placebo 
For any skin reaction that is CTCAE Grade >3 or clinically significant or 
intolerable withhold dose for up to 14 days until improvement of toxicity.  
If toxicity improves to CTCAE Grade <1 within 14 days reinstate 
AZD5363/matching placebo at the current dose maintaining treatment for 
toxicity as necessary 
If toxicity improves to CTCAE Grade 2 within 14 days reinstate 
AZD5363/matching placebo at a reduced dose (1 dose level) maintaining 
treatment for toxicity as necessary 
Where a CTCAE Grade >3 or clinically significant or intolerable toxicity does 
not improve to a lower CTCAE Grade within 14 days of AZD5363/matching 
placebo dose interruption, AZD5363/matching placebo should be 
permanently discontinued. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 89 of 134
Stomatitis 
Stomatitis is a very common clinical observation, affecting 32 patients (14.0%) in AZD5363 intermittent 
monotherapy, 10 patients (26.3%) in combination with paclitaxel, and 2 patients (7.7%) in combination 
with fulvestrant. 
In AZD5363 intermittent monotherapy, the majority of stomatitis AEs were Grade 1 or 2 (91.4%), and 
the maximum severity of AEs experienced by patients was CTCAE Grade 3 (8.6%). There were 3 AEs 
leading to dose interruption, and of these, all resulted in a positive de-challenge, and in the 2 patients 
subsequently re-administered the study drug, both received a reduced AZD5363 dose and both 
experienced negative re-challenge. The median duration of all AEs was 15 days. 
Dry skin 
Dry skin is a very common clinical observation, affecting 27 patients (11.8%) in AZD5363 intermittent 
monotherapy, 6 patients (15.8%) in combination with paclitaxel, and 1 patient (3.8%) in combination 
with fulvestrant. 
In AZD5363 intermittent monotherapy, the majority of dry skin AEs were Grade 1 (92.9%), and the 
maximum severity of AEs experienced by patients was CTCAE Grade 2 (7.1%). There were no AEs 
leading to dose interruption, reduction, or study discontinuation. The median duration of all AEs was 
91.5 days. 
Pruritus 
Pruritus is a common clinical observation, affecting 21 patients (9.2%) in AZD5363 intermittent 
monotherapy group, 7 patients (18.4%) in combination with paclitaxel, and none in combination with 
fulvestrant. 
In AZD5363 intermittent monotherapy, the majority of pruritus AEs were CTCAE Grade 1 or 2, 
and 1 AE was Grade 3. There were no AEs leading to dose interruption or study discontinuation. 
The median duration of all AEs was 37 days. Cardiovascular effects 
In all patients, cardiac function will be monitored regularly throughout the study. Heart rate, 
electrolytes (sodium, chloride, potassium and bicarbonate), ECG measurements, systolic and diastolic 
blood pressure will be monitored prior to and 1, 2, 6 and 24 hours following administration of AZD5363, 
then weekly during the first cycle (labs and blood pressure pre-dose and ECG assessments up to 6 
hours post-dose), at the start of each subsequent cycle thereafter (labs and blood pressure pre-dose 
and ECG assessments up to 6 hours post-dose) and at discontinuation. Troponin I or T will be 
monitored prior to administration of AZD5363, weekly during the first cycle, at the start of each 
subsequent cycle and at discontinuation. In addition, a MUGA scan or echocardiogram to assess 
LVEF will be conducted at screening, and as clinically indicated as management of AEs. 
d. Metabolism and Drug Interactions
In vivo experiments indicate that AZD5363 is a time-dependent inhibitor of CYP3A4, which may result 
in increased exposure of drugs metabolized via CYP3A4 and with the potential to increase the toxicity 
of these drugs when co-administered with AZD5363. AZD5363 is itself a substrate of CYP3A4 
although data available to date suggests that glucuronidation may be the major metabolic route. Co- 
administration of CYP3A4 inhibitors may increase exposure to AZD5363 and hence potentially affect 
efficacy/toxicity, and hence increase the risk of time-dependent inhibition (and resultant toxicity of 
CYP3A4 substrates). In addition, co-administration of CYP3A4 inducers may decrease the exposure 
to AZD5363 and may potentially affect efficacy. AZD5363 is also a moderate inhibitor of CYP2D6 in 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 90 of 134
vitro. This may increase the exposure of drugs metabolized via CYP2D6 with the potential to increase 
the toxicity of these drugs when co-administered. 
Use of strong inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment 
(3 weeks for St John’s Wort) should be avoided. A list of these drugs will be provided as an appendix 
to the clinical study protocols. All patients should avoid concomitant use of drugs, herbal supplements 
and/or ingestion of foods known to potently modulate CYP3A4 enzyme activity from the time they 
enter the screening period until 2 weeks after the last dose of study treatment. All patients should 
avoid concomitant use of drugs and herbal supplements known to be CYP3A4 or CYP2D6 substrates 
from the time they enter the screening period until 2 weeks after the last dose of study treatment 
wherever possible. If co-administration is necessary for appropriate clinical care then additional 
monitoring for signs of toxicity related to increased exposure to the substrates may be required. A list 
of these drugs will be provided as an appendix to the clinical study protocols. 
Emerging in vitro data has revealed that AZD5363 has a potential to inhibit the OATP1B1 transporter. 
This transporter is implicated in the distribution and clearance of many of the statins. Of the statins 
that are minimally affected by CYP3A4 inhibition, rosuvastatin and pravastatin (but not fluvastatin) 
can be affected by OATP1B1 inhibition. In an assessment of the potential for AZD5363 to inhibit 
OATP1B1 based on the in vitro signal, the AUC of these drugs may be increased by 1.3-fold for 
pravastatin and 1.5-fold for rosuvastatin (static assessment based on maximal free liver inlet 
concentration of AZD5363). As a conservative response to this emerging data it is recommended that 
doses of rosuvastatin be capped to 10 mg once daily and pravastatin to 40 mg once daily when 
combined with AZD5363, and for a 2-week period before and after AZD5363 treatment. 
Drugs affecting CYP3A4 metabolism that AstraZeneca strongly recommend are not 
combined with AZD5363 
There are currently no data confirming that there are any pharmacokinetic (PK) interactions between 
any agents and AZD5363. The potential interactions detailed below are considered on the basis of 
the preclinical data only. The following lists are not intended to be exhaustive, and a similar restriction 
will apply to other agents that are known to strongly modulate CYP3A4 activity. Appropriate medical 
judgment is required.  Please contact AstraZeneca with any queries you have on this issue. 
AC-Table 5 CYP3A4 potential interactions with AZD5363 
(1) Strong CYP3A4 inhibitors that may increase exposure to AZD5363 more than 5-fold 
Ketoconazole 
Protease 
inhibitors 
(danoprevir, 
ritonavir, 
saquinavir, 
indanavir, 
tapranavir, 
telaprevir, 
elvitegravir, 
lopinavir, nelfinavir, bocepravir) 
Cobicistat 
Conivaptan 
Nefazodone 
Mebefradil 
Minimum of 2 weeks washout prior to AZD5363 
administration 
and 
for 
2 
weeks 
following 
discontinuation of AZD5363 


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Date 07 Feb 2019 
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Itraconazole 
Posaconazole 
Voriconazole 
Clarithromycin 
Telithromycin 
Troleandomycin 
Minimum of -week washout prior to AZD5363 
administration 
and 
for 
2 
weeks 
following 
discontinuation of AZD5363 
(2) Strong Inducers of CYP3A4 that may reduce exposure to AZD5363 by more than 5- 
fold 
Phenobarbital 
Carbamazepine 
Phenytoin 
Rifampicin 
Rifabutin 
Mitotane 
Enzalutamide 
Minimum 
of 
2-weeks washout prior to 
AZD5363 administration and for 2 weeks 
following discontinuation of AZD5363 
St John’s Wort 
Minimum 
of 
3-weeks washout prior to 
AZD5363 administration and for 2 weeks 
following discontinuation of AZD5363 
(3) Drugs affecting CYP3A4 metabolism that AstraZeneca considers may be allowed 
with caution. 
Moderate Inhibitors of CYP3A4 that may increase exposure to AZD5363 
Diltiazem 
Verapamil 
Erythromycin 
Fluconazole 
Aprepitant 
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions. Please refer to full 
prescribing information for all drugs prior to 
co-administration with AZD5363. 
Grapefruit juice 
Seville 
oranges 
(and 
other 
products 
containing Seville oranges) 
Patients should abstain from eating large 
amounts of grapefruit and Seville oranges 
(and other products containing these fruits eg, 
grapefruit juice or marmalade) during the 
study (e.g., no more than a small glass of 
grapefruit juice (120 mL) or half a grapefruit or 
1-2 teaspoons 
(15 
g) of Seville orange 
marmalade daily). 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 92 of 134
(4) Medicines that are significantly metabolized by CYP3A4 that AstraZeneca 
strongly recommend are not combined with AZD5363 
There are currently no data confirming that there are any pharmacokinetic (PK) interactions between 
AZD5363 and the following CYP3A4 substrates. The potential interactions detailed below are 
considered on the basis of the preclinical data only. The following list is not intended to be exhaustive, 
and a similar restriction will apply to other agents that are known to be sensitive to CYP3A4 inhibitors. 
Appropriate medical judgment is required. Please contact AstraZeneca with any queries you have 
on this issue. 
Exposure, pharmacological action and toxicity that may be increased by inhibition of 
CYP3A4 by AZD5363 
Alfentanil 
Cyclosporin 
Diergotamine 
Ergotamine 
Fentanyl 
Sirolimus 
Tacrolimus 
Atorvastatin 
Lovastatin 
Simvastatin 
Cerivastatin 
Minimum of 1 week washout prior to AZD5363 
administration and for 2 weeks following 
discontinuation of AZD5363 
Carbamazepine 
Minimum of 2 weeks washout prior to 
AZD5363 administration and for 2 weeks 
following discontinuation of AZD5363. 
(5) Medicines that are significantly metabolized by CYP3A4 that AstraZeneca considers may 
be allowed with caution 
Exposure, pharmacological action and toxicity that may be increased by inhibition of 
CYP3A4 by AZD5363 
Erythromycin 
Trazodone 
Tamoxifen 
Alprazolam 
Midazolam 
Triazolam 
Felodipine 
Isradipine 
Nifedipine 
Methylprednisolone 
Pimozide 
Quinidine 
Domperidone 
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions. Please refer to full 
prescribing information for all drugs prior to 
co-administration with AZD5363. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 93 of 134
AC-Table 6: CYP2D6 potential interactions with AZD5363 
(1) Agents that are sensitive to CYP2D6 inhibition that AstraZeneca strongly recommends 
are not combined with AZD5363 
There are currently no data confirming that there are any pharmacokinetic (PK) interactions between 
AZD5363 and the following CYP2D6 substrates. The potential interactions detailed below are 
considered on the basis of the preclinical data only. The following list is not intended to be exhaustive, 
and a similar restriction will apply to other agents that are known to be sensitive to CYP2D6 inhibitors. 
Appropriate medical judgment is required. Please contact AstraZeneca with any queries you have 
on this issue. 
Exposure, pharmacological action and toxicity that may be increased by inhibition of 
CYP2D6 by AZD5363 
Amitryptyline 
Desipramine 
Trimipramine 
Doxepin 
Minimum 
of 
2-weeks washout prior to 
AZD5363 administration and for 2- weeks 
following discontinuation of AZD5363 
Atomoxetine 
Metoprolol 
Nefazodone 
Nebivolol 
Perphenazine 
Tropisetron 
Tolterodine 
Minimum of 1-week washout prior to AZD5363 
administration and for 2 weeks following 
discontinuation of AZD5363 
(2) Agents that are sensitive to CYP2D6 inhibition that AstraZeneca considers may be 
allowed with caution 
Exposure, pharmacological action and toxicity that may be increased by inhibition of 
CYP2D6 by AZD5363 
Venlafaxine 
Paroxetine 
Fluoxetine 
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions. Please refer to full 
prescribing information for all drugs prior to 
co-administration with AZD5363. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 94 of 134
(3) Agents that are sensitive to combined CYP3A4 and CYP2D6 inhibition that AstraZeneca 
strongly recommend are not combined with AZD5363 
There are currently no data confirming that there is a pharmacokinetic (PK) interaction between 
AZD5363 and the following agents; a potential interaction is considered on the basis of the preclinical 
data only. This list is not intended to be exhaustive, and a similar restriction will apply to other agents 
with narrow therapeutic windows that are known to depend on combined CYP3A4 and CYP2D6 
metabolism. Appropriate medical judgment is required. Please contact AstraZeneca with any queries 
you have on this issue. 
AC-Table 7: Other potential interactions with AZD5363 
(1) Exposure, pharmacological action and toxicity that may be increased by inhibition 
of CYP3A4 and CYP2D6 by AZD5363 
Haloperidol 
Minimum 
of 
2-weeks washout prior to 
AZD5363 administration and for 2 weeks 
following discontinuation of AZD5363 
Tramadol 
Minimum of 1-week washout prior to AZD5363 
administration and for 2 weeks following 
discontinuation of AZD5363 
(2) Guidance for drugs that are that are significantly metabolized by CYP2B6, CYP2C9 or 
CYP2C19 and have a narrow therapeutic margin that AstraZeneca considers may be allowed 
with caution 
Weak signals for competitive inhibition of CYP2B6, CYP2C9 and CYP2C19 cytochrome  P450 
activities have been demonstrated by in vitro laboratory investigations. There are currently no data 
confirming that there is a pharmacokinetic (PK) interaction between AZD5363 and substrates of these 
isoforms; a potential interaction is considered on the basis of the preclinical data only. The following 
list is intended to identify known sensitive substrates of CYP2B6, CYP 2C9 and CYP 2C19 that have 
a narrow therapeutic margin. The list is not intended to be exhaustive, and a similar restriction should 
be applied to any other sensitive substrate with narrow therapeutic margin. Appropriate medical 
judgment is required.  Please contact AstraZeneca with any queries you have on this issue. 
Exposure, pharmacological action and toxicity that may be increased by inhibition of 
CYP2B6, CYP2C9 and CYP2C19 by AZD5363 
CYP2B6 
Bupropion 
CYP2C9 
Warfarin 
CYP2C19 
Clobazam 
Drugs are permitted but caution should be 
exercised and patients monitored closely for 
possible drug interactions. Please refer to full 
prescribing information for all drugs prior to 
co-administration with AZD5363. 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 95 of 134
AC-1.4 CONCOMITANT AND EXCLUDED THERAPIES 
AC-1.4.1 Concomitant Therapy 
Refer to the main body of the protocol (Concomitant and Excluded Therapies) for concomitant 
therapies allowed. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that were 
present at baseline, provided the Investigator does not feel that these are indicative of clinical disease 
progression during the study period. Full details of all of these treatments are recorded in the patient’s 
notes and appropriate section of the eCRF. Study treatment should be discontinued for a minimum 
of 3 days before the patient undergoes palliative radiation treatment. Study treatment should be 
restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
AC-1.4.2 Excluded Therapy 
The following restrictions apply during the entire duration of study treatment: 
•
No other investigational therapy should be given to patients.
•
No concomitant cancer treatment of any type (including chemotherapy, biologic therapy,
hormonal therapy, immunotherapy, herbal therapy, radiation therapy) should be administered
at any time while the patient is taking study treatment. If such treatment is required, then the
patient must first be withdrawn from the trial. The patient can receive a stable dose of
corticosteroids during the study if these were started at least 4 weeks prior to treatment,
as per exclusion criteria. Bisphosphonates and Denosumab for bone metastases are allowed
if these were started at least 4 weeks prior to treatment with study drug.  Octreotide is allowed
if dose is stable for >3 months with no worsening of carcinoid syndrome. Hormonal therapy with
luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients
with castrate-resistant prostate cancer are permitted. Palliative radiotherapy is allowed for
pre-existing small areas of painful metastases that cannot be managed with local or
systemic analgesics if no evidence of disease progression is present.
•
Live virus and bacterial vaccines should not be administered whilst the patient is receiving
study medication and during the 30 day follow up period. An increased risk of infection by the
administration of live virus and bacterial vaccines has been observed with conventional
chemotherapy drugs and the effects with olaparib are unknown.
•
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods
known to modulate CYP3A4 enzyme activity from the time they enter the screening period
until 30 days after the last dose of study medication.


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 96 of 134
AC-1.5 STUDY ASSESSMENTS 
Screening Day 1 
of 
Cycle 
1 
C1D8 
C1D15 
C1D22 
Day 
1 
of 
each 
cycleo 
Every 
8 
weeks 
End of 
Study 
30 Day 
Follow- 
up 
Long 
term 
follow up 
as per 
main 
protocol 
Visit window (days) 
28m 
+/- 3 
+/- 3 
+/- 3 
+/- 3 
+/- 3 
+/- 7 
+/- 7 
Informed consent 
X 
Inclusion/Exclusion  Criteria 
X 
Pregnancy Testa 
X 
X 
Molecular Selection of Patients based on 
Archival Tumor Tissue (Paraffin 
X 
Medical History 
X 
Physical examination, 
weight and vital signs b 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
Laboratory tests (Clinical 
Chemistry/hematology/urinalysis 
/coagulation)c 
X 
Xl
X 
X 
Xd 
Glucose, Insulin 
X 
X 
Xe 
Xd 
Concomitant  medications 
X 
X 
X 
X 
Dosing compliance 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Echocardiology/MUGAf 
X 
ECGg 
X 
X 
X 
Xh 
X 
RECIST Assessments i
X 
X 
X 
X 
Tumor Tissue (Paraffin embedded) (optional)j 
X 
X 
Plasma Samplek 
X 
X 
X 
Anti-cancer therapy follow-up 
X 
a Two pregnancy tests on blood or urine samples will be performed for pre-menopausal women of childbearing potential 
one within 28 days prior to the start of study treatment and the other on Day 1 of the study prior to commencing treatment. 
Tests will be performed by the hospital’s local laboratory. If results are positive the patient is ineligible/must be discontinued 
from the study.  In the event of a suspected pregnancy during the study, the test should be repeated. 
b A complete physical examination will be performed at the following timepoints (within 24 hours of visit): Screening Visit, 
Day 1 Every Cycle, Discontinuation Visit, Follow-up Visit. Constitutional symptoms will be collected during screening and 
pre-dose at all other visits. Constitutional symptoms will include the presence/absence of pruritus, night sweats, recurrent 
fever ≥38.0ºC, fatigue, weakness and nocturia (a history of weight loss is to be collected at screening visit only). Vital signs 
(heart rate, systolic and diastolic blood pressure, oxygen saturation (pulse oximetry), respiration rate, weight, height (at 
screening) and temperature) 
Heart rate and systolic and diastolic blood pressure will be monitored prior to and 1, 2, 6 and 24 hours following C1D1, on 
pre-dose on cycle 1 day 8, on cycle 1 day 15, and on cycle 1 day 22. In all other cycles at pre-dose on day 1, and then at 
discontinuation. 
c Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell volume [MCV], mean cell 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019  
Page 97 of 134
hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white cell 
count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or segmented 
neutrophil count and Band forms should be performed at each visit and when clinically indicated. If absolute differentials 
not available please provide % differentials. Coagulation [activated partial thromboplastin time {APTT} and international 
normalized ratio {INR}] will be performed at baseline and if clinically indicated unless the patient is receiving warfarin. 
Patients taking warfarin may participate in this study; however, it is recommended that prothrombin time (INR and APTT) 
be monitored carefully at least once per week for the first month, then monthly if the INR is stable. If APTT testing is not 
locally available, Partial Thromboplastin Time (PTT) testing may be done along with INR. Any clinically significant results on 
PTT will be confirmed with APTT. 
Bone marrow or blood cytogenetic analysis may be performed according to standard hematological practice for patients 
with prolonged hematological toxicities. 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 cytometry on the bone marrow aspirate, then attempts should be made to carry out the tests 
on a blood sample. If findings are consistent with MDS/AML, study drug should be discontinued and a full description of 
findings should be submitted with an SAE report by the investigator to AstraZeneca Patient Safety for documentation on 
the Patient Safety database. Presence or absence of blood cytogenetic abnormalities and flow cytometry will be 
documented on the clinical database. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged hematological toxicities. 
These tests will be performed by the hospital’s local laboratory. Additional analyses may be performed if clinically indicated. 
Biochemistry assessments for safety (sodium, chloride, potassium, bicarbonate, calcium, magnesium, fasting glucose, 
creatinine, total bilirubin, gamma glutamyltransferase [GGT], alkaline phosphatase [ALP], aspartate transaminase [AST], 
alanine transaminase   [ALT], urea or blood urea nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]). 
Laboratory tests to also include Hgba1c, triglycerides and cholesterol. 
Cardiac markers CK, CK-MB, Troponin (isoform as per institutional norm), LDH and AST should be assessed at screening 
and pre-dose on first day of treatment. 
Troponin (additionally other cardiac markers, i.e. CK, CK-MB, AST and LDH depending on the investigators decision if 
clinically indicated) should also be assessed on identification of abnormal ECG findings, e.g. new repolarization 
abnormalities, found to be possibly clinically significant by investigators judgment. A repeat cardiac marker assessment 
should also be performed 24 hours later if such changes have been observed. The same Troponin isoform should be 
assessed at each of the visits. 
Troponin will be monitored routinely pre-dose on cycle 1 day 1, on cycle 1 day 8, on cycle 1 day 15, and on cycle 1 day 22. In 
all other cycles at pre-dose on day 1, and then at discontinuation. 
Sodium, chloride, potassium and bicarbonate will be monitored prior to and 1, 2, 6 and 24 hours following C1D1, and pre-dose 
on cycle 1 day 8, on cycle 1 day 15, and on cycle 1 day 22. In all other cycles at pre-dose on day 1, and then at discontinuation. 
An unscheduled serum urea and creatinine test should be performed in every case of an SAE of diarrhea. 
Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. Microscopic analysis should be 
performed by the hospital’s local laboratory if required. 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated and recorded on the eCRF. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to G ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
There is a 48 hr window for performance of lab testing for each visit 
d All patients with clinically significant abnormal laboratory results at treatment completion or study drug discontinuation 
visit are to be followed until the results return to normal (or patient’s baseline), or until a valid reason, other than a drug- 
related effect, is identified 
Patients with an unresolved AE or SAE event at treatment completion or study drug discontinuation will be contacted by the 
investigator or his or her designee to determine the status of the event until the event is resolved or stabilized, the patient 
is lost to follow up, or it has been determined that the study treatment or participation is not the cause of the event. 
e Glucose and insulin will be checked at screening, baseline, and on day 1 (pre-, 2-4 hours post-) of each cycle. Note that 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 98 of 134
this glucose monitoring is in addition to the usual laboratory monitoring stated in c. 
f Echocardiography will also be carried out if a patient develops signs and/or symptoms suggestive of a deterioration in left 
ventricular function or in case of the pre-specified ECG finding such as T-wave inversions. 
Echocardiography should include assessment of left ventricular end-systolic volume, left ventricular end-diastolic volume 
and LVEF. If an Echocardiography scan cannot be taken a MUGA scan to assess left ventricular ejection fraction (LVEF) 
will be conducted. The modality of the cardiac function assessments must be consistent within patient, ie, if echocardiogram 
is used for the screening assessment then echocardiogram should also be used for subsequent scans if required. The 
patient should also be examined using the same machine and operator throughout the study wherever possible. Other 
alternative methods of assessments could be used additionally if they are a part of the local standard of care, or if the 
investigator considers them necessary for the therapeutic management of the patient. Important cardiac symptoms should 
be reported as AEs/SAEs and should be carefully evaluated in regard to developing of acute or worsening of chronic cardiac 
failure, especially in anthracycline treated patients. Congestive cardiac failure should be treated and followed according to 
standard medical practice. 
g Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10 minutes. All ECGs 
should be recorded with the patient in the same physical position. For each time point 3 ECG recordings should be taken 
one after another. A standardized ECG machine should be used and the patient should be examined using the same 
machine throughout the study. 
If an abnormal ECG finding at baseline is considered by the investigator to be clinically significant, it should be reported as 
a concurrent condition. During the study, clinically significant abnormal ECG findings not present at baseline should be 
reported as an AE. If present, the clinical signs and symptoms associated with the abnormal finding should be reported as 
the AE with the ECG abnormality given as explanatory information. 
Troponin (additionally other cardiac markers, i.e. CK, CK-MB, AST and LDH depending on the investigators decision if 
clinically indicated) should also be assessed on identification of abnormal ECG findings, e.g. new repolarization 
abnormalities. A repeat cardiac marker assessment should also be performed 24 hours later, if such findings occur the 
same Troponin isoform should be assessed at each of the visits. 
An ECG should be performed at any cardiac event with symptoms that may be due to cardiac ischemia, or arrhythmia (such 
as chest pain or palpitations). An ECG will also be captured in all cases of dyspnea and pulmonary edema and additionally 
at the discretion of the investigator if clinically indicated. 
h ECGs to be taken routinely on cycle 1 day1 pre-dose, 1 hr post dose, 2 hrs post dose, 6 hrs post dose, and 24 hrs post 
dose; on cycle 1 day 8 (up to 6 hrs post dose); on cycle 1 day 15 (up to 6 hrs post dose); and cycle 1 day 22 (up to 6 hrs 
post dose), Post dose ECGs may be taken at the time specified +/- 15 minutes. In all other cycles at pre-dose on day 1, 
and then at discontinuation. 
i Patients will be evaluated until objective disease progression by RECIST 1.1. If a chest CT scan at baseline (screening 
CT will be the baseline scan) is not performed as part of the RECIST assessment, the patient should undergo a chest CT 
scan in order to document the lung parenchyma status at baseline. High resolution CT should be performed if clinically 
indicated by pulmonary symptoms any time during the study. For any new respiratory symptoms (cough, dyspnea, lower 
respiratory infection) not clearly explained by other factors (eg, dyspnea associated with substantial drop in hemoglobin), 
patients should have oxygen saturation measured. If <92%, the high resolution CT scan of the chest should be repeated 
and pulmonary function tests should be performed. 
Scans will be performed every 8 weeks. If partial response (PR) or complete response (CR) is documented, a confirmatory 
scan will be performed 4 weeks later for PR/CR (whichever occurs first). 
j Tumor sample at baseline if feasible (optional). The sample can be collected up to 4 weeks before the first dose. Therefore, 
any sample collected during this time period prior to study enrollment can be used as baseline sample. The tumor sample 
for use in genetic and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures 
at each institution. Additional tumor samples may also be collected and used fresh or frozen. 
Tumor sample at progression or discontinuation if feasible (optional). The sample can be collected at progression or 
discontinuation, or any time between progression and discontinuation from the study. The tumor sample for use in genetic 
and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures at each 
institution. Additional tumor samples may also be collected and used fresh or frozen 
k Plasma samples (optional) will be collected at baseline, on treatment and at progression/ discontinuation on study to 
isolate ctDNA to determine the mutational profile and changes thereof. The plasma sample at baseline should can be 
collected up to 2 weeks before the first dose. Samples on study should be taken at the end of the first cycle (+/- 7 days), 


OLAPCO APPENDIX C: AZD5363 plus olaparib 
Date 07 Feb 2019 
Page 99 of 1434
and at the end of the cycles 4, 6 and 10 (+/- 7 days) and at progression or discontinuation or any time between progression 
and discontinuation from the study 
Additional samples (optional) after cycle 10 and before progression can be collected, if the investigator deems a particular 
time   point   of   interest.   However,   samples   should   not   be   collected   more   frequent   than   every   2   cycles. 
F describes  the procedures for collection, processing, storage and shipment of plasma. 
l Results of all cycle 1 day 1 laboratory tests must re-meet eligibility criteria 
m: Screening to be performed within 28 days unless otherwise specified 
o: Continuous use of Olaparib is suitable during this window 


Page 100 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
APPENDIX D: AZD6738 plus Olaparib in Patients with DNA Damage Repair Gene Mutations 
Treatment of patients with solid tumors that harbor DNA damage repair gene mutations is part of the 
clinical trial outlined in the main protocol. 
Defects in components of the HDR/DSB repair mechanism require affected cells to depend on 
alternative error-prone pathways of DNA repair, including BER and B-NHEJ. PARP1 hyperactivity 
has been demonstrated in HDR-defective cells and ought to confer a similar sensitivity to PARP 
inhibitors, which target the essential DDR pathway remaining intact in HDR deficient cells [45]. This 
has led to the concept of “BRCA-ness”, which proposes that somatic mutations in the BRCA 1 and 2 
genes, as well as other HDR genes as noted above, should confer a similar sensitivity to PARP 
inhibitors as gBRCA mutations. This expanded repertoire of mutations in HDR should be considered 
as potential clinical targets for DDR-focused therapies such as PARP inhibitors. This would include 
somatic mutations of BRCA 1 & 2, the BRCA interacting proteins of the MRN complex (MRE11, RAD 
50, NBS), RAD51, PALB2/FANCN, FANCD2, FANCC and DSS1. This grouping of BRCA-interacting 
proteins can be considered the HR effector arm or RAD51 foci-forming proteins. Another grouping 
of DDR proteins includes the checkpoint controllers ATM, ATR, CHK1 and CHK2, which regulate cell 
all cycle and the expression of the HR effector proteins such as BRCA1. Other DDR proteins comprise 
the FANCA/B/C/E/F/G/L/M complex core, which activates FANCD2, thus localizing the HDR repair 
effector complex to the site of DSB and SSB, plays a critical role in DDR such that loss of any of the 
components has a profound repair-defective phenotype. 
In 50 consecutive tumors profiled at Yale, nonsense mutations and mutations considered to have 
major effects on DNA damage repair pathways at critical functional sites (COSMIC) were detected 
in 8 (16%). This incidence makes identifying appropriate patients for this study feasible. These 
aberrations were detected in multiple different tumor types including GBM, H&N cancer, NSCLC, 
prostate, breast, colorectal and other solid and hematological malignancies. 
ATR is an atypical kinase in one of the DNA-damage induced checkpoint pathways, and during 
normal DNA replication is recruited at stalled replication forks, which can progress to double strand 
breaks if left unrepaired. Following resection of double strand breaks ATR is recruited to single strand 
DNA coated with Replication Protein A (RPA) following single strand DNA damage. Recruitment and 
activation of ATR leads to cell cycle arrest in the S phase while the DNA is repaired and the stalled 
replication fork resolved, or nuclear fragmentation and entry into programmed cell death (apoptosis). 
Loss of ATR function leads to the inability to resolve stalled replication forks, the accumulation of 
DNA damage and rapid cell death exemplified by nuclear fragmentation 
Although ATM-deficient cells have a greater sensitivity to AZD6738, AZD6738 is cytotoxic in cell line 
panels of ATM-proficient hematological malignancies in vitro. In vivo combinations of AZD6738 with 
radiation induces a dose-dependent anti-tumor response, with regressions in ATM-deficient models 
and growth inhibition in ATM-proficient models. Anti-tumor activity of AZD6738 may, therefore, also 
be seen more broadly. 
The combination of AZD6738 and olaparib are synergistically cytotoxic in HDR ovarian cancer cell 
lines in vitro and in vivo in a BRCA2-/- PDX model. PARP inhibition activates ATR/CHK1 as a survival 
mechanism and concurrent inhibition of this pathway permits the BRCA -/-  cells to enter into mitotic 
catastrophe and apoptosis (B). The ATR-Chk1 checkpoint pathway serves to ensure cell survival after 
replication stress of many types, therefore a normal and robust checkpoint is thought to be a 
mechanism of resistance to chemotherapy. 


Page 101 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
This appendix contains details and study requirements that are specific to treatment with olaparib 
and AZD6738 including: 
Appendix D-1 
MATERIALS AND METHODS 
Appendix D-1.1 
PATIENTS 
Appendix D-1.2 
METHOD OF TREATMENT ASSIGNMENT 
Appendix D-1.3 
STUDY TREATMENT 
Appendix D-1.4 
CONCOMITANT AND EXCLUDED THERAPIES 
Appendix D-1.5 
STUDY ASSESSMENTS 
AD-Figure 1 
Study Schema: AZD6738 plus Olaparib 
AD-Table 1 
Olaparib dosage form and strength 
AD-Table 2 
Dose Modifications for Hematologic Toxicity 
AD-Table 3 
Dose Modifications for Non-Hematologic Toxicity 
AD-Table 4 
Module 1: Combination with AUC5 
AD-Table 5 
Module 2: Monotherapy 
AD-Table 6 
Module 2: Combination with Olaparib 
AD-Table 7 
Dose Modifications for Non-Hematologic Toxicity 
AD-1 
MATERIALS AND METHODS 
AD-1.1 
PATIENTS 
Eligible patients must meet all eligibility requirements contained in the main study protocol. 
AD-1.1.1 Inclusion Criteria 
Refer to the main protocol Inclusion Criteria. 
AD-1.1.2 Additional Exclusion Criteria 
Refer to the main protocol Exclusion Criteria. 
AD-1.2 METHOD OF TREATMENT ASSIGNMENT 
Please refer to the main body of the protocol for the methods of treatment enrollment and study 
drug procurement (STUDY DESIGN AND RATIONALE). 
AD-1.3 STUDY TREATMENT 
All patients will receive treatment with olaparib and AZD6738, given at a daily dose of AZD6738 
160 mg orally ( PO) daily between days 1 - 7 and bid daily dose of 300 mg orally (PO) in 
cycles of 28 days (4 weeks) duration. A schema of the study design is presented in Study Schema: 
A Z D 6 7 3 8  a n d  Olaparib. 
All patients will receive: 
•
Olaparib 300 mg bid daily tablets.
•
AZD6738 one 100mg and three 20 mg tablets
•
No routine premedications are required.


Page 102 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
AD-Figure 1: Study Schema: AZD6738 plus Olaparib 
AD-1.3.1 Olaparib 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB) 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose] 
polymerization (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. 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair mechanisms. 
PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARPs leads 
to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks 
(DSBs) during the process of DNA replication. During the process of cell division, DSBs can be 
efficiently repaired in normal cells by homologous DNA recombination repair (HDR). Tumors with 
HDR deficiencies, such as serous ovarian cancers, cannot accurately repair the DNA damage, 
which may become lethal to cells as it accumulates. In such tumor types, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared 
with currently available 
chemotherapy regimens. 
Olaparib has been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment or 
in combination with established chemotherapies. Cells deficient in homologous recombination DNA 
repair factors, notably BRCA1/2, are particularly sensitive to olaparib treatment. 


Page 103 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of chemotherapy. 
For further information please refer to the current version of the olaparib IB. 
a. Formulation
Chemical Name: 4-[(3-[[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl]-4-
fluorophenyl)methyl]phthalazin-1(2H)-one
Laboratory Codes: AZD2281; KU-0059436; CO-CE 42
CAS No.: 763113-22-0
Molecular Formula:  C24H23FN4O3 
Molecular Weight: 434.46 
b. Dosage, Administration, and Storage
The AstraZeneca Pharmaceutical Development  R&D  Supply Chain  will supply olaparib to the 
investigator as round or oval green film coated tablets 
AD-Table 1: Olaparib dosage form and strength  
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
For all centers, olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child- 
resistant closures. Each dosing container will contain 32 tablets and desiccant. Multiple bottles of 
study treatment may be required for dispensing in order to make up the desired dose. 
Olaparib will be dispensed to patients on Day 1 of each cycle until the patient completes the study, 
withdraws from the study or closure of the study. 
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be replaced 
if all remaining tablets can be seen and counted. Should any patient enrolled on the study miss a 
scheduled dose for whatever reason (e.g. forgetting to take the tablets or vomiting) or need to modify 
the timing of a scheduled dose for any reason, the patient will be allowed to take the scheduled dose 
up to a maximum of 2 hours after that scheduled dose time. The dose should not be taken more than 
2 hours in advance of the 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. Doses should not be taken fewer than 10 hours apart 
Combination drug should be given at least 1 hour after the patient has taken their olaparib morning 
dose. 


Page 104 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Food intake restrictions 
Olaparib doses can be taken without regard to food. The olaparib tablets should be swallowed whole 
and not chewed, crushed, dissolved or divided 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions. The product 
should be stored in the pack provided and used according to the instructions on the label. 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label text will be translated 
into local language. 
Each bottle of 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 enrolment 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
•
enrolment code (E-code)
•
date of dispensing
•
Instructions stating that the olaparib tablets should be taken at approximately the same time
each morning and evening
c. Dosage Modification
Dose reduction for AZD6738 and olaparib 
Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events version 4.0 (NCI CTCAE v4.0). If toxicity occurs, the toxicity will be graded, and 
appropriate supportive care treatment will be administered to decrease the signs and symptoms 
thereof. 
AD-Table 2: Guidance for dose reductions for AZD6738 and olaparib 
Dose Level 
AZD6738 
Olaparib 
Initial dose level 
160 mg QD Days 1-7 
300 mg BID Days 1-28 
1st dose reduction 
Dose reduce either AZD6738 or Olaparib or Both 
Hematological Toxicity 
160mg QD Days 1-4 
250 mg BID Days 1-28 
Non-Hematological 
Toxicity 
120mg QD Days 1-7 
250 mg BID Days 1-28 
2nd dose reduction 
Dose reduce either AZD6738 or Olaparib or Both 
120 mg OD Days 1-4 
200 mg BD Days 1-28 
3rd dose reduction: No further reduction permitted, withdraw patient and treat as clinically 
indicated. Dose must not be re-escalated even if toxicities have resolved. 
Note: filgrastim or PEG-filgrastim may be used at the investigator’s discretion 
Management of hematological toxicity 
At the first occurrence of CTCAE grade 3 and 4 hematological toxicity, AZD6738 and olaparib should 
be held until resolution of toxicity. At the resolution of the first occurrence of any of these toxicities, no 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019  
Page 105 of 134
change must be made to the dose. The second occurrence, upon resolution of toxicity, AZD6738 and/or 
olaparib should be reduced by the 1st dose reduction for hematological toxicity to 160 mg qd for 4 days 
and/or 250mg bid q 12 hours daily(Table 3). At the third occurrence, AZD6738 and olaparib should be 
reduced by the 2nd dose reduction to 120 mg qd Days 1-4 and 200mg bid q 12 hours daily(Table 3). If 
despite these changes there is a fourth occurrence of toxicity, the patient should be withdrawn from the 
treatment. Please note that, for each dose reduction, the investigator may choose to reduce AZD6738 
or olaparib or both drugs. If only one drug is dose reduced, the second drug may be reduced as an 
additional step. for simultaneous toxicities (for example, neutropenia and thrombocytopenia), if either 
AZD6738 and olaparib has been recently held or dose-reduced, and a second toxicity develops, the 
event should be considered singular and no further dose modification should be made, providing that 
both toxicities resolve within 28 days. However, sequential toxicities (for example, neutropenia followed 
by thrombocytopenia) should follow Table 4; if a recent dose reduction has been made, a second 
modification may be required before beginning the next cycle. Refer to Table 3 and 4 for specific dose 
modification guidance regarding hematological toxicity. 
AD-Table 3: Summary of guidance on the management of hematologic toxicity for AZD6738 and 
olaparib 
Toxicity 
AZD6738 and olaparib 
Any hematologic toxicity 
(CTCAE grade ≥ 3) 
1st occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at original dose level. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib. 
2nd occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 1st reduced dose level 
for hematological toxicity The investigator may choose 
to reduce AZD6738 or olaparib or both drugs. If only 
one drug is dose reduced, the second drug may be 
reduced as an additional step ir the toxicity recurs. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib. 
3rd occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 2nd reduced dose  
level for hematological toxicity. The investigator may 
choose to reduce AZD6738 or olaparib or both drugs. If 
only one drug is dose reduced, the second drug may be 
reduced as an additional step ir the toxicity recurs. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib. 
4th occurrence 
Off-study 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 106 of 134
AD-Table 4: Neutropenia, Infection, Febrile Neutropenia Dose Modifications and Management 
Toxicity 
AZD6738 and olaparib 
- Fever ( 101°F [38.5°C]) and/or systemic 
infection 
Hold dose until recovery. 
Then, upon resuming dosing, reduce 
Toxicity 
AZD6738 and olaparib 
- Grade 3 neutropenia (ANC ≥500 to 
<1000/L) of any duration 
- Grade 4 neutropenia (ANC<500/L >4 
days) 
- Grade 3 thrombocytopenia (platelet 
count 25,000 to <50,000/L) with bleeding 
AZD6738 and olaparib to the next lower 
dose levela. 
Grade 4 febrile neutropenia or Grade 4 
infection with neutropenia (both defined as 
septic shock) 
Thromboctyopenic hemorrhage (gross 
occult bleeding) associated with a platelet 
count <50,000/L 
Discontinue treatment and follow for disease 
progression. 
Hematologic toxicity management guideline 
Management of anemia 
Adverse events of anemia CTCAE grade 1 or 2 (Hb ≥8 g/L) should be investigated and managed as 
deemed appropriate by the investigator with or without interruption of study drug or change in dose, 
taking into account previous history of anemia. Common treatable causes of anemia (eg, iron, vitamin 
B12 or folate deficiencies and hypothyroidism) should be investigated and appropriately managed. In 
some cases management of anemia may require blood transfusions. However, if a patient develops 
anemia CTCAE grade 3 (Hb <8 g/L) or worse, study treatment should be interrupted for up to maximum 
of 4 weeks. Study treatment can be restarted at the same dose if Hb has recovered to >9 g/L. Any 
subsequently required anemia related interruptions, considered likely to be dose related, or coexistent 
with newly developed neutropenia, and or thrombocytopenia, will require study treatment dose 
reductions 
If a patient has been treated for anemia with multiple blood transfusions without study treatment 
interruptions and becomes blood transfusion dependent as judged by investigator, study treatment 
should be interrupted as outlined in Table 3. Study treatment should be restarted at a reduced dose. 
Management of neutropenia and leukopenia 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC grade 3 or worse neutropenia 
occurs. Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, study treatment should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines. Please note that 
G-CSF should not be used within at least 24 h of the last dose of study treatment. 
Study treatment can be restarted at the same dose if an adverse event of neutropenia or leucopenia 
have been recovered up to CTC AE grade >1 (ANC > 1.5 x 109/L). Growth factor support should be 
stopped at least 24h before restarting study drug (7 days for pegylated G-CSF). 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019  
Page 107 of 134
Management of thrombocytopenia 
An adverse event of thrombocytopenia should be managed as deemed appropriate by the investigator. 
If a patient develops thrombocytopenia CTCAE grade 3 or worse study treatment should be interrupted 
for a maximum of 4 weeks. In some cases management of thrombocytopenia may require platelet 
transfusions.  Platelet transfusions should be done according to local hospital guidelines. 
If a patient develops prolonged hematological toxicity such as: 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or development 
of blood transfusion dependence 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia (ANC < 1 x 
109/L) 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia (Platelets 
< 50 x 109/L) 
Weekly  differential  blood  counts  including  reticulocytes  and  peripheral  blood  smear  should  be 
performed.  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. 
Development of a confirmed myelodysplastic syndrome 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 diagnosis of MDS and/or AML is confirmed. 
Management of non-hematological toxicity 
For non-hematological toxicity, upon resolution of toxicity, AZD6738 and/or olaparib may be reduced 
by the 1st dose reduction to 120 mg QD Days 1-7 and/or 250 mg BID Days 1-28At the first occurrence 
of CTCAE grade 3 and 4 non-hematological toxicity, AZD6738 and olaparib should be held until 
resolution of toxicity. At the resolution of the first occurrence of any of these toxicities, no change must 
be made to dose. At the second occurrence, upon resolution of toxicity, AZD6738 and/or olaparib 
should be reduced by the 1st  dose reduction for non-hematological toxicity to 120 mg qd for 7 days 
and 250 mg bid q 12 hours daily). Despite this change, at the third occurrence, upon resolution of 
toxicity, AZD6738 and/or olaparib should be reduced by the 2nd dose reduction to 120 mg qd for 4 
days and 200 mg bid q 12 hours daily. If despite these changes, there is a fourth occurrence of 
toxicity, the patient should be withdrawn from the treatment. Please note that, for each dose reduction, 
the investigator may choose to reduce AZD6738 or olaparib or both drugs. If only one drug is dose 
reduced, the second drug may be reduced as an additional step. Refer to Table 5 for specific dose 
modification guidance regarding non-hematological toxicity. 
AD-Table 5: Summary of guidance on the management of  non- hematologic toxicity for AZD6738 
and olaparib 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 108 of 134
Any non-hematologic toxicity 
(CTCAE grade ≥ 3) 
1st occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at original dose level. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib . 
2nd occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 1st reduced dose level 
for non-hematological toxicity The investigator may 
choose to reduce AZD6738 or olaparib or both drugs. If 
only one drug is dose reduced, the second drug may be 
reduced as an additional step if the toxicity recurs. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib . 
3rd occurrence 
Withhold dose for up to 28 days until recovery to 
≤CTCAE grade 1 then resume at 2nd reduced dose 
level for non-hematological toxicity The investigator 
may choose to reduce AZD6738 or olaparib or both 
Toxicity 
AZD6738 and olaparib 
drugs. If only one drug is dose reduced, the second 
drug may be reduced as an additional step ir the 
toxicity recurs. 
If symptoms do not recover to ≤CTCAE grade 1, 
discontinue AZD6738 and olaparib. 
4th occurrence 
Off-study 
Non-hematologic toxicity management guidelines 
Non-hematological CTCAE grade 3 and 4 toxicities observed during the course of the study and 
attributable to AZD6738 and olaparib will first be managed by interruption of the dose. Repeat dose 
interruptions are to be allowed as required. The maximum duration of any dose interruption is 28 days. 
Treatment must be interrupted until the patient recovers completely or the toxicity reverts to NCI CTCAE 
grade 1 or to the baseline CTCAE grade. If an interruption of longer than 28 days is required, the patient 
should be withdrawn from the study. Where toxicity recurs following re-treatment with AZD6738 and 
olaparib, and where further dose interruptions are considered inadequate for management of toxicity, 
then dose reduction or withdrawal is indicated. Upon appropriate resolution of the toxicity (i.e. to CTCAE 
grade 1 or to baseline CTCAE grade), the patient should restart treatment with AZD6738 and olaparib 
but with a dose level reduction (as per Table 5). If toxicity recurs, treatment should be interrupted again 
and, on resolution, a further dose level reduction made. 
Management of new or worsening pulmonary symptoms 
If new or  worsening pulmonary symptoms (e.g.  dyspnea)  or radiological abnormality occurs, an 
interruption in olaparib dosing is recommended and a diagnostic workup (including a high resolution CT 
scan) should be performed, to exclude pneumonitis. Following investigation, if no evidence of 
abnormality is observed on CT imaging and symptoms resolve, then olaparib treatment can be restarted, 
if deemed appropriate by the investigator. If significant pulmonary abnormalities are identified, these 
need to be discussed with the Sponsor. 
Toxicity 
AZD6738 and olaparib 


Page 109 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
All dose reductions and interruptions (including any missed doses), and the reasons for 
the reductions/interruptions are to be recorded in the CRF. 
AZD6738 and olaparib should be stopped before surgery and re-started after wound has healed 
following recovery. 
No stoppage of AZD6738 and olaparib are required for any biopsy procedures. 
AZD6738 and olaparib should be discontinued for a minimum of 7 days before a patient undergoes 
therapeutic palliative radiation treatment. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the placebo 
treated patients and vomiting was reported in 34% of the olaparib treated patients and 14% in the 
placebo treated patients. They 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 with the incidence of nausea and vomiting not showing an increase over the treatment 
cycles. 
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 
Additional information for patients 
Olaparib should be stopped before surgery and re-started after wound has healed following recovery. 
No stoppage of olaparib is required for any biopsy procedures. 
Olaparib should be discontinued for a minimum of 7 days before a patient undergoes therapeutic 
palliative radiation treatment. 
Other Toxicities 
Olaparib dosing should be discontinued for any severe toxicity that does not respond to treatment. 
d. Olaparib Warnings and Precautions
MDS/AML
The incidence of MDS/AML in patients treated in clinical trials with olaparib monotherapy, including long-
term survival follow-up, was <1.5% and the majority of events had a fatal outcome. All patients had 
potential contributing factors for the development of MDS/AML, having received previous chemotherapy 
with platinum agents. Many had also received other DNA damaging treatments. The majority of reports 
were in gBRCA mutation carriers and some of the patients had a history of previous cancer or of bone 
marrow dysplasia. If MDS and/or AML are confirmed while on treatment with olaparib, it is recommended 
that olaparib should be discontinued and the patient be treated appropriately 
New Primary Malignancies 
New primary malignancies have been reported in <1% of patients. There were other contributing factors/potential 
alternative explanations for the development of the new primary malignancy in all cases, including documented 
BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, 
anthracyclines and other alkylating and DNA damaging agents.  


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019  
Page 110 of 134
Pneumonitis 
Pneumonitis events have been reported in <1% of patients receiving olaparib. The reports of 
pneumonitis had no consistent clinical pattern and were confounded by a number of pre-disposing 
factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy).  When olaparib was used in clinical studies in combination 
with other therapies there have been events with a fatal outcome. If patients present with new or 
worsening respiratory symptoms such as dyspnea, cough and fever, or an abnormal chest radiologic 
finding is observed, olaparib treatment should be interrupted and prompt investigation initiated. If 
pneumonitis is confirmed, olaparib treatment should be discontinued and the patient treated 
appropriately. 
Pregnancy 
Pre-clinical data indicate that olaparib can have adverse effects on embryo-fetal survival and 
development and pregnancy is an Exclusion Criterion for the clinical studies with Olaparib. If any 
patient becomes pregnant during a study, olaparib must be discontinued and the patient followed up 
until birth or termination of pregnancy. The clinical protocol gives details on the requirements to report 
pregnancy and its outcome. Should pregnancy occur, the physician and patient should discuss the 
risks of continuing the pregnancy. 
Male patients should refrain from fathering a child or donating sperm during a study and for 6 months 
following the last dose of Olaparib. 
Contraception 
Patients of child bearing potential and their partners, who are sexually active, must agree to the use 
of two highly effective forms of contraception throughout their participation in the study and for 6 
months after last dose of study drug(s). 
Condom with spermicide and one of the following: 
•
Oral contraceptive or hormonal therapy (e.g. hormone implants)
•
Placement of an intra-uterine device
Acceptable non-hormonal birth control methods include: 
•
Total sexual abstinence.  Abstinence must be for the total duration of the study and the drug
washout period.
•
Vasectomised sexual partner plus male condom.   With participant assurance that partner
received post-vasectomy confirmation of azoospermia
•
Tubal occlusion plus male condom with spermicide
•
Intrauterine Device (IUD) plus male condom+spermicide.  Provided coils are copper-banded
Acceptable hormonal methods: 
•
Etonogestrel implants (eg, Implanon, Norplan)+male condom with spermicide
•
Normal and low dose combined oral pills+male condom with spermicide
•
Hormonal shot or injection (eg, Depo-Provera) + male condom
•
Intrauterine system device (eg, levonorgestrel-releasing intrauterine system -Mirena®)
•
+ male condomNorelgestromin/ethinyl estradiol (EE) transdermal system+male condom with
spermicide
•
Intravaginal device+male condom with spermicide (eg, EE and etonogestrel)
•
Cerazette (desogestrel)+male condom with spermicide.  Cerazette is currently the only highly
efficacious progesterone based pill.
Lactation 
Lactation is an Exclusion Criterion within the study protocols for olaparib. It is not known whether 
olaparib is excreted in human milk. 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 114 of 134
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
Maternal exposure 
If a patient becomes pregnant during the course of the study olaparib should be discontinued 
immediately. 
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. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should be followed up and documented even if the patient was withdrawn 
from the study. 
If any pregnancy occurs in the course of the study, then Investigators or other site personnel must 
inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 days for SAEs, 
and within 30 days for all other pregnancies 
The same timelines apply when outcome information is available. 
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. 
Overdose 
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 bid (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.


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 112 of 134
If an overdose on an AstraZeneca study drug occurs in the course of the study, then investigators or 
other site personnel inform appropriate AstraZeneca representatives 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 designated AstraZeneca representative works with the investigator 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. For other overdoses, reporting 
should be done within 30 days. 
e. Metabolism and Drug Interactions
The use of any natural/herbal products or other “folk remedies” should be discouraged but use of
these products, as well as use of all vitamins, nutritional supplements and all other concomitant
medications must be recorded in the eCRF.
Based on in vitro data and clinical exposure data, olaparib is considered unlikely to cause clinically 
significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. In 
vitro data have, however, also shown that the principal enzyme responsible for the formation of the 3 
main metabolites of olaparib is CYP3A4 and consequently, to ensure patient safety, the following 
strong inhibitors of CYP3A4 must not be used during this study for any patient receiving olaparib. 
While this is not an exhaustive list, it covers the known strong inhibitors, which have most often 
previously been reported to be associated with clinically significant drug interactions: 
•
ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, telithromycin, clarithromycin and nelfinavir
For patients taking any of the above, the required wash-out period prior to starting olaparib is one
week.
In addition, to avoid potential reductions in exposure due to drug interactions and therefore a potential
reduction in efficacy, the following CYP3A4 inducers should be avoided:
•
Phenytoin,  rifampicin,  rifapentine,  rifabutin,  carbamazepine,  phenobarbitol,  nevirapine,
modafinil and St John’s Wort (Hypericum perforatum)
For patients taking any of the above, the required wash-out periods prior to starting olaparib are: 
•
phenobarbitol 5 weeks, and for any of the others, 3 weeks.
After randomization, if the use of any strong inducers or inhibitors of CYP3A4 are considered 
necessary for the patient’s safety and welfare, the Investigator must contact the AstraZeneca Study 
Physician. A decision to allow the patient to continue in the study will be made on a case-by-case 
basis. 
Other Concomitant Medications 
Any medications, other than those listed as excluded therapies, which are considered necessary for the 
patient's welfare, and which it is believed will not interfere with the study medication, may be given at the 
discretion of the Investigator, providing the medications, the doses, dates and reasons for 
administration are recorded in the eCRF. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the study 
period must be recorded in the eCRF. 
Anticoagulant Therapy: Patients who are taking warfarin may participate in this study; however, it is 
recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week for 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 113 of 134
the first month, then monthly if the INR is stable.  Subcutaneous heparin is permitted. 
The reason(s) for the use, doses and dates of treatment should be recorded in the patient’s medical 
records and appropriate section of the eCRF. 
All medications (prescriptions or over-the-counter medications) continued at the start of the trial or 
started during the study or until 30 days from the end of the last protocol treatment and different from the 
study medication must be documented. 
For further detail, see the olaparib Investigator’s Brochure (IB). 
AD-1.3.2 AZD6738 
AZD6738 is a potent, selective inhibitor of the serine/threonine-specific protein kinase, ataxia 
telangiectasia and Rad3-related protein (ATR), with good selectivity against other phosphatidylinositol 
3-kinase-related kinase (PIKK) family members. This compound is being developed as an oral anti-tumor 
agent with an initial focus on patients with ATM-deficient disease, although there is preclinical evidence 
for activity in broader malignant disease types. 
Clinical data 
At the time of preparation of this amendment, there is one ongoing AstraZeneca sponsored clinical 
study with AZD6738, study D5330C00004. 
Study D5330C00004 is a modular, phase I, 2 part, open-label, multicenter study of AZD6738, 
administered orally, in combination with cytotoxic chemotherapy regimens or novel anti- cancer agents, 
to patients with advanced/metastatic solid malignancies. The study design allows an escalation of the 
dose of AZD6738 as monotherapy and in combination with the standard dose and schedule of either 
cytotoxic chemotherapies or novel anti-cancer agents, with intensive safety monitoring to ensure the 
safety of the patients. 
The first module, Module 1, of the study is investigating AZD6738 administered orally in combination 
with Carboplatin, to patients with advanced malignancies in order to establish the Recommended Phase 
2 Dose of AZD6738. 
The second module, Module 2, of the study is investigating AZD6738 administered orally in combination 
with olaparib, to patients with advanced malignancies. The purpose of this module is to establish the 
RP2D of AZD6738 given in combination with olaparib, and assess preliminary efficacy in a subsequent 
expansion(s) 
in patients with advanced ATM-deficient (Part B1) and ATM-proficient gastric 
adenocarcinoma (Part B2) and breast cancer patients with BRCA mutations excluding HER2-positive 
breast cancer patients (Part B3) and TNBC patients with no known BRCA mutations (Part B4).. 
The third module, Module 3, of the study is investigating AZD6738 administered orally in combination 
with MEDI4736, to patients with advanced Non-Small Lung Cancer (NSCLC) or Head and Neck 
Squamous Cell Carcinoma (HNSCC) with a subsequent expansion in HNSCC patients to assess 
preliminary efficacy. 
As of 1st June 2017, 36 patients in Module 1, 64 patients in Module 2 and 15 patients in Module 
3 of Study D5330C00004 have received treatment with AZD6738.  In Module 2, the RP2D 
has been established and patients with gastric cancer are being recruited to expansions in 
Parts B1 and B2. Amendment 8, which adds Parts B3 and B4 to the study, has been submitted to 
the regulatory authorities for approval. 
AD-Table 6: Cumulative number of patients exposed to AZD6738 and olaparib in Study 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 114 of 134
D5330C00004 
Data generated from Module 2 has been utilized to evaluate the risks and benefits in the current 
study which contains the same combination of olaparib and AZD6738. 
Cohort 
Dose 
level 
Dose 
frequency 
Schedule 
(28 day cycle) 
Key AE observations 
1 
80mg 
BD 
Day 1 to Day 21 
No AEs > CTCAE G2 
2 
160mg 
BD 
Day 1 to Day 21 
No AEs > CTCAE G2 
AD-Table 7: Module 2 - combination with olaparib 
Cohort 
AZD6738 
QD Dose 
level 
AZD6738 
Schedule 
(28 day cycle) 
Dose level 
Olaparib 
BD 
Continuous 
schedule 
Key AE observations 
1 
60mg 
Days 1 to 5 
and 15-19 
100mg 
No AEs > CTCAE G2 
2 
160mg 
Days 1 to 7 
100mg 
No AEs > CTCAE G1 
3 
80mg 
Days 1 to 7 
200mg 
No AEs > CTCAE G2 
4 
160mg 
Days 1 to 7 
200mg 
No AEs > CTCAE G2 
AE and Efficacy Summary 
Dose-limiting toxicities of AZD6738 and olaparib, observed in the escalation phase included three events 
of G4 thrombocytopenia associated with bleeding (one each of hematuria, epistaxis, and bleeding from 
a chest wall tumor) and a prolonged G4 neutropenia. Very common adverse events (≥1/10 according to 
CIOMS III frequency classification) considered possibly related to AZD6738 and /or olaparib by the 
investigator include anemia and fatigue. Common adverse events (≥1/100 to < 1/10) include anemia, 
thrombocytopenia, neutropenia, leucopenia, fatigue, anorexia, nausea and vomiting, diarrhea, 
dizziness, increased blood creatinine and asthenia. Effects on bone marrow are anticipated in the clinic 
and may occur in the second or third week of dosing but may also arise after the first cycle resulting in 
dosing delays. These events are deemed schedule limiting, rather than dose limiting toxicities as the 
main issue is a delayed recovery of the platelets. Myelosuppression has been successfully managed 
with dose interruptions, dose reductions (dose and schedule) and supportive measures such as blood 
transfusions. Hematology and biochemistry blood counts will be monitored each cycle in the clinic and 
patients will be excluded from clinical studies with AZD6738 if they have significant baseline 
gastrointestinal pathology. 
The combination of Olaparib and AZD6738 has been administered to 64 patients with advanced 
malignancy with the goal of establishing the dosing schedule. The recommended phase 2 dose was 
established as 160 mg OD AZD6738 days 1-7 in combination with 300 mg BD olaparib on a 28 day 
cycle. The dosing schedule of AZD6738 was supported by the PK-PD model of thrombocytopenia, 
predicting a period of 21 days free of drug to achieve a full platelet recovery. The recommended dose 
160 mg OD was predicted to maintain AZD6738 mean steady state concentrations above the estimated 
IC90 threshold (based on ATR enzyme inhibition assay in LoVo cells) and the GI90 threshold (based on 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 115 of 134
the cellular growth inhibition activity in LoVo cells) across the full dosing interval i.e 24 h. Please refer to 
AZD6738 IB for further information around the in-vitro threshold values. In addition, this daily dose level 
was associated with a decrease in peripheral monocytes in most of the patients and the preliminary 
blood cell count data from D5330C00004 and D5330C00002 studies suggested this decrease to be 
AZD6738 specific and dose dependent (monocyte decrease was not observed with either single agent 
olaparib or durvalumab). Monocytes have been characterized as being deficient in DNA base excision 
repair and PARP1 expression [71], suggesting an on-target synthetic lethal effect of AZD6738 mediated 
ATR inhibition in this cell type. Utilizing the monocyte decrease as a quantitative measure of AZD6738 
pharmacological activity, the recommended Phase 2 dose of 160mg OD D1-7 was driven by maintaining 
maximally active exposure consistent with manageable safety. 
Potential Benefits 
To date, AZD6738 has been administered to approximately 167 subjects (64 in combination 
with olaparib) as part of AZ sponsored studies or as part of the AZ Externally Sponsored Research 
program. AZD6738 has shown some clinical activity as monotherapy. Data is presently limited to 
24 evaluable subjects from a non-AZ sponsored Phase I dose escalation study in advanced solid 
tumors (NCT02223923); PRs were observed in 2 patients (8%), one confirmed, a recurrent 
squamous cell cancer of the oral cavity and a recurrent undifferentiated nasopharyngeal 
carcinoma, and SD for 6 months or more in observed in 5 patients (21%). (ref AACR study). 
AZD6738 in combination with olaparib is considered to have a positive benefit-risk profile for all 
patients with advanced cancer. In Module 2 of Study D5330C00004, the clinical validity of this 
approach has been demonstrated with five patients experiencing confirmed RECIST partial 
responses: two confirmed responses in two patients with BRCA1 mutant triple-negative breast 
cancer, one confirmed response in a patient with BRCA2 mutant ER+ breast cancer, one confirmed 
response in a patient with BRCA1 mutated pancreatic cancer and one confirmed response in a 
patient with BRCA1 mutated pancreatic cancer. In addition, radiological response have been 
observed in sporadic tumors in combination with radiation (PATRIOT) and in combination with 
paclitaxel (Pre-VIKTORY). 
Potential Risks 
As of 1st June 2017, no AZD6738 monotherapy studies have been completed, and AZD6738 has 
been administered to approximately 49 subjects as monotherapy in Studies D5330C00001, 
D5330C00004 and D5330C00002). Thrombocytopenia and raised amylase have been reported 
when AZD6738 has been given as monotherapy and hematological toxicities (thrombocytopenia, 
neutropenia and anemia) when AZD6738 has been given in combination. Anemia, nausea and 
fatigue are very common across the program. Overall, such events were predictable from pre-clinical 
data and from what is known about the mechanism of action of AZD6738 and the combination drug 
olaparib. The observed toxicities in the clinical setting have been manageable with current practice. 
None of the events have been fatal. 
No reproductive toxicology nor teratogenic studies have been conducted with AZD6738 to date, and 
it is unknown whether the drug is excreted in human milk. Therefore, women of childbearing potential 
and men should agree to use adequate contraception prior to study entry and for the duration 
of study participation and women who are breast feeding are excluded from the study. Both women 
and men should be fully informed of the lack of reproductive toxicity testing, and women must have 
a negative pregnancy test prior to enrolment. 
A number of potential safety signals have been identified on the basis of general toxicology, 
safety pharmacology, genotoxicity and clinical studies, which were predictable from pre-clinical 
studies and the mode of action of AZD6738. Most of these signals have not been confirmed to be 
causally related to AZD6738; some are considered potential risks which are being monitored in 
ongoing clinical trials e.g. gastrointestinal toxicity, hepatic toxicity. The principal risk associated 
with the AZD6738 + olaparib 
combination is exacerbation of hematologic toxicity which is 
considered an Adverse Drug Reaction or identified risk for the AZD6738. In addition, some clinical 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 116 of 134
toxicities from AZD6738 overlap with those seen with olaparib use in humans e.g. anemia, 
neutropenia, leukopenia, thrombocytopenia of potential prolonged duration. While only a small 
number of patients have been exposed to the combination, a tolerable dose and schedule has 
been reached. Risk minimization and detailed toxicity management guidelines ae incorporated in 
the current protocol and the sponsor will continued to monitor the clinical and nonclinical data for 
emerging safety information. The risks are manageable within current clinical practice with the 
measures already in place and do not change the benefit / risk profile for AZD6738 in the ongoing 
and planned clinical studies. 
The safety profile of AZD6738 when combined with olaparib has been shown to be acceptable, and 
AZD6738 has shown activity in several tumor types in the clinical development program to date.   
Considering the 
measures taken to minimize risk to patients participating in the Phase I and II clinical studies, the 
identified and potential risks associated with AZD6738 in combination with olaparib are justified by 
the anticipated benefits that may be afforded to patients with advanced cancer. 
Please refer to the Investigator’s Brochure (IB) for additional information regarding AZD6738. 
a. Formulation
Laboratory code: AZD6738, AZ13386215 
CAS No.: 1352226-88-0 
Molecular formula: C20H24N6O2S 
Relative molecular mass: 412.51 
b. Dosage, Administration, and Storage
AZD6738 is a crystalline powder. The solubility of AZD6738 free base has been measured as
>100 mg/mL in Simulated Gastric Fluid (pH 1.6) and 0.76 mg/mL in Fasted State Simulated
Intestinal Fluid (pH 6.5). It has an estimated pKa of 3.7.
The drug product is presented as a range of oral, direct compression, coated tablets containing 20
to 100 mg of AZD6738.
AZD6738 coated tablets contain a blend of AZD6738, mannitol, microcrystalline cellulose, sodium
starch glycolate, magnesium stearate and silicon dioxide. The coating is Opadry® II white.
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be
replaced if all remaining tablets can be seen and counted. Should any patient enrolled on the
study miss a scheduled dose for whatever reason (e.g. forgetting to take the tablets or
vomiting) or need to modify the timing of a scheduled dose for any reason, the patient will
be allowed to take the scheduled dose up to a maximum of 2 hours after that scheduled dose
time. The dose should not be taken more than 2 hours in advance of the 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. Doses should not
be taken fewer than 10 hours apart
Storage
AZD6738 tablets should be stored below 30°C in induction sealed HDPE bottles until use.


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 117 of 134
The product should be stored in the pack provided and used according to the instructions on the label. 
c.
Dosage Modification
See Section 1.3.1c above for olaparib + AZD6738 combination dose modification guidelines. 
d. AZD6738 Warnings and Precautions
Possible drug interactions 
The potential effect of concomitant medication, herbal supplements and/or ingestion of foods that 
significantly modulate or induce CYP3A4 or Pgp activity are considered in the individual study protocol. 
AZD6738 has a low potential to induce CYP1A2, CYP2B6 and CYP3A4 mRNA in 
vitro. Evidence of induction will be monitored for in clinical studies via measurement of 4β- 
hydroxycholesterol. Guidance on concomitant use of medications that are metabolized by CYP3A4 
and have a narrow therapeutic index is provided in individual study protocol. 
AZD6738 is an inhibitor of human OATP1B1. Guidance on concomitant use of medications that are 
OATP1B1 substrates is provided in individual study protocol. 
Bone marrow and haematological effects 
Thrombocytopenia and anaemia have been reported during clinical use of AZD6738 as monotherapy, 
and thrombocytopenia, neutropenia and anaemia when AZD6738 is used in combination with 
myelosuppressive agents (see Section 5.4 for further details). The timing  of observed nadirs, 
especially of platelets when AZD6738 is used in combination with myelosuppressive drugs appears to 
vary by schedule as well as dose of AZD6738, and remains the subject of investigation in ongoing 
clinical studies and for at least for some schedules may occur later than might be expected from 
administration of the myelosuppressive agent alone. Patients starting on AZD6738 therapy should 
have adequate baseline bone marrow function, as defined in the individual study protocol, with full 
blood counts monitored closely through study treatment. Any occurrence of clinically significant 
changes in haematological parameters in a patient will result in interruption of treatment with AZD6738 
immediately until all abnormalities return to normal or to their baseline state. 
Gastrointestinal effects 
Patients will be excluded from clinical studies with AZD6738 if they have significant gastrointestinal 
symptoms or pathology. The occurrence of GI effects will be monitored for as part of the routine 
collection of adverse events and patients treated appropriately. 
Hepatobiliary effects 
Patients starting on AZD6738 therapy should have adequate baseline hepatobiliary function, as 
defined in the individual study protocol, with liver function tests monitored closely through study 
treatment. Any occurrence of clinically significant changes in ALT, AST, ALP, INR or other evidence 
of impairment to the synthesis function of the liver in a patient will result in interruption of treatment 
with AZD6738 immediately until all abnormalities return to normal or to their baseline state. 
Additionally, energy drinks, herbal remedies and food supplements will be restricted. 
Patients’ laboratory findings will be assessed against the FDA’s guidelines (Hy’s law) for drug 
induced liver injury (FDA Guideline 2007). 
Cardiovascular effects 
Patients will be excluded from clinical studies with AZD6738 if they have significant cardiovascular 
morbidity. Any occurrence of clinically significant changes in blood pressure will result in interruption 
of treatment with AZD6738 immediately until all abnormalities return to normal or to their baseline 


Page 118 of 134
OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
state. 
The results of pharmacokinetic-pharmacodynamic modelling conducted to ascertain the likelihood for 
effects on blood pressure in the clinic, indicate that clinically significant effects  of blood pressure are 
unlikely at those doses to be explored in this study (see Section 4.2.8.3 for further details). 
Reproductive precautions 
Conception must be avoided during exposure to AZD6738. Women of childbearing potential 
and men will be required to agree to use adequate contraception prior to study participation 
and for an appropriate period thereafter (as described in the clinical study protocol). 
Male subjects should abstain from sperm donation during exposure to AZD6738. 
Both men and women will be fully informed of the lack of reproductive toxicity testing, and 
women of child bearing potential must have a negative pregnancy test prior to enrolment. 
AstraZeneca should be notified of any pregnancy (including partners of male subjects) that 
occurs during participation in studies of AZD6738. AZD6738 should not be administered to 
pregnant or breast-feeding women. 
Photosensitising potential 
Non-clinical evaluation of AZD6738 for phototoxic potential produced positive in vitro but 
negative in vivo findings (4.3.8.1, 4.3.9.9). Two cases of sunburn in patients receiving 
AZD6738 have been reported. Phototoxicity is not designated an important risk, but 
AZD6738 is an inhibitor of DNA damage repair it is probably reasonable to advise patients to 
avoid excessive sun exposure while receiving AZD6738. 
e. Metabolism and Drug Interactions
Avoid concomitant medications, herbal supplements and/or ingestion of foods that strongly modulate 
CYP3A4 activity. 
If the Investigator feels that concomitant administration of medications, herbal supplements or foods that 
strongly modulate CYP3A4 activity is necessary based upon medical judgement, such products may be 
administered with caution following discussion between the Investigator and the Sponsor. 
Concomitant medication may be given as medically indicated with the following exceptions: 
• The principal enzyme for metabolizing AZD6738 is CYP3A4. Patients should avoid concomitant
drugs, herbal supplements and/or ingestion of foods known to modulate CYP3A4 activity from the
time they enter the screening period until 28 days after the last dose of study medication.
• AZD6738 is a potential inducer of CYP3A4. Caution should be applied with coadministration of drugs
that are either completely metabolized by CYP3A4 or that are CYP3A4 substrates and also have a
narrow therapeutic index.
• Strong CYP3A4 inducers for patients taking any of these drugs the required wash-out periods prior
to starting AZD6738 is 2 weeks, except for St. John’s Wort, which is 3 weeks.
• If the use of any strong inducers or inhibitors of CYP3A4 are considered necessary for the patient’s
safety and welfare, the Investigator must contact the trials office and a decision to allow the patient
to continue in the study will be made on a case-by-case basis. Following the DLT assessment period
and if the patient is continuing to receive AZD6738 on the basis of clinical benefit, as judged by the
Investigator, and in the absence of discontinuation criteria, if the Investigator feels that concomitant
administration of medications, herbal supplements or foods that significantly modulate CYP3A4
activity is necessary based upon medical judgement, such products may be administered with
caution following discussion between the Investigator and the AZ Study Physician.


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 119 of 134
AZD6738 is an inhibitor of OATP1B1. Co-administration of substrates of OATP1B1 may affect exposure 
to AZD6738; therefore, it is recommended that caution should be applied when such drugs are to be 
administered with AZD6738. 
The use of any natural/herbal products or other ‘folk remedies’ should be discouraged. 
AD-1.4 CONCOMITANT AND EXCLUDED THERAPIES 
AD-1.4.1 Concomitant Therapy 
Refer to the main body of the protocol (Concomitant and Excluded Therapies) for concomitant 
therapies allowed. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that were 
present at baseline, provided the Investigator does not feel that these are indicative of clinical disease 
progression during the study period. Full details of all of these treatments are recorded in the patient’s 
notes and appropriate section of the eCRF. Study treatment should be discontinued for a minimum 
of 3 days before the patient undergoes palliative radiation treatment. Study treatment should be 
restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
AD-1.4.2 Excluded Therapy 
The following restrictions apply during the entire duration of study treatment: 
•
No other investigational therapy should be given to patients.
•
No concomitant cancer treatment of any type (including chemotherapy, biologic therapy,
hormonal therapy, immunotherapy, herbal therapy, radiation therapy) should be administered at
any time while the patient is taking study treatment. If such treatment is required, then the patient
must first be withdrawn from  the trial. The patient can receive a  stable dose of corticosteroids
during the study if these were started at least 4 weeks prior to treatment, as per exclusion
criteria. Bisphosphonates and Denosumab for bone metastases are allowed if these were started
at least 4 weeks prior to treatment with study drug. Octreotide is allowed if dose is stable for >3
months with no worsening of carcinoid syndrome. Hormonal therapy with luteinizing hormone-
releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant
prostate cancer are permitted. Palliative radiotherapy is  allowed for pre- existing small
areas of painful metastases that cannot be managed with local or systemic analgesics if no
evidence of disease progression is present.
•
Live virus and bacterial vaccines should not be administered whilst the patient is receiving
study medication and during the 30 day follow up period. An increased risk of infection by the
administration of live virus  and bacterial vaccines has been observed with conventional
chemotherapy drugs and the effects with olaparib are unknown. 
•
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods
known to modulate CYP3A4 enzyme activity from the time they enter the screening period
until 30 days after the last dose of study medication. In vitro data have shown that the principal
enzyme responsible for the formation of the 3 main metabolites of olaparib is CYP3A4 and
consequently, this restriction is required to ensure patient safety.


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 120 of 134
AD-1.5 STUDY ASSESSMENTS 
Screening 
Day 1 of 
Cycle 1 
Day 
1 
of 
each 
cyclel 
Every 
8 
weeks 
End 
of 
Study 
30 Day 
Follow- 
up 
Long 
term 
Follow 
Up as 
per main 
protocol 
Visit window (days) 
28i 
+/- 3 
+/- 
+/- 3 
+/- 3 
+/- 7 
+/- 7 
Informed consent 
X 
Inclusion/Exclusion  Criteria 
X 
Pregnancy Testa 
X 
X 
Molecular Selection of Patients based on 
Archival Tumor Tissue (Paraffin 
X 
Medical History 
X 
Physical examination, weight and vital signs b 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
Laboratory tests (Clinical 
Chemistry/hematology/urinalysis/coagulation)c 
X 
Xh 
X 
Xd 
Concomitant  medications 
X 
X 
X 
X 
Dosing compliance 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Echocardiology/MUGA j
X 
ECG k 
X 
RECIST Assessments e 
X 
X 
X 
X 
Tumor Tissue (Paraffin embedded) (optional)f 
X 
X 
Plasma Sampleg 
X 
X 
X 
Anti-cancer therapy follow-up 
X 
a Two pregnancy tests on blood or urine samples will be performed for pre-menopausal women of childbearing potential 
one within 28 days prior to the start of study treatment and the other on Day 1 of the study prior to commencing treatment. 
Tests will be performed by the hospital’s local laboratory. If results are positive the patient is ineligible/must be discontinued 
from the study.  In the event of a suspected pregnancy during the study, the test should be repeated. 
b A complete physical examination will be performed at the following timepoints (within 24 hours of visit): Screening Visit, 
Day 1 Every Cycle, Discontinuation Visit, Follow-up Visit. Constitutional symptoms will be collected during screening and 
pre-dose at all other visits. Constitutional symptoms will include the presence/absence of pruritus, night sweats, recurrent 
fever ≥38.0ºC, fatigue, weakness and nocturia (a history of weight loss is to be collected at screening visit only). Vital signs 
(heart rate, systolic and diastolic blood pressure, oxygen saturation (pulse oximetry), respiration rate, weight, height (at 
screening) and temperature) 
c Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell volume [MCV], mean cell 
hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white cell 
count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or segmented 
neutrophil count and Band forms should be performed at each visit and when clinically indicated. If absolute differentials 
not available please provide % differentials. Coagulation [activated partial thromboplastin time {APTT} and international 
normalized ratio {INR}] will be performed at baseline and if clinically indicated unless the patient is receiving warfarin. 
Patients taking warfarin may participate in this study; however, it is recommended that prothrombin time (INR and APTT) 
be monitored carefully at least once per week for the first month, then monthly if the INR is stable. If APTT testing is not 
locally available, Partial Thromboplastin Time (PTT) testing may be done along with INR. Any clinically significant results on 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019  
Page 121 of 134
PTT will be confirmed with APTT. 
Bone marrow or blood cytogenetic analysis may be performed according to standard hematological practice for patients 
with prolonged hematological toxicities. 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 cytometry on the bone marrow aspirate, then attempts should be made to carry out the tests 
on a blood sample. If findings are consistent with MDS/AML, study drug should be discontinued and a full description of 
findings should be submitted with an SAE report by the investigator to AstraZeneca Patient Safety for documentation on 
the Patient Safety database.       Presence or absence of blood cytogenetic abnormalities and flow cytometry will be 
documented on the clinical database. 
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, fasting glucose, creatinine, total bilirubin, 
gamma glutamyltransferase [GGT], alkaline phosphatase [ALP], aspartate transaminase [AST],  alanine  transaminase [ALT], 
urea or blood urea nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]). 
Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. Microscopic analysis should be 
performed by the hospital’s local laboratory if required. 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged hematological toxicities. 
These tests will be performed by the hospital’s local laboratory. There is a 48 hr window for performance of lab testing for 
each visit. Additional analyses may be performed if clinically indicated. Any clinically significant abnormal laboratory values 
should be repeated as clinically indicated and recorded on the eCRF. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to G ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. 
d All patients with clinically significant abnormal laboratory results at treatment completion or study drug discontinuation 
visit are to be followed until the results return to normal (or patient’s baseline), or until a valid reason, other than a drug- 
related effect, is identified 
Patients with an unresolved AE or SAE event at treatment completion or study drug discontinuation will be contacted by the 
investigator or his or her designee to determine the status of the event until the event is resolved or stabilized, the patient 
is lost to follow up, or it has been determined that the study treatment or participation is not the cause of the event. 
e Patients will be evaluated until objective disease progression by RECIST 1.1. If a chest CT scan at baseline (screening 
CT will be the baseline scan) is not performed as part of the RECIST assessment, the patient should undergo a chest CT 
scan in order to document the lung parenchyma status at baseline. High resolution CT should be performed if clinically 
indicated by pulmonary symptoms any time during the study. For any new respiratory symptoms (cough, dyspnea, lower 
respiratory infection) not clearly explained by other factors (eg, dyspnea associated with substantial drop in hemoglobin), 
patients should have oxygen saturation measured. If <92%, the high resolution CT scan of the chest should be repeated 
and pulmonary function tests should be performed. 
Scans will be performed every 8 weeks. If partial response (PR) or complete response (CR) is documented, a confirmatory 
scan will be performed 4 weeks later for PR/CR (whichever occurs first). 
f Tumor sample at baseline if feasible (optional). The sample can be collected up to 4 weeks before the first dose. Therefore, 
any sample collected during this time period prior to study enrollment can be used as baseline sample. The tumor sample 
for use in genetic and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures 
at each institution. Additional tumor samples may also be collected and used fresh or frozen. 
Tumor sample at progression or discontinuation if feasible (optional). The sample can be collected at progression or 
discontinuation, or any time between progression and discontinuation from the study. The tumor sample for use in genetic 
and protein analyses should be formalin-fixed and embedded in paraffin according to standard procedures at each 
institution. Additional tumor samples may also be collected and used fresh or frozen 
g Plasma samples (optional) will be collected at baseline, on treatment and at progression/ discontinuation on study to 
isolate ctDNA to determine the mutational profile and changes thereof. The plasma sample at baseline can be collected up 
to 2 weeks before the first dose. Samples on study should be taken at the end of the first cycle (+/- 7 days), and at the end 
of the cycles 4, 6 and 10 (+/- 7 days) and at progression or discontinuation or any time between progression and 
discontinuation from the study 
Additional samples (optional) after cycle 10 and before progression can be collected, if the investigator deems a particular 
time point of interest. However, samples should not be collected more frequent than every 2 cycles. F describes the procedures 


OLAPCO APPENDIX D: AZD6738 plus olaparib 
Date 07 Feb 2019 
Page 122 of 134
for collection, processing, storage and shipment of plasma criteria. 
h. Results of all cycle 1 day 1 laboratory tests must re-meet eligibility criteria
i: Screening to be performed within 28 days unless otherwise specified 
j: Echocardiography will also be carried out if a patient develops signs and/or symptoms suggestive of a deterioration in left 
ventricular function or in case of the pre-specified ECG finding such as T-wave inversions. 
Echocardiography should include assessment of left ventricular end-systolic volume, left ventricular end-diastolic volume 
and LVEF. If an Echocardiography scan cannot be taken a MUGA scan to assess left ventricular ejection fraction (LVEF) 
will be conducted. The modality of the cardiac function assessments must be consistent within patient, ie, if echocardiogram is 
used for the screening assessment then echocardiogram should also be used for subsequent scans if required. The 
patient should also be examined using the same machine and operator throughout the study wherever possible. Other 
alternative methods of assessments could be used additionally if they are a part of the local standard of care, or if the 
investigator considers them necessary for the therapeutic management of the patient. Important cardiac symptoms should be 
reported as AEs/SAEs and should be carefully evaluated in regard to developing of acute or worsening of chronic cardiac 
failure, especially in anthracycline treated patients. Congestive cardiac failure should be treated and followed according to 
standard medical practice. 
k: Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10 minutes. All ECGs 
should be recorded with the patient in the same physical position. For each time point 3 ECG recordings should be taken 
one after another. A standardized ECG machine should be used and the patient should be examined using the same 
machine throughout the study. 
If an abnormal ECG finding at baseline is considered by the investigator to be clinically significant, it should be reported as a 
concurrent condition. 
l: Continuous use of Olaparib is suitable during this window 


OLAPCO APPENDIX E: AZD1775 plus olaparib 
Date 07 Feb 2019 
Page 123 of 134
APPENDIX E: AZD1775 plus olaparib in patients with either TP53 or KRAS mutations or 
mutations in both, TP53 and KRAS 
This page is intentionally left blank. 


OLAPCO APPENDIX F 
Date 07 Feb 2019 
Page 124 of 134
APPENDIX F: Collection of plasma, preparation and shipment of ctDNA samples 
Plasma should be collected in two 10 mL purple-top EDTA-containing vacutainer tubes and 
gently turned end over end 3-4 times upon collection to dissolve the EDTA and prevent 
coagulation.  Tubes can then be kept at room temperature, and should be centrifuged at 1000 x 
g for 10 minutes in a clinical centrifuge within 4 hours of collection (sooner is better). Tubes 
should be carefully balanced in the centrifuge to avoid vibrations which might disrupt WBCs. The 
centrifuge should be stopped in "brake off" mode. 
Plasma should be dispensed into cryovials in 1mL aliquots, and frozen at -80oC. Care should 
be taken to avoid the buffy coat by not pipetting the last 5mm of plasma above the buffy coat 
layer. Once the plasma is frozen, it should not be thawed until it is ready to be processed for 
sequencing.  Samples should be shipped to the following laboratory on dry ice overnight: 
As plasma samples are analyzed for mutations in ctDNA in a retrospective manner, samples 
should be stored at the other sites outside Yale and shipped in batches at a later time to be 
agreed with the analyzing laboratory. 
Samples from participating sites outside of Yale should be shipped to the following laboratory on 
dry ice overnight: 
Attn: Azeet Narayan 
Laboratory of Abhijit Patel 
Department of Therapeutic Radiology 
Yale School of Medicine 
15 York Street 
Room HRT 213C 
New Haven, CT 06510 


Page 125 of 134
OLAPCO APPENDIX G 
Date 07 Feb 2019 
Appendix G: Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Briefly, Hy’s Law cases have the following three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo 
2. Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN,
one or more also show elevation of serum TBL to >2xULN, without initial findings of cholestasis 
(elevated serum ALP) 
3. No other reason can be found to explain the combination of increased AT and TBL, such as
viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing 
the observed injury 
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered 
highly predictive that the drug has the potential to cause severe drug induced liver injury (DILI) 
when given to a larger population. 
The following actions are required in cases of combined increase of aminotransferase and total 
bilirubin: 
1. Confirmation
In general, an increase of serum AST/A:T to >3xULN should be followed by repeat testing within 
48 to 72 hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) to confirm the 
abnormalities and to determine if they are increasing or decreasing. There also should be inquiry 
made about symptoms. Serum AT may rise and fall quite rapidly, and waiting a week or two 
before obtaining confirmation of elevations may lead to a false conclusion that the initially 
observed abnormality was spurious. Of greater concern, delay in retesting may allow progression 
to severe worsening if the initial abnormality was the herald of a severe reaction to follow. The 
need for prompt repeat testing is especially great if AST/ALT is much greater than 3xULN and/or 
TBL is greater than 2xULN. For outpatient trials, or trials in which subjects are far away from the 
trial site, it may be difficult for the subjects to return to the trial site promptly. In this case, the 
subjects should be retested locally, but normal laboratory ranges should be recorded, results 
should be made available to trial investigators immediately, and the data should be included in 
the case reports. If symptoms persist or repeat testing shows AST/ALT >3xULN for subjects with 
normal baseline measures or 2-fold increases above baseline values for subjects with elevated 
values before drug exposure, it is appropriate to initiate close observation to determine whether 
the abnormalities are improving or worsening. If close monitoring is not possible, the drug should 
be discontinued. 
2. Close Observation
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval. A 
threshold of aminotransferase levels greater than 3xULN seems reasonable, as lesser elevations 
are common and nonspecific. If additional testing, beyond that specified in the trial protocol, is 
carried out, it is important that the subject’s information be added to the case report forms and 
database. 


OLAPCO APPENDIX G 
Date 07 Feb 2019 
Page 126 of 134
Close observation includes: 
• Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been 
discontinued and the subject is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases.
• Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents.
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin).
• Considering gastroenterology or hepatology consultations.
3. Decision to Stop Drug Administration
It has been observed that de-challenge (stopping drug administration) does not always result in 
immediate improvement in abnormal lab values. Abnormal test values and symptoms may 
progress for several days or even weeks after discontinuation of the drug that caused the 
abnormality. For example, rising TBL usually follows serum AT increases by a few days to weeks. 
The primary goal of close observation is to determine as quickly as possible whether observed 
abnormal findings are transient and will resolve spontaneously or will progress. For most DILI, 
no specific antidotes are available (except N-acetylcysteine for acute acetaminophen overdose 
if given promptly, and, possibly, intravenous carnitine for valproic acid hepatotoxicity). 
Promptly stopping the offending drug usually is the only potentially effective therapy. 
Because transient fluctuations of ALT or AST are common, and progression to severe DILI or 
acute liver failure is uncommon, automatic discontinuation of trial drug upon finding a greater 
than 3xULN elevation of ALT or AST may be unnecessary. For most people, the liver appears 
capable of adapting to injury by foreign chemical substances, which may render a person tolerant 
to the drug despite continued exposure. Stopping a drug at the first hint of mild injury does not 
permit learning whether adaptation will occur, as it does for drugs such as tacrine, which cause 
liver injury but do not cause severe DILI. On the other hand, continuing drug appears 
unacceptably dangerous if there is marked serum aminotransferase elevation or evidence of 
functional impairment, as indicated by rising bilirubin or INR, which represent substantial liver 
injury. Although there is no published consensus on exactly when to stop a drug in the face of 
laboratory abnormalities and the decision will be affected by information on related drugs, the 
accumulating clinical experience, the clinical status of the patient, and many other factors, the 
following can be considered a basic guide. Discontinuation of treatment should be considered if: 
• ALT or AST >8xULN
• ALT or AST >5xULN for more than 2 weeks
• ALT or AST >3xULN and (TBL >2xULN or INR >1.5)
• ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
It should be noted that although these guidelines have not been evaluated systematically in 
a prospective fashion, they represent an approach that is similar to current practice. 


OLAPCO APPENDIX G 
Date 07 Feb 2019 
Page 127 of 134
4. Evaluating Data for Alternative Causes
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes: 
• Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from acute viral
hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to be insidious, but it 
sometimes can resemble acute DILI. The presence of acute viral hepatitis A, B, and C should be 
evaluated by serological markers. Viral hepatitis D (requires concomitant hepatitis B infection) 
and E are relatively rare in the United States. Hepatitis E is more common in developing 
countries, including Southeast Asia, and should be considered in recent travelers to those 
countries and in patients in trials conducted in those countries. Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, 
varicella, and parvovirus, although these infections are seen more typically in immuno- 
suppressed individuals. Adolescent and young adult patients with possible DILI should be tested 
for Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease. 
• Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a history
of binging exposure to alcohol preceding episodes, and it has some characteristic features, such 
as associated fever, leukocytosis, right upper quadrant pain and tenderness, hepatomegaly, and 
AST >ALT, that may help distinguish it from other causes of liver injury. Other features of the 
physical examination may include the presence of stigmata of cirrhosis, such as spider nevi, 
palmar erythema, estrogenic changes in males, and Dupuytren’s contractures. Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and laboratory 
testing, including serologic testing (e.g., antinuclear or other antibodies). 
• Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or intrahepatic
lesions, more often causes cholestatic injury initially and should be investigated with gall bladder 
and ductal imaging studies, especially if ALP is increased. Malignant interruption of the biliary 
tract also should be considered. 
• NASH. NASH may be seen in obese, hyperlipoproteinemic, and/or diabetic patients and may
be associated with fluctuating aminotransferase levels, and hepatic and sometimes splenic 
enlargement. It is sometimes associated with cirrhosis and portal hypertension. 
• Cardiovascular causes. Cardiovascular disease, especially right heart failure and hypotension
or any cause of impaired oxygenation of the liver, may cause acute centrilobular hypoxic cell 
necrosis (ischemic hepatitis) with rapid and sometimes spectacular increases of serum AT (e.g., 
AT >10,000 U/L). Cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure, should be assessed by physical examination and history. 
• Concomitant treatments. It is critical to discover concomitant treatments, including exposure to
nonprescription and dietary supplement products that might be responsible for injury. Many 
people take multiple drugs, perhaps less often in controlled clinical trials because of exclusion 
criteria, but subjects may not report taking disallowed drugs or other agents. The possible 
exposure to potentially toxic herbal or dietary supplement mixtures (sometimes of unknown 
composition), nonprescription medications such as acetaminophen, or to occupational chemical 
agents may not be volunteered unless subjects are specifically questioned. 


OLAPCO APPENDIX G 
Date 07 Feb 2019  
Page 128 of 134
5. Follow-Up to Resolution
All trial subjects showing possible DILI should be followed until all abnormalities return to normal 
or to the baseline state. DILI may develop or progress even after the causative drug has been 
stopped. Results should be recorded on the case report form and in the database. Note that 
longer follow-up can sometimes reveal an off-drug repetition of what had appeared to be DILI, 
indicating that liver injury was related to underlying liver disease. 
6. Re-challenge
Whether or not to re-challenge a subject who showed mild DILI is a difficult decision. Re- 
exposure may initiate a sometimes explosive and more severe reaction, as was observed with 
halothane several decades ago. Some cases of DILI show indicators of immunological reaction 
such as eosinophilia, rash, fever, or other symptoms or findings, and it is possible that such 
cases are more prone to recur with re-exposure. Re-challenge may not be considered negative 
unless the subject is exposed to and tolerates the same dose and treatment duration that 
preceded the original reaction. A negative re-challenge does not necessarily allow a conclusion 
that the drug did not cause the injury. Most people can adapt to xenobiotic substances, including 
new drugs, and develop tolerance for them. This has been observed even for drugs that can 
cause severe injury, such as isoniazid. The large majority of people showing hepatocellular injury 
while taking isoniazid recover fully or recover while continuing to take the drug, and some, but 
not all, can resume or continue taking the drug without further adverse consequence. If such 
tolerance has developed, the use of re-challenge to verify drug causation would give a false 
negative result. 
Generally, re-challenge of subjects with significant AT elevations (>5xULN) should not be 
attempted. If such subjects are re-challenged, they should be followed closely. Re-challenge can 
be considered if the subject has shown important benefit from the drug and other options are not 
available or if substantial accumulated data with the test drug do not show a potential for severe 
injury. The subject should be made aware of the potential risk, and consent to the re-challenge, 
and the PI consulted. 


Page 129 of 134
OLAPCO APPENDIX H 
Date 07 Feb 2019 
Appendix H: Acknowledgment of the Investigators 
PROTOCOL TITLE: A Phase II Study of the PARP Inhibitor Olaparib (AZD2281) Alone and in 
Combination with AZD1775, AZD5363, and AZD6738 in Advanced Solid Tumors- OLAPCO 
(OLAParib COmbinations) 
Version Date: 
Acknowledgement of the Investigator: 
1.) I have read this protocol and agree that the study is ethical 
2.) I agree to conduct the study as outlined and in accordance with all 
applicable regulations and guidelines 
3.) I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol 
Signature of Investigator: 
Date: 
Name of Investigator (Printed or Typed) 


Page 130 of 134
OLAPCO 
Date 07 Feb 2019  
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