Conditions: Metastatic Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Stage IV Pancreatic Cancer AJCC v6 and v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This phase II trial studies how well olaparib works in treating patients with stage IV pancreatic cancer. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the efficacy of olaparib monotherapy in stage IV pancreatic ductal adenocarcinoma (PDAC) with breast cancer, early onset (BRCA)ness.

SECONDARY OBJECTIVES:

I. To further determine the efficacy of olaparib in the study population.

SAFETY OBJECTIVES:

I. To assess the safety and tolerability of olaparib.

EXPLORATORY OBJECTIVES:

I. To identify tissue based biomarkers of defective homologous recombination repair (HRD).

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 8 weeks thereafter.

Arms:
arm 1: Patients receive olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 0 (73) 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0503 
Protocol Title 
OLAPARIB FOR BRCANESS PHENOTYPE IN PANCREATIC CANCER: 
PHASE II STUDY 
Phase 
II 
Protocol Version 
4 
Version Date 
10/10/2018 
Protocol PI 
Milind Javle, MD 
Department 
GI Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
129,049 
Proprietary of MD Anderson Cancer Center


1(73) 
 
 
Clinical Study Protocol 2015-0503 
 
Drug Substance: 
Olaparib 
 
Study Code: 
ISS22810097 
 
Version Number: 
4 
 
Date: 
October 10, 2018 
 
 
 
 
OLAPARIB FOR BRCANESS PHENOTYPE IN PANCREATIC 
CANCER: PHASE II STUDY 
 
 
 
Principal Investigator: 
 
Milind Javle MD 
 
 
 
 
 
Department of GI Medical Oncology 
 
 
 
 
 
UT MD Anderson Cancer Center 
 
 
 
 
 
1515 Holcombe Blvd. – Unit 426 
 
 
 
 
 
Houston, TX  77030 
 
 
 
 
 
Phone:  713-792-2828 
 
 
 
 
 
Email:  mjavle@mdanderson.org 
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 7 
1. 
INTRODUCTION ................................................................................................. 12 
1.1 
Background and rationale for conducting this study ............................................. 12 
1.1.1 
Advanced Pancreas Cancer .................................................................................... 12 
1.1.2 
Chemotherapy for advanced pancreas cancer ........................................................ 12 
1.1.3 
Pancreatic Cancer with Family History of Cancer or Germline BRCA 
Mutation ................................................................................................................. 13 
1.1.4 
BRCA and PARP inhibition .................................................................................. 13 
1.1.5 
PARPi Beyond Germline BRCA Mutations ........................................................... 14 
1.1.6 
PDAC with ‘BRCA-ness’ Phenotype .................................................................... 14 
1.1.7 
Exploiting HR Deficiency in PDAC ...................................................................... 16 
1.1.8 
Pre-clinical experience ........................................................................................... 16 
1.1.9 
Toxicology and safety pharmacology summary .................................................... 16 
1.1.10 
Clinical experience with olaparib .......................................................................... 17 
1.1.10.1 Olaparib monotherapy studies in pancreas cancer patients ................................... 17 
1.2 
Research hypothesis ............................................................................................... 17 
1.3 
Rationale for study design and doses ..................................................................... 18 
1.4 
Benefit/risk and ethical assessment ....................................................................... 18 
1.4.1 
Important potential risks ........................................................................................ 19 
1.4.1.1 
Myelodysplastic syndrome/acute myeloid leukaemia ........................................... 19 
1.4.1.2 
Pneumonitis ............................................................................................................ 19 
1.4.1.3 
New Primary Malignancies .................................................................................... 20 
1.4.2 
Potential benefit ..................................................................................................... 21 
1.5 
Study design ........................................................................................................... 21 
2. 
STUDY OBJECTIVES .......................................................................................... 23 
3. 
PATIENT SELECTION, ENROLLMENT, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL .................................................... 23 
3.1 
Inclusion criteria .................................................................................................... 23 
3.2 
Exclusion Criteria .................................................................................................. 25 
3.3 
Patient Enrollment Allocation ................................................................................ 26 
3.4 
Procedures for handling incorrectly enrolled patients ........................................... 26 
3.5 
Restrictions ............................................................................................................ 26 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
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3.5.1 
Contraception ......................................................................................................... 26 
3.5.2 
Olaparib and CYP3A4/5 ........................................................................................ 26 
3.6 
Discontinuation of investigational product ............................................................ 27 
3.6.1 
Procedures for discontinuation of a patient from investigational product ............. 27 
3.7 
Criteria for withdrawal ........................................................................................... 28 
3.7.1 
Screen failures ........................................................................................................ 29 
3.7.2 
Withdrawal of the informed consent ...................................................................... 29 
3.8 
Discontinuation of the study .................................................................................. 29 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 30 
4.1 
Enrollment/screening period .................................................................................. 35 
4.1.1 
Pre-screening period .............................................................................................. 35 
4.1.2 
Screening period .................................................................................................... 35 
4.2 
Treatment period .................................................................................................... 36 
4.3 
Follow-up period .................................................................................................... 37 
4.3.1 
Treatment discontinuation visit due to objective radiological disease 
progression ............................................................................................................. 37 
4.3.2 
Treatment discontinuation visit due to any other discontinuation criteria ............. 37 
4.3.3 
Survival .................................................................................................................. 38 
4.3.4 
Subsequent Treatment ............................................................................................ 38 
4.4 
Patient management post final analysis ................................................................. 38 
5. 
STUDY ASSESSMENTS ..................................................................................... 39 
5.1 
Efficacy assessments .............................................................................................. 39 
5.1.1 
CT and MRI scans tumor assessments (RECIST 1.1) ........................................... 39 
5.1.2 
Tumor Evaluation .................................................................................................. 39 
5.2 
Safety assessments ................................................................................................. 40 
5.2.1 
Laboratory safety assessments ............................................................................... 40 
5.2.2 
Physical examination ............................................................................................. 42 
5.2.3 
ECOG ..................................................................................................................... 42 
5.2.4 
ECG ........................................................................................................................ 42 
5.2.4.1 
Resting 12-lead ECG ............................................................................................. 42 
5.2.5 
Vital signs .............................................................................................................. 43 
5.2.5.1 
Pulse and blood pressure ........................................................................................ 43 
5.2.5.2 
Body temperature ................................................................................................... 43 
5.2.6 
Other safety assessments ........................................................................................ 43 
5.2.6.1 
Serum or urine pregnancy test ............................................................................... 43 
5.2.7 
Bone marrow or blood cytogenetic samples .......................................................... 43 
5.3 
Biomarkers ............................................................................................................. 43 
5.3.1 
Biomarker samples ................................................................................................. 44 
5.3.1.1 
Guidance for BRCA testing of patients with unknown BRCA status. .................... 44 
5.3.1.2 
Collection of blood sample for exploratory assay(s) ............................................. 44 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
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5.3.2 
Exploratory Biomarker Research on Archival Tumor Samples (Paraffin 
block or tissue cytology slides) (Requested, if available) ...................................... 45 
5.3.3 
Exploratory Blood samples for biomarker analysis (Mandatory) .......................... 45 
5.4 
Biological sampling procedures ............................................................................. 45 
5.4.1 
Volume of blood .................................................................................................... 45 
5.4.2 
Handling, storage and destruction of biological samples ...................................... 46 
5.4.3 
Labelling and shipment of biohazard samples ....................................................... 47 
5.4.4 
Chain of custody of biological samples ................................................................. 47 
5.4.5 
Withdrawal of informed consent for donated biological samples ......................... 47 
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 48 
6.1 
Definition of adverse events .................................................................................. 48 
6.2 
Recording of adverse events .................................................................................. 48 
6.2.1 
Time period for collection of adverse events ......................................................... 48 
6.2.2 
Follow-up of unresolved adverse events ................................................................ 49 
6.2.3 
Variables ................................................................................................................ 49 
6.2.4 
Causality collection ................................................................................................ 50 
6.2.5 
Adverse events based on signs and symptoms ...................................................... 51 
6.2.6 
Adverse events based on examinations and tests ................................................... 51 
6.2.7 
Hy’s Law ................................................................................................................ 51 
6.2.8 
Disease progression ............................................................................................... 51 
6.3 
Serious Adverse Event Reporting (SAE) ............................................................... 52 
6.4 
Overdose ................................................................................................................ 54 
6.5 
Pregnancy ............................................................................................................... 54 
6.5.1 
Maternal exposure .................................................................................................. 54 
6.5.2 
Paternal exposure ................................................................................................... 55 
6.6 
Management of toxicity of olaparib ....................................................................... 55 
6.6.1 
Management of haematological toxicity olaparib .................................................. 56 
6.6.1.1 
Management of anaemia ........................................................................................ 56 
6.6.1.2 
Management of neutropenia and leukopenia ......................................................... 56 
6.6.1.3 
Management of thrombocytopenia ........................................................................ 57 
6.6.2 
Management of non-haematological toxicity Olaparib ......................................... 57 
6.6.2.1 
Management of new or worsening pulmonary symptoms ..................................... 57 
6.6.2.2 
Management of nausea and vomiting .................................................................... 58 
6.6.2.3 
Interruptions for intercurrent non-toxicity related events ...................................... 58 
6.7 
Study governance and oversight ............................................................................ 58 
6.7.1 
Data Monitoring ..................................................................................................... 58 
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 59 
7.1 
Identity of investigational product(s) ..................................................................... 59 
7.2 
Dose and treatment regimens ................................................................................. 59 
7.3 
Labelling ................................................................................................................ 60 
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7.4 
Storage ................................................................................................................... 60 
7.5 
Compliance ............................................................................................................ 60 
7.6 
Accountability ........................................................................................................ 60 
7.7 
Concomitant and other treatments ......................................................................... 61 
7.7.1 
Medications that may NOT be administered ......................................................... 61 
7.7.2 
CYP3A4/5 restrictions ........................................................................................... 61 
7.7.3 
Other concomitant treatment .................................................................................. 62 
7.7.4 
Anti-emetics/ Anti-diarrheal .................................................................................. 63 
7.7.5 
Anticoagulant Therapy ........................................................................................... 63 
7.7.6 
Administration of other anti-cancer agents ............................................................ 63 
7.7.7 
Subsequent therapies for cancer ............................................................................. 63 
8.
STATISTICAL ANALYSIS AND SAMPLE SIZE DETERMINATION ........... 63 
8.1 
Statistical considerations ........................................................................................ 63 
9.
STUDY AND DATA MANAGEMENT ............................................................... 66 
9.1 
Training of study site personnel ............................................................................. 66 
9.2 
Monitoring of the study ......................................................................................... 66 
9.2.1 
Study agreements ................................................................................................... 67 
9.2.2 
Archiving of study documents ............................................................................... 67 
9.3 
Study timetable and end of study ........................................................................... 67 
9.4 
Data management ................................................................................................... 67 
10.
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 68 
10.1 
Ethical conduct of the study ................................................................................... 68 
10.2 
Patient data protection ............................................................................................ 68 
10.3 
Ethics and regulatory review ................................................................................. 68 
10.4 
Informed consent ................................................................................................... 69 
10.5 
Changes to the protocol and informed consent form ............................................. 70 
10.6 
Audits and inspections ........................................................................................... 70 
11.
LIST OF REFERENCES ....................................................................................... 71 
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Study Code:  ISS22810097 
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LIST OF TABLES 
Table 1                 Effect of family history on OS associated with platinum-based therapy..18 
Table 2 
Study Schedule – Screening, On Study Treatment, Discontinuation 
and Follow-up ........................................................................................... 31 
Table 3 
Laboratory Safety Variables ..................................................................... 41 
Table 4 
ECOG Performance Status a ..................................................................... 42 
Table 5  
Samples for Biomarker Research ............................................................. 44 
Table 6  
Volume of blood to be drawn from each patient ...................................... 46 
Table 7  
Management of Haematological Toxicity from Olaparib ........................ 56 
 
 
 
 
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Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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Abbreviation or 
special term 
Explanation 
AE 
Adverse event (see definition in Section 6.1) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukaemia 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
Baseline 
Refers to the most recent assessment of any variable prior to dosing with 
study treatment 
bid 
Bis in die (twice daily) 
BoR 
Best Overall RECIST Response 
BP 
Blood pressure 
gBRCA 
germline Breast Cancer susceptibility gene 
BRCA mutation or 
BRCAm 
BRCAness 
Breast Cancer susceptibility gene mutation (see gBRCA mutation or 
gBRCAm) 
Clinical features similar to BRCA mutation 
BUN 
Blood urea nitrogen 
CHO 
Chinese hamster ovary 
CI 
Confidence Interval  
CR 
Complete Response 
CRF 
Case Report Form (electronic/paper) 
CRO 
Clinical Research Organisation 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DCO 
Data Cut Off 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid  
DSB 
Double strand break 
ECG 
Electrocardiogram 
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
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EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
E-code
Enrollment code (allocated by IVRS/IWRS) 
ECOG
Eastern Cooperative Oncology Group: A performance status using scales 
and criteria to assess how a patient’s disease is progressing 
eCRF 
Electronic Case Report form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FSH 
GA 
Follicle stimulating hormone 
Genetic Aberration 
gBRCA mutation or 
gBRCAm 
The term "gBRCA mutation" is used to refer to a germline BRCA1 or 
BRCA2 mutation classified as "deleterious" or "suspected deleterious" in 
accordance with the American College of Medical Genetics and Genomics 
recommendations for standards for interpretation and reporting of sequence 
variants  
gBRCA wt 
gBRCA wildtype (patients without evidence of BRCA1 or BRCA2 
deleterious or suspected deleterious mutations) 
GCP 
Good Clinical Practice 
G-CSF
Granulocyte colony-stimulating factor 
GGT
Gamma glutamyl transferase 
GMP
Good Manufacturing Practice 
Hb
Haemoglobin  
HDPE
High-density polyethylene 
HIV
Human Immunodeficiency Virus 
HR
Hazard Ratio 
HRD
Homologous recombination repair deficiencies 
HRQoL
Health-related Quality of Life 
IATA
International Air Transport Association  
IB
Investigator’s brochure 
ICH
International Conference on Harmonisation 
International 
Co-ordinating 
investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
IDMC   
Independent Data Monitoring Committee 
INR 
International Normalised Ratio 
IPCW 
Inverse Probability of Censoring Weighting 
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IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KM 
Kaplan Meier 
LDH 
Lactic dehydrogenase 
LH 
Luteinizing hormone 
LIMS 
Laboratory Information Management System 
m 
Metre 
MCH 
Mean cell haemoglobin 
MCHC 
Mean cell haemoglobin concentration 
MCV 
Mean cell volume 
MDS 
Myelodysplastic syndrome 
mg 
Milligram 
MRI 
Magnetic resonance imaging 
nab 
nanoparticle albumen bound 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NTL 
Non-target lesions 
OAE 
Other Significant Adverse Event  
ORR 
Objective response rates 
OS 
Overall survival 
PARP 
PARPi 
Polyadenosine 5’diphosphoribose [poly (ADP ribose)] polymerisation 
PARP inhibitors 
PD 
PDAC 
Progressive disease 
Pancreatic ductal adenocarcinoma 
PFS 
Progression Free Survival 
p.o.
Per os (by mouth, orally) 
PR
Partial response 
RECIST
Response Evaluation Criteria In Solid Tumors.  This study will use 
RECIST version 1.1 
RPSFT 
Rank Preserving Structural Failure Time 
SAE 
Serious adverse event (see definition in Section 6.3). 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
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SSB 
Single strand break 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
Study treatment 
Olaparib or control arm chemotherapy 
tBRCA mutation or 
tBRCAm 
The term "tBRCA mutation" is used to refer to a somatic tumor BRCA1 or 
BRCA2 mutation classified as "deleterious" or "suspected deleterious" in 
accordance with the American College of Medical Genetics and Genomics 
recommendations for standards for interpretation and reporting of sequence 
variants  
TL 
Target lesions 
US 
United States 
WBC 
White blood cells 
WBDC 
Web Based Data Capture 
wt 
Wildtype (patients without evidence of BRCA1 or BRCA2 deleterious or 
suspected deleterious mutations) 
 
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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
1.1.1 
Advanced Pancreas Cancer 
Pancreas cancer is a life-threatening disease and is the fourth leading cause of cancer death in 
the western world.  In 2013, it is estimated that there were 45,220 newly diagnosed pancreas 
cancer cases in the US, and approximately 38,460 people deaths from pancreas cancer.  
Worldwide, it was estimated that 266,000 people died of pancreas cancer in 2008.1 Pancreatic 
adenocarcinoma (PDAC) has a 5-year survival less than 5%. Only 10-20% of patients have 
surgically resectable disease at time of diagnosis, and even then approximately 80-85% die 
within 5 years.2 The poor prognosis of PDAC is a function of late presentation of the disease 
typically at an inoperable/ locally advanced or metastatic stage.  
The development of active and safe regimens for the treatment of advanced pancreatic cancer 
is an important unmet need.  
1.1.2 
Chemotherapy for advanced pancreas cancer  
Recently, a large phase III study demonstrated that the addition of nanoparticle albumin-
bound (nab)-paclitaxel to gemcitabine significantly improved overall survival in treatment-
naive patients with metastatic pancreatic cancer, compared with gemcitabine alone.3 
Specifically, in the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) of 
861 patients, overall survival was about 2 months better with the chemotherapy combination 
than with gemcitabine alone (median, 8.5 vs. 6.7 months; hazard ratio [HR], 0.72; P = 
.000015). In a prior phase I/II study with this combination (n=67), the PR rate was 42% and 
disease control rate (defined as PR plus SD >16 weeks) was 64%. The median OS for all cases 
was 10.2 months and PFS 7.1 months.4  Conroy et al, assigned 342 patients with an ECOG PS 
of 0 or 1 to receive FOLFIRINOX or gemcitabine.5 Six months of chemotherapy were 
recommended in both groups in patients who had a response. The primary end point was 
overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as 
compared with 6.8 months in the gemcitabine group (HR for death, 0.57; P<0.001). Median 
progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the 
gemcitabine group (HR for disease progression, 0.47; P<0.001). The objective response rate 
was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). 
More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group 
had febrile neutropenia. The treatment of metastatic pancreas cancer is associated with modest 
survival results, even with the most “active” regimens such as FOLFIRINOX or gemcitabine 
+ nab paclitaxel.3,5   
Unfortunately, these two commonly prescribed regimens also have dose-limiting toxicities. 
The neurotoxicity and hematologic toxicities of both FOLFIRINOX and gemcitabine + nab 
paclitaxel and the gastrointestinal toxicities of the former are a significant limitation for this 
frail population. Second line regimens have a limited impact in this disease, with survival 
benefit limited to few months only.6 FOLFOX, gemcitabine, capecitabine or XELOX are the 
commonly used regimens in this setting.7,8 Rahma et al, evaluated 44 clinical trials of second 
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line therapy for pancreatic cancer which enrolled an aggregate total of 1503 patients and 
showed that second-line chemotherapy was superior to best supportive care in this setting.8 
1.1.3 
Pancreatic Cancer with Family History of Cancer or Germline BRCA 
Mutation  
About 5% of PDAC occurs in cases with germline BRCA mutation. Conversely, PDAC is 
notably over-represented in families with a clustering of breast and ovarian cancers 9-12. 
Recently, Princess Margaret Hospital investigators demonstrated pathogenic germline BRCA1 
and BRCA2 mutations in 13/271 (4.8%) consecutive, ethnically diverse, incident PDAC 
patients at over about 18 months. BRCA1 mutations accounted for 1.1% (3/271) and BRCA2 
mutations accounted for 3.7% (10/271) of the cases.13 However, familial clustering occurs in 
10% of PDAC cases often with an autosomal dominant pattern of genetic transmission, 
suggestive of an inherited cancer syndrome.14 It seems plausible that there are other genetic 
aberrations (GAs) other than BRCA in these cases with familial clustering. We hypothesize 
that the latter cases also share the clinical phenotype of BRCA mutation. 
BRCA1 and BRCA2 deficient tumors, particularly in BRCA1/BRCA2 germline mutation 
carriers, have a distinct clinical outcome and responsiveness to cisplatin-based therapy.  The 
largest study to date demonstrated superior overall survival data of BRCA-associated 
pancreatic cancer as compared with historic controls.15,16 Median all–stage OS for all stages of 
pancreatic cancer (n=58) was 14 months (95% CI 10-23 months). Median OS for patients with 
stage 1-2 disease has not been reached at 60 months. Median OS for stage 3-4 was 12 months 
(95% CI 6-15). Superior OS was observed for patients with stage III and IV BRCA- associated 
PDAC treated with platinum versus those treated with non-platinum chemotherapies (22 vs 9 
months; p=0.039). 
1.1.4 
BRCA and PARP inhibition 
The BRCA1 and BRCA2 proteins are involved in the regulation of cell cycle checkpoints in 
response to DNA damage, including the repair of DNA double-strand breaks via homologous 
recombination (HR).17 BRCA1/2-deficient cells with HR deficiency (HRD) accumulate DNA 
double-strand breaks, resulting in genomic instability and increased predisposition to malignant 
transformation and progression.18 Somatic, biallelic inactivation of the BRCA1/2 genes confers 
sensitivity to inhibition of poly(ADP-ribose)-polymerase (PARP),  an enzyme involved in base 
excision repair 19 as the loss of both HR and PARP1 pathways leads to synthetic lethality during 
DNA replication. PARP inhibitors (PARPi) increase the sensitivity to chemoradiotherapy 
treatment in BRCA-2-deficient pancreatic cancer cells.20  BRCA-defective cells are also more 
sensitive to platinums, anthracyclines and radiation, as these treatments are selectively lethal in 
HR-defective cells.21-23 
To date, the published clinical data supporting the use of individualized therapeutics for BRCA 
associated PDAC is limited. Fogelman et al, described a patient with BRCA2 associated PDAC 
who attained a complete pathologic response after treatment with a PARP inhibitor (PARPi) in 
combination with gemcitabine.24  In a retrospective study of 15 subjects with BRCA1/2 associated 
PDAC, of four patients treated with a PARPi alone or in combination with chemotherapy, three 
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demonstrated an initial radiographic partial response whereas one had stable disease for 6 months. 
Furthermore, five of the six patients treated with first line platinum-based chemotherapy also had 
a radiographic partial response.25 Single agent PARPi therapy has demonstrated clinical responses 
in BRCA associated PC and additional clinical trials evaluating PARPi in combination with 
platinum based chemotherapy are currently underway.26 Study D0810C00042 is the largest study 
of PARPi in advanced PDAC. A single-arm phase II study of olaparib (capsules) 400mg po bid 
was conducted in patients with germline BRCA mutant malignancies across multiple tumor types. 
Twenty-three patients with germline BRCA mutation-associated advanced pancreas cancer after 
therapy with gemcitabine were treated with olaparib capsules 400mg po bid. All patients had 
received a prior gemcitabine regimen and over 50% received a prior platinum containing 
regimen. The ORR was 22%, DCR 57%, PFS 4.6 mos. and OS 9.8 mos. (Kaufman et al ASCO 
poster discussion 2013).  
To summarize, patients with germline BRCA associated PDAC have a more favorable, stage -
independent outcome and PARPi may offer therapeutic promise in these cases. 
1.1.5 
PARPi Beyond Germline BRCA Mutations 
Homologous recombination repair deficient (HRD) PDAC may involve other genotypes beyond 
germline BRCA mutations.  There exists a subtype of cancer patients who display remarkable 
clinical response to DNA damaging agents 27,  thus suggesting that the potential therapeutic 
effects of PARPi extend beyond germline BRCA 1/2 mutation carriers.28 In the pre-clinical 
setting, PARPi are synthetically lethal in pancreatic sporadic cancers with somatic or epigenetic 
silencing in the presence of HRD.29 Molecular profiling of tumors indicate that approximately 
10% of pancreatic tumors display a BRCA–like signature .30  These tumors are enriched with 
unstable genomes with widespread structural variation and have genetic mutations in various 
DNA repair pathways leading to genomic instability (for instance, PALB2, Rad51, ATM, RPA1, 
FANCM, REV1L, XRCC and HUWE1). Recently, deleterious ATM mutations have been 
recognized in the germ-line of families with familial PDAC, suggesting that ATM is a 
susceptibility gene in hereditary PDAC.31 Somatic ATM loss by IHC was observed in 50 out of 
396 (12.8%) PDACs. When the sporadic (n = 347) and familial (n = 49) pancreatic cancers were 
analyzed separately, ATM loss occurred significantly more frequently in familial cases as 
compared with sporadic cases (24% vs. 11%, p=0.019).  ATM loss occurred in 11% of surgically-
resected PDAC and was significantly associated with worse OS than those PDAC cases with 
preserved ATM (p=0.005). 32 ATM deficiency is associated with responsiveness to PARPi, 
including olaparib.33-35 
1.1.6 
PDAC with ‘BRCA-ness’ Phenotype  
Our group (MD Anderson and Johns Hopkins) recently conducted a large retrospective 
analysis of 549 cases with metastatic PDAC to investigate its familial clustering with BRCA- 
associated cancers but who did not meet the MEDICARE guidelines for BRCA testing. In this 
study, patients with 2 or more family members with breast, ovarian or pancreatic cancers 
constituted 16% of the population of pancreatic cancer; these cases had superior OS than the 
sporadic PDAC population.  This was especially true in patients with 3 or more relatives with 
either breast, ovarian, or pancreatic cancers (HR=0.41, P=0.004).  Patients with 2 or more 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
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relatives having the above cancers experienced improved survival with platinum-based 
therapy as compared with their sporadic counterparts (Table 1). 
No platinum therapy  
Number of relatives 
with breast, ovarian, or 
pancreatic cancer 
Number of 
patients 
Number 
of 
Deaths 
Overall 
Survival (CI) 
Hazard ratio 
Adjusted 
P value 
0 
151 
140 
7.5 (6.4, 8.8) 
1 (Reference) 
 
1 
45 
40 
6.9 (5.5, 9.6) 
1.13 (0.78 to 
1.63) 
0.50 
2 
22 
21 
5.3 (4.0, 11.0) 
1.12 (0.70 to 
1.78) 
0.64 
3 or more 
6 
5 
12.0 (5.7, Inf) 
0.65 (0.26 to 
1.60) 
0.35 
Platinum therapy  
Number of relatives 
with breast, ovarian, or 
pancreatic cancer 
 
 
 
 
 
0 
190 
163 
8.3 (7.3, 10.1) 1 (Reference) 
 
1 
83 
73 
8.0 (6.5, 11.5) 
0.97 (0.73 to 
1.30) 
0.87 
2 
36 
33 
10.6 (9.0, 
17.0) 
0.82 (0.56 to 
1.20) 
0.30 
3 or more 
16 
13 
21.7 (12.3, 
47.2) 
0.41 (0.22 to 
0.76) 
0.004 
Table 1: Effect of family history on OS associated with platinum-based therapy 
These findings suggest that familial clustering of cancers may serve as a positive predictive 
marker for platinum therapy in patients with metastatic PDAC, even in the absence of BRCA 
mutation. This clinical phenotype bears close resemblance to BRCA- positive PDAC and 
deserves further exploration for presence of HRD as a target for PARPi. 
 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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1.1.7 
Exploiting HR Deficiency in PDAC 
 
HRD in PDAC represents a potential target for PARPi as mentioned above. PALB2, Rad51, 
ATM, RPA1, FANCM, REV1L, XRCC and HUWE1 GAs lead to DNA repair defects and may 
represent potential targets for PARPi. Unfortunately, targeting of these genotypes in the 
clinical setting is complicated by lack of validated assays. Next generation sequencing (NGS) 
may identify many of these genetic aberrations, but the low incidence of these genetic 
aberrations and high costs of testing makes NGS impractical as a screening tool at the present 
time. Therefore, it is critical that we identify novel functional and cost-effective tools to 
identify high-risk HRD cases without the necessarily interrogating each of these genetic 
aberrations individually. Recently, our group performed genome-wide transcriptome profiling 
to identify a HRD signature that can accurately predict response to PARPi. Peng et al 
evaluated gene expression in several breast cancer cell lines with mutations in either BRCA1 
or RAD51 or BRIT1.36 These genes are known to be associated with HRD. There was a set of 
230 genes that were consistently altered in all the cell lines. This set was referred to as the 
HRD gene signature. The same signature was found in BRCA-wt cell lines after knockdown 
of different DNA-repair genes, including ATM. The signature was also tested in ovarian, 
prostate, lung and kidney cell lines and was found to be a predictor of PARP-1 inhibitor 
sensitivity regardless of BRCA status. We believe that patients with ATM loss/abnormal p53 
express the same HRD gene signature as BRCA-mut patients.  
 
In the proposed study, we plan to utilize this novel tool to interrogate cases with PDAC that are 
BRCA-negative but have a familial profile suggestive of HRD. 
1.1.8 
Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib IB. 
1.1.9 
Toxicology and safety pharmacology summary 
Olaparib has been tested in a standard range of safety pharmacology studies eg, dog 
cardiovascular and respiratory function tests, and the rat Irwin test.  There were no noticeable 
effects on the cardiovascular or respiratory parameters in the anaesthetised dog or any 
behavioural, autonomic or motor effects in the rat at the doses studied. 
Rodent and dog toxicology studies have indicated that the primary target organ of toxicity is 
the bone marrow with recovery seen following withdrawal of olaparib.  Ex vivo studies have 
confirmed that olaparib is cytotoxic to human bone marrow cells. 
Olaparib was not mutagenic in the Ames test but was clastogenic in the Chinese hamster 
ovary (CHO) chromosome aberration test in vitro.  When dosed orally, olaparib also induced 
micronuclei in the bone marrow of rats.  This profile is consistent with the potential for 
genotoxicity in man.  
Reproductive toxicology data indicate that olaparib can have adverse effects on embryofoetal 
survival and development at dose levels that do not induce significant maternal toxicity.  
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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Further information can be found in the current version of the olaparib IB. 
1.1.10 
Clinical experience with olaparib 
Below is an outline of the monotherapy olaparib studies conducted in pancreas cancer 
patients. 
1.1.10.1 Olaparib monotherapy studies in pancreas cancer patients 
Study D0810C00042 (Study 42): This was a single arm phase II study of olaparib (capsules) 
400mg po bid in patients with germline BRCAm malignancies across multiple tumor types. 
Twenty-three patients with germline BRCAm-associated advanced pancreas cancer after 
therapy with gemcitabine were treated with olaparib capsules 400mg po bid. All patients had 
received a prior gemcitabine regimen and over half a prior platinum-containing regimen. The 
ORR was 22%, DCR 57%, PFS 4.6 mos. and OS 9.8 mos. This level of activity compares 
favourably with that reported for other therapies reported in advanced previously treated 
pancreas cancer. A retrospective analysis of the patient data from study 42 suggested greatest 
benefit from olaparib in those patients whose tumors had not progressed on a prior platinum 
treatment (ORR 33%, DCR 66%, PFS 6.4 mos., OS 13.1 mos.). 
1.1.10.2 Olaparib monotherapy in metastatic pancreatic adenocarcinoma 
Thus far, 23 metastatic PDAC patients have been enrolled in a single arm, phase II trial 
to determine the efficacy of olaparib in advanced PDAC with BRCAness (protocol 2015-
0503). Patients who received ≥ 1 prior systemic therapy for metastatic PDAC, ECOG 0-
1, patients known to have DDR genetic aberrations (DDR-GA), or have a family history 
of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA) are eligible. 
Olaparib was well tolerated with grade 1-2 anemia, fatigue and nausea were the 
commonly reported toxicities. The median PFS was 24.7 weeks (range 3.9 – 41.1). The 
median treatment duration was 20 weeks and the disease control rate was 72.7% 
including 2 patients achieved PR and 6 patients had stable disease. This PFS is higher 
than historically reported in PDAC (3 months) and therefore we wish to expand this 
study.  The trial included optional biopsies to examine the DNA repair aberrations, 
particularly in patients with family history alone but without detectable genetic 
aberrations. We wish to expand the study cohort by 10 patients so as to obtain more 
correlative information that will increase our understanding about potential eligibility for 
this targeted therapy. 
1.2 
Research hypothesis 
a) PDAC cases with BRCAness have HRD and b) these tumors can be targeted effectively
with PARPi. We hypothesize that olaparib will be efficacious and safe in PDAC patients with
BRCAness. These cases can be identified by family history, ATM loss and HRD signature.
The efficacy in this study will be assessed by objective response rate using the RECIST1.1
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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1.3 
Rationale for study design and doses 
We hypothesize that PARPi have broader clinical applications than initially proposed. 
Assessment of HR function examining markers of HR function is feasible.30,36 Transcriptome 
profiling to determine PARPi-sensitive, HRD in PDAC maybe a promising avenue for 
personalized therapy in this otherwise chemo-refractory disease and a HRD signature was 
proposed recently by Peng et al, from MD Anderson Cancer Center (MDACC) as described 
above.36 
We will focus on the following subsets in this study of stage IV PDAC patients negative for 
BRCA 1/2 testing with: a) ATM loss as identified by IHC, b) PDAC cases with 2 or more 
immediate family members having the above cancers, and c) previously identified GAs known 
to be associated with HRD.  
All treated patients have the option to undergo pre-treatment biopsy. Correlative studies will 
be performed on all treated patients. These studies will include transcriptome profiling for 
HRD signature and IHC for ATM IHC using validated assays.  No prospective NGS is planned 
for this study. As mentioned above, cases previously identified to have HR genetic aberrations 
on NGS will be offered the opportunity to participate in this PARPi trial. A second research 
biopsy will be performed at progression. Based on the available data on efficacy and safety of 
PARPi in germline BRCA1/2 mutations, we anticipate that olaparib will have a positive 
benefit risk profile for the treatment of this sub population of PDAC patients with HRD repair. 
1.4 
Benefit/risk and ethical assessment 
As of 2 October 2013, an estimated 2103 patients with ovarian, breast, gastric, pancreas, and a 
variety of other solid tumors are estimated to have received treatment with olaparib across the 
dose range 10 mg qd to 600 mg bid in AstraZeneca-sponsored, investigator-sponsored, and 
collaborative group studies.  Olaparib has been given as either monotherapy (18 studies, an 
estimated 1214 patients) or in combination with other chemotherapy/anticancer agents 
(25 studies, an estimated 889 patients).  Many of these combinations studies are ongoing.  The 
majority of patients to date have received the capsule formulation of olaparib (an estimated 
1635 patients).  Approximately 468 patients have received the tablet formulation to 
date.  Approximately 304 patients have received comparator or placebo across the olaparib 
development programme. 
An analysis of monotherapy data across 12 AstraZeneca sponsored monotherapy studies in 
975 patients who have been given olaparib capsule estimated that 16.1% (157/975) of patients 
had been exposed to olaparib capsule for ≥12 months at the time of database closure for the 12 
studies.  Furthermore, 41/ 975 patients received treatment for >24 months (longest duration 
was 44 months).  From the available data to date, there is no evidence of any unexpected 
toxicity following long-term olaparib (capsule) monotherapy exposure.  
Olaparib as monotherapy at doses up to 400 mg bid capsule is generally well tolerated, with 
most common AEs including nausea, fatigue, vomiting, anaemia mainly mild-to-moderate 
(CTCAE Grade ≤ 2) in severity.  In addition, in a small number of patients MDS/AML or 
pneumonitis have been observed and identified as important risks.  
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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1.4.1 
Important potential risks 
1.4.1.1 
Myelodysplastic syndrome/acute myeloid leukaemia 
There have been 16 reports of myelodysplastic syndrome (MDS) and/or acute myeloid 
leukaemia (AML) in patients treated with olaparib as of 02 Oct 2013; 11 cases in olaparib 
monotherapy trials and 5 cases in olaparib combination studies with carboplatin and paclitaxel 
(n=4) or cediranib (n=1).  A total of 2103 patients are estimated to have received olaparib, 
giving a cumulative incidence of 0.76% for MDS/AML, similar to the cumulative incidence 
reported from control arms of olaparib randomised studies 0.7% (2/304 patients).  All 16 
patients had primary ovarian or peritoneal cancer and 12 of them were gBRCA1/2 positive (3 
cases gBRCA status unknown; 1 case negative).  It has been hypothesised that a deficiency in 
the expression of BRCA genes may leave patients more vulnerable to the adverse effects of 
chemotherapy, and therefore, at an increased risk of MDS/AML as a result of cancer 
treatment. Most patients had been treated with extensive previous chemotherapy ranging from 
6 to 95 cycles over periods of 3.5 months to 15 years, including platinum agents, 
topoisomerase II inhibitors, alkylating agents and taxanes.  The median time from diagnosis of 
cancer to onset of MDS was 5.3 yrs (range 2.9 -12.7).  The median time from start of olaparib 
treatment to onset of MDS was 0.9 years (0.1 to 4.8 years).  The reported events of 
MDS/AML occurred post discontinuation of olaparib treatment in 8 of the 16 patients 
following a median of 0.1 years post treatment discontinuation (range: 0.1 to 1 years).  Half of 
the patients (n=8) had received olaparib for ≤ 12 months (5 patients had ≤ 6 months exposure) 
and the other 8 cases occurred following longer than 12 month olaparib exposure (3 patients 
following 12-18 months exposure and 5 patients following >2 years exposure to olaparib).  
Since bone marrow is known to be a target organ for olaparib toxicity, a risk of MDS/AML 
with long-term exposure to olaparib cannot be excluded, but there is insufficient data at 
present to evaluate the strength, if any, of this relationship. Moreover, while non-clinical data 
suggest bone marrow progenitor cell populations are reduced temporarily following olaparib 
treatment, there is no evidence to date linking olaparib treatment to the generation of abnormal 
bone marrow precursors.  Furthermore, all patients who developed MDS/AML had extensive 
prior chemotherapy and while it is not possible to exclude the contribution of olaparib, it is 
also considered that there were other potential contributing factors in all cases.  Preclinical 
data also suggest potential benefit with PARP inhibitors in MDS/AML and clinical trials are 
now underway to assess this effect  
To ensure robust safety monitoring, patients in this clinical trial will have weekly safety 
assessments during the first cycle and then safety assessments every 2 weeks for the first 4 
weeks and every 4 weeks thereafter during the rest of the treatment period. Clinical guideline 
of managing bone marrow toxicity and use of G-CSF is implemented as the safety 
management plan. 
1.4.1.2 
Pneumonitis 
As of 2nd of Oct 2013, 10 patients out of a total of 2103 patients estimated to have received 
olaparib have reported pneumonitis, giving a cumulative incidence of 0.5% for pneumonitis.  
Pneumonitis was also reported for 2 patients (0.7%) of 304 patients that received placebo or 
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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comparator in the olaparib trial programme (1 patient on placebo in Study 19 and 1 patient on 
paclitaxel in Study 39).  The patients were treated with olaparib for breast cancer (n=2), 
ovarian cancer (n=2), non-small cell lung cancer (n=2), small cell lung cancer (n=1), pancreas 
cancer (n=1), gastric cancer (n=1) and thymic cancer (n=1).  Five of the 10 patients had a 
history of tobacco smoking.  The majority of patients had received prior radiotherapy and/or 
chemotherapy.  The majority of patients had relevant medical histories including pneumonitis, 
interstitial lung fibrosis, dyspnoea, haemoptysis, chest infection, allergic asthma, pleural 
effusion, and pleural metastases.   
Investigation of any new or worsening pulmonary symptoms has been implemented as a 
safety management plan (section 6.6.2). 
1.4.1.3 
New Primary Malignancies 
Overall, the number of reports of new primary malignancies is low, with 21 events (in 19 
patients) being reported in 02 Oct 2103 olaparib treated patients (0.9%) and one event 
(bladder cancer) reported in the placebo arm of the double-blind Study 19.  In randomised 
controlled studies, 5 events of new primary malignancies have been reported in four olaparib 
treated patients and one event in a placebo treated patient: 
In the double blind maintenance Study 19, two events of new primary malignancies have been 
reported in olaparib treated patients and one event in a placebo treated patient.  In the open 
label ovarian monotherapy dose-finding Study 12, three events were reported in two olaparib 
treated patients.  
Of the 21 reported events in olaparib treated patients, in ten the events were non-melanoma 
skin cancers.  There was one report of malignant melanoma.  The other 10 events of new 
primary malignancies were breast cancer (n=2), breast cancer in situ, gastric cancer, lung 
neoplasm (plus event of recurrence of the lung carcinoma), plasma cell myeloma, colon 
cancer, malignant muscle neoplasm (lesion present pre-olaparib treatment) and one fatal event 
of T-lymphoblastic lymphoma/leukaemia.  
Of the 19 olaparib treated patients subsequently diagnosed with a new primary malignancy, 
the majority were reported whilst receiving olaparib treatment (16 patients).  In 3 patients the 
event was reported after olaparib discontinuation  
 The duration of olaparib treatment for the 19 patients was: 
•
<6 months for 3 patients
•
6 to 12 months for 6 patients
•
12 to 18 months for 2 patients
•
18 to 24 months for 2 patients
•
>2 years for 6 patients.
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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The type of new primary cancers reported were generally in line with secondary cancers 
observed in ovarian and breast cancer populations reported in the literature 37 or were cancers 
such as skin cancer, known to be the most common cancer in the general population and 
associated with high cure rates. Ovarian cancer patients have been reported to have an 
increased risk of developing second primary malignancies.  Patients with BRCA mutations are 
at risk of developing other primary cancers notably breast cancer and skin cancer.38 
There were other contributing factors/potential alternative explanations for the development of 
the new primary malignancy in all 19 olaparib treated patients.  All patients had previously 
received various chemotherapy agents including multiple cycles of DNA damaging platinum 
containing chemotherapies, taxanes, anthracyclines and other alkylating and DNA damaging 
agents.  Four patients were reported to have had prior radiotherapy. Seven of the 19 patients 
had previous medical histories of cancer (ovarian, cervix, breast, peritoneal) and 3 patients 
with skin cancers had either had previous basal cell carcinoma reported or had skin lesions 
evident prior to study treatment) prior to the cancer under investigation in the olaparib studies. 
There is insufficient evidence for an association between olaparib treatment and the 
development of new primary malignancies in the clinical trial programme to date. 
1.4.2 
Potential benefit 
Homologous recombination repair deficient (HRD) PDAC may involve other genotypes 
beyond germline BRCA mutations.  There exists a subtype of cancer patients who display 
remarkable clinical response to DNA damaging agents 27,  thus suggesting that the potential 
therapeutic effects of PARPi extend beyond germline BRCA 1/2 mutation carriers. 28 In the 
pre-clinical setting, PARPi are synthetically lethal in pancreatic sporadic cancers with somatic 
or epigenetic silencing in the presence of HRD.29 Molecular profiling of tumors indicate that 
approximately 10% of pancreatic tumors display a BRCA–like signature.30 Familial clustering 
of cancers in PDAC patients may serve as a positive predictive marker for platinum therapy in 
patients with metastatic PDAC, even in the absence of BRCA mutation. This clinical 
phenotype bears close resemblance to BRCA- positive PDAC and deserves further exploration 
for presence of HRD as a target for PARPi. We hypothesize that PARPi have broader clinical 
applications than initially proposed. 
Based on the available data on efficacy and safety, we anticipate that in the metastatic disease 
setting, olaparib will have a positive benefit risk profile for the treatment of this sub 
population of PDAC patients with HRD repair. 
1.5 
Study design 
This is a phase II, open-label, non-randomised, study of olaparib monotherapy in advanced 
PDAC patients with:  
a) Clinical phenotype of HRD in the absence of BRCA mutation: PDAC cases with 2 or
more immediate family members having breast, ovarian, pancreatic, gastric or prostate
cancers
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Clinical Study Protocol 2015-0503 
Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
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b) Previously identified GAs known to be associated with HRD.
All patients will be retrospectively investigated for HRD signature using transcriptome profiling 
and ATM expression and the results correlated with PARPi response rates. 
Eligible patients will receive treatment with olaparib tablets p.o. 300mg twice daily until 
progression. Each treatment cycle is described as 28 days long. Patients will have tumor 
assessments according to RECIST 1.1 at baseline. Patients will then be followed for the final 
analysis of OS. 
Eligible patients will be those patients with stage IV pancreas cancer previously treated for 
metastatic disease. Patients must have received one prior therapy for the treatment of 
metastatic disease or refused chemotherapy.  
Following study entry, patients will attend clinic visits every two weeks for the first 4 weeks 
of treatment (Days 1 and 15,).  Patients will then attend clinic visits every 4 weeks whilst on 
study treatment.  
Patients should continue to receive study treatment until objective radiological disease 
progression as per RECIST as assessed by the investigator and as long as in the investigator’s 
opinion they are benefiting from treatment and they do not meet any other discontinuation 
criteria as outlined in Section 3.6. 
Following discontinuation of study treatment, patients should be seen at 30 days post 
discontinuation for the evaluations outlined in the study schedule.  Patients will be contacted 
in the 7 days following a specified date (data cut-off date) to capture survival status at that 
point for each survival analysis.  Assessments will be performed as described in Table 2. 
Patients will have tumor assessments according to RECIST at baseline and every 8 weeks 
(±1week) up to 40 weeks and then every 12 weeks (±1 week) until objective radiological 
disease progression according to modified RECIST criteria.  Ongoing collection of site review 
tumor assessment is required and must be recorded in the electronic case report form (eCRF). 
Any patient who discontinues study treatment for reasons other than objective radiological 
progression should continue to undergo scheduled objective tumor assessments according to 
the study schedule (see Table 2) in order to assess objective radiological progression of 
disease. Failure to do so may result in bias to the study results. 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
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2.
STUDY OBJECTIVES
2.1) Primary Objective: 
Outcome Measure: 
•
To determine the efficacy of olaparib
monotherapy in stage IV pancreatic ductal
adenocarcinoma (PDAC) with BRCAness
•
Objective Response Rate by using RECIST 1.1
2.2) Secondary Objectives: 
Outcome Measure: 
•
To further determine the efficacy of
olaparib in the study population
•
Overall Survival (OS)
•
Progression Free Survival (PFS)
•
CA 19-9 response
2.3) Safety Objective: 
Outcome Measure: 
•
To assess the safety and tolerability of
olaparib
•
Safety: Type, frequency, and severity of AEs
and SAEs;
•
Tolerability: dose interruptions, reductions and
dose intensity
2.4) Exploratory Objective: 
Outcome Measure: 
To identify tissue-based biomarkers of 
defective homologous recombination repair 
(HRD) 
•
Retrospective analysis of HRD signature
developed by our group
•
ATM expression (IHC)
3.
PATIENT SELECTION, ENROLLMENT, RESTRICTIONS,
DISCONTINUATION AND WITHDRAWAL
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study prior to allocation.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
•
Patients with histologically or cytologically confirmed metastatic adenocarcinoma of the
pancreas.
•
Family history: one or more close blood relative with ovarian carcinoma at any age or breast
cancer age 50 or younger  or two relatives with breast, pancreatic or prostate cancer (Gleason
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
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7 or higher) at any age, or patients with Ashkenazi Jewish ancestry. However, patients with 
previously identified genetic aberrations that are associated with HRD will be eligible even 
in the absence of family history [e.g. somatic BRCA mutation, Fanconi Anemia gene, ATM 
or RAD51 mutations]. 
•
Patients must be germline BRCA 1 or 2 negative. (Note:  If BRCA status was previously
determined, that result is acceptable but documentation of status must be available; subjects
with unknown status will be referred to genetic counselling for BRCA testing as per standard
of care.)
•
Patients must have received at least one prior therapy for metastatic disease to be eligible.
•
Patients must have measurable disease, defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) as >20 mm with
conventional techniques or as >10 mm with spiral CT scan.
•
All treated patients have the option to undergo pre-treatment biopsy (liver, omentum, lung
or lymph node) to be eligible.
•
Patients with prior malignancy and treated with no evidence of active disease, and more
than 2 years from initial diagnosis are eligible.
•
ECOG Performance Status 0-1 (Karnofsky >70).
•
Patients must have adequate organ and marrow function as defined below:
-
leukocytes
>3,000 cells/mm3
-
absolute neutrophil count  
>1,500 cells/mm3
-
platelets
>75,000 cells/mm3
- 
hemoglobin
>9 g/dl (no blood transfusions within 4
weeks prior to enrollment)
-
total bilirubin
<1.5 X institutional upper limit of normal 
(IULN)  
-
AST(SGOT)/ALT(SGPT) 
<2.5 X  IULN  without liver metastasis
<5 X  IULN  for patients with liver 
metastasis 
-
creatinine
Not greater than Upper Institutional limits 
OR 
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Drug Substance:  Olaparib  
Study Code:  ISS22810097 
Version:  4 
Date:   October 10, 2018 
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-
creatinine clearance
>60 mL/min/1.73 m2 for patients with
creatinine levels above institutional
normal
•
INR <1.5.
•
Patients must be ≥ 18 years of age.
•
Women of childbearing potential (defined as not post-menopausal for 12 months or no
previous surgical sterilization) and fertile men must agree to use two highly effective
forms of contraception while they are receiving study treatment and for one month for
female patients and for 3 months for male patients after last dose of study drug. Male
subjects must agree to refrain from sperm donation during the study and for 90 days after
the last dose of study drugs.
•
Ability to understand and the willingness to sign a written informed consent document.
Signed informed consent form must be obtained prior to initiation of study evaluations
and/or activities.
3.2 
Exclusion Criteria 
•
Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia and myocardial infarction (MI) within 3 months of
initiation of therapy.
• Patients whose tumors are deemed to be platinum-refractory will be excluded from the trial.
•
Pregnancy or lactation.
•
Patient has active and uncontrolled bacterial, viral, or fungal infection(s) requiring
systemic therapy.
•
Patient has undergone major surgical resection within 4 weeks prior to enrollment.
•
Patient received radiotherapy, surgery, chemotherapy, or an investigational therapy within
2 weeks prior to study entry.
•
Patient has serious medical risk factors involving any of the major organ systems such that
the investigator considers it unsafe for the patient to receive an experimental research
drug.
•
Serious psychiatric or medical conditions that could interfere with treatment.
•
Major bleeding in the last 4 weeks prior to study entry.
•
Concomitant use of CYP3A4 inhibitors.
•
Resting ECG with QTc  >470msec (Fredericia’s scale).
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Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient Enrollment Allocation 
Investigator(s) should keep a record, the patient-screening log, of patients who entered pre-
study screening. 
The Principal Investigator will: 
1. Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. Determine patient eligibility. See Sections 3.1 and 3.2. 
The Study Coordinator will enter eligible patients on study.   The Core System administered 
by the Office of Protocol Research at UT MD Anderson Cancer Center will be used to register 
patients.   
3.4 
Procedures for handling incorrectly enrolled patients 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be allocated or receive study medication.  There can be no exceptions to this rule. 
Where patients that do not meet the selection criteria are incorrectly started on treatment, or 
where patients subsequently fail to meet the study criteria post initiation, a discussion should 
occur between the MD Anderson IND Medical Monitor and the investigator regarding 
whether to continue or discontinue the patient from treatment. Once a decision is made, 
Investigators need to ensure they comply with all applicable requirements for human patient 
protection and ethical review. 
3.5 
Restrictions 
3.5.1 
Contraception 
Women of childbearing potential (defined as not post-menopausal for 12 months or no 
previous surgical sterilization) and fertile men must agree to use two highly effective forms of 
contraception while they are receiving study treatment and for one month for female patients 
and for 3 months for male patients after last dose of study drug. Male subjects must agree to 
refrain from sperm donation during the study and for 90 days after the last dose of study 
drugs. 
 
3.5.2 
Olaparib and CYP3A4/5 
Patients should avoid concomitant use of drugs, herbal supplements and/or ingestion of foods 
known to modulate CYP3A4/5 enzyme activity (see Section 7.7.2) starting 5 days before 
study enrollment until 30 days after the last dose of study medication. 
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3.6 
Discontinuation of investigational product 
Patients may discontinue study treatment in the following situations: 
• Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
• Objective radiological disease progression 
•  Intolerable toxicity as defined in Section 6.3 Severe Adverse Event if related to study 
drug.  
• Severe non-compliance to study protocol  
• Death 
3.6.1 
Procedures for discontinuation of a patient from investigational product  
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any adverse events.  If possible, they will be seen and assessed by an 
investigator(s).  Adverse events will be followed up (See Sections 6.2 and6.3); all study drugs 
should be returned by the patient. 
If a patient is withdrawn from study, see Section 3.7. 
Any patient discontinuing study treatment should be seen at 30 days post discontinuation for 
the evaluations outlined in the study schedule.  The patient’s tumor status should be assessed 
clinically and, if appropriate, disease progression should be confirmed by radiological 
assessment.  After discontinuation of study treatment, the principal investigator/sub-
investigator will perform the best possible observation(s), test(s) and evaluation(s) as well as 
give appropriate medication and all possible measures for the safety of the patient.  In 
addition, they will record on the eCRF the date of discontinuation, the reasons, manifestation 
and treatment at the time of discontinuation.  Patients will be required to attend the treatment 
discontinuation visit.  The patient should return all study medication. 
After discontinuation of the study treatment at any point in the study, all ongoing 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 
(see Sections 6.2 and 6.3).  All new AEs and SAEs occurring during the 30 calendar days after 
the last dose of study medication must be reported (if SAEs, they must be reported to 
AstraZeneca within 24 hours as described in Section 6.3) and followed to resolution as above.  
Patients should be seen at least 30 days after discontinuing study treatment to collect and / or 
complete AE information.  Any untoward event occurring subsequent to the 30-day follow-up 
AE reporting period that the investigator assesses as possibly related to the study treatment 
should also be reported as an AE. 
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Patients who discontinue treatment prior to disease progression should continue to have 
RECIST assessments as per the study schedule. All patients must be followed for objective 
progression (as per RECIST 1.1) and survival, up to the final analysis. 
3.7 
Criteria for withdrawal 
Patients are at any time free to withdraw from study (study treatment and assessments), 
without prejudice to further treatment (withdrawal of consent).  Such patients will always be 
asked about the reason(s) and the presence of any adverse events.  If possible, they will be 
seen and assessed by an investigator.  Adverse events will be followed up (See Sections 6.2 
and 6.3). All study tools and drug supply should be returned by the patient. 
Withdrawn patients will not be replaced. 
Reasons for withdrawal from the study: 
•
Voluntary withdrawal by the patient who is at any time free to discontinue their
participation in the study, without prejudice to further treatment*
•
Incorrectly enrolled patients ie, the patient does not meet the required
inclusion/exclusion criteria for the study
•
Patient lost to follow-up
•
Death
*If a patient decides at any point in the trial that they do not wish to continue with the full
study schedule of assessments but are still willing to provide important study information (eg
disease recurrence information and/or survival status information) then the patient should
continue in the study and information should continue to be collected on the clinical database.
However if a patient does not wish to have any further data collected, only then should they be
considered as withdrawing consent from the study.  To minimise the number of cases of early
withdrawal the investigator should discuss the options with the patient in case they would still
be willing to undergo reduced assessments and/or reduced data collection, in which case they
would remain in the study.
*If a patient withdraws consent, they will be specifically asked if they are withdrawing
consent to:
−
to further participation in the study including any further follow up (eg, survival
calls)
−
withdrawal of consent to the use of their study generated data
−
withdrawal to the use of any samples (see Section 5.4.5)
Data obtained prior to withdrawal of consent will be maintained in the clinical database and 
used in the study reporting. 
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The status of ongoing, withdrawn (from the study) and ‘lost to follow up’ patients at the time 
of an overall survival analysis should be obtained by the site personnel by checking the 
patients notes, hospital records, contacting the patients general practitioner and checking 
publicly available death registries.  In the event that the patient has actively withdrawn 
consent to collection of further data, the vital status of the patient can be obtained by site 
personnel from publicly available resources where it is possible to do so under applicable 
local laws. 
3.7.1 
Screen failures 
Screen failures are patients who do not fulfil the eligibility criteria for the study. These 
patients should have the reason for study withdrawal recorded as ‘Incorrect Enrollment’ (ie, 
patient does not meet the required inclusion/exclusion criteria).  This reason for study 
withdrawal is only valid for screen failures.  To reach the planned 34 patients, up to 51 
patients may need to be screened (consented).  Those patients who do not meet eligibility will 
be considered screen failures and will be replaced.   
3.7.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws from participation in the study, then his/her enrollment code cannot be 
reused. Withdrawn patients will not be replaced.  
3.8 
Discontinuation of the study 
The study may be stopped if, in the judgment of the investigators, trial patients are placed at 
undue risk because of clinically significant findings that: 
•
meet individual stopping criteria or are otherwise considered significant,
•
are assessed as causally related to study drug,
•
are not considered to be consistent with continuation of the study.
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
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4.
STUDY PLAN AND TIMING OF PROCEDURES
A study initiation visit must be conducted at the centre prior to the commencement of any 
study activities requiring informed consent. A schedule for the tests and evaluations to be 
conducted in this study is contained in this section and in Table 2.
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Table 2 
Study Schedule – Screening, On Study Treatment, Discontinuation and Follow-up 
Pre- 
Screening 
Screening 
Treatment Duration 
Study 
treatment 
discontinued 
30-Day
follow-up 
Survival 
Follow-up 
Cycle/ Visit 
1 
(28 days) 
2 
3+ 
(every 
28 days) 
Day 
-28 to 0
1 
15 
29 
57+ 
Every 8 
weeks 
Visit window 
±2d 
±2d 
±2d 
±7d 
±7d 
±7d 
Informed consent 
X 
Demographics 
X 
Medical and surgical history, 
including previous cancer and 
radiotherapy 
X 
Inclusion/exclusion criteria 
X 
X 
BRCA testing/ Genetic 
counselling 
X 
Archival tumor tissue (FFPE) 
if availablea 
X 
Research Core Needle Biopsy 
(CNB) 
XP
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
Vital signs 
X b 
X  b 
X 
X 
X 
X 
X 
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Pre- 
Screening 
Screening 
Treatment Duration 
Study 
treatment 
discontinued 
30-Day
follow-up 
Survival 
Follow-up 
Cycle/ Visit 
1 
(28 days) 
2 
3+ 
(every 
28 days) 
Day 
-28 to 0
1 
15 
29 
57+ 
Every 8 
weeks 
Visit window 
±2d 
±2d 
±2d 
±7d 
±7d 
±7d 
Physical examination c 
X 
X 
X 
X 
X 
X 
X 
ECG d 
X 
As clinically indicated 
Imaging studies: CT scan or 
MRI 
Tumor assessment 
(RECIST 1.1) e 
Xe 
(no more 
than 28 days 
before start 
of treatment) 
Every 8 weeks (± 1 week) for the 
first 40 weeks then every 12 weeks 
(±1 week) e 
If patient does 
not have 
disease 
progression at 
the time of 
treatment 
discontinua-
tion, tumor 
assessments 
should be 
continued if 
they stay on 
study 
protocol.f 
Haematology/clinical 
chemistry  
X 
X  g 
X 
X 
X 
X 
X 
Coagulation h 
X 
As clinically indicated 
Urinalysis i 
X 
As clinically indicated 
Pregnancy test  j 
X 
X 
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Pre- 
Screening 
Screening 
Treatment Duration 
Study 
treatment 
discontinued 
30-Day
follow-up 
Survival 
Follow-up 
Cycle/ Visit 
1 
(28 days) 
2 
3+ 
(every 
28 days) 
Day 
-28 to 0
1 
15 
29 
57+ 
Every 8 
weeks 
Visit window 
±2d 
±2d 
±2d 
±7d 
±7d 
±7d 
Biomarker blood sample k 
X 
X 
(only at 
progres-
sion)
Adverse event l 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing m 
X 
X 
X 
Study drug return 
X 
X 
X 
Subsequent cancer treatment 
n
X 
X 
Survival status o 
Xo 
a 
Collection of an archival tumor sample is requested in screening period. 
b 
Vital signs performed at screening, cycle 1 days 1 and 15, and on day 1 of every cycle. If vital signs assessed within 7 days before starting study 
treatment, it does not need to be repeated on Day 1 of study treatment unless investigator believes that it is likely to have changed significantly. 
c 
Physical examination should be performed according to the schedule. After the baseline assessment it is not necessary to record the details on the eCRF. 
Any clinically significant changes not unequivocally related to disease progression should be reported as adverse events. 
d 
ECG assessments to be completed within 7 days before starting treatment if patient is eligible following completion of all other assessments. After 
screening, ECGs will only be required if clinically indicated. 
e 
 Baseline RECIST assessments will be performed using CT scans of the chest, abdomen and pelvis (or MRI where CT is contraindicated) and should be 
performed no more than 28 days before start of study treatment. RECIST follow-up assessments will be performed every 8 weeks (±1 week) for the first 
40 weeks, then every 12 weeks (±1 week) irrespective of treatment decisions. Follow-up assessment will include CT assessments of chest, abdomen and 
pelvis (or MRI where CT is contraindicated) for all patients. Any other sites at which new disease is suspected should also be appropriately imaged. 
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Patients must be followed until disease progression assessed using RECIST 1.1 criteria.  If an unscheduled assessment was performed and the patient has 
not progressed, every attempt should be made to perform the subsequent assessments at their scheduled visits. 
f 
For patients who discontinue study treatment prior to disease progression, RECIST assessments will continue until objective disease progression (every 
8 weeks (±1 week) for the first 40 weeks, then every 12 weeks (±1 week), until objective disease progression as defined by  RECIST 1.1.) as long as 
they stay on study.  
g 
 Haematology and clinical chemistry should be performed at screening, cycle 1 days 1 and 15, and day 1 of every cycle (+ 2 days) . 
h 
Coagulation test should be performed at screening and if clinically indicated 
i 
Urinalysis should be performed at screening. After screening, urinalysis will only be required if clinically indicated. 
j 
In the event of suspected pregnancy during the study, the test should be repeated and, if positive, the patient discontinued from study treatment 
immediately.  
k 
Mandatory blood samples for biomarker analysis to be taken prior to dosing on Cycle 1 Day 1 and at disease progression. 
l
Adverse events must be captured from time of first protocol intervention (start of study medication). During Screening: baseline sign and symptoms will
be captured. SAEs will be recorded from first protocol specific intervention (start of study medication).
m 
Continuous olaparib 300mg twice daily dosing. Sufficient study treatment should be dispensed for at least each treatment period plus overage, however 
additional treatment can be dispensed to patients to last longer in accordance with local practice. 
n 
All anti-cancer treatments (including, but not limited to, chemotherapy and targeted agents), and the Investigator’s opinion of response to them, plus the 
date of progression post discontinuation of study treatment, need to be recorded. 
o
The status of ongoing, withdrawn (from the study) and ‘lost to follow-up’ patients at the time of an OS analysis should be obtained by the site  personnel
by checking the patient’s notes, hospital records, contacting the patient’s general practitioner and checking publicly available death registries.  In the
event that the patient has actively withdrawn consent to the processing of their personal data the vital status of the patient can be obtained by site
personnel from publicly available resources where it is possible to do so under applicable local laws (see Section3.7). In addition to their regular 8
weekly contacts, patients will be contacted in the 7 days following a specified date (data cut-off date) for each survival analysis.
p. Research Core Needle Biopsy (CNB) from metastatic site will be optional during the screening period.
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4.1 
Enrollment/screening period 
4.1.1 
Pre-screening period 
The pre-screening period may be utilized to identify potential subjects (pancreatic cancer 
patients who have advanced disease and are receiving or going to receive first-line treatment).  
Potential patients with family history of breast, ovarian, pancreatic, gastric or prostate cancer 
will be identified.  These cases will be referred to genetic counselling for BRCA testing as per 
standard of care. If patients have already been screened and are BRCA mutation negative, they 
are potentially eligible (as long as other inclusions are met). If somatic mutation testing has 
identified mutations in other DNA repair genes, they will also be potentially eligible (as long 
as other inclusions are met). 
4.1.2 
Screening period 
The following assessments and procedures should be performed during screening. 
For details of the schedule and nature of assessments see below: 
•
Month/ year of birth, sex, race and ethnicity
•
Medical and surgical history including previous cancer and radiotherapy
•
Previous chemotherapy
−
If patient received a prior platinum drug, describe the setting (adjuvant or
advanced), time on treatment (dates), and reason for discontinuation
(progression on therapy, discontinuation of therapy for reason other than
progression, completion of planned program without progression).  Patients
who progressed on platinum-based therapy will not be excluded from this
current study.
•
Current and concomitant medications including previous cancer therapies
•
ECOG Performance Status
•
Vital signs (blood pressure and pulse; body temperature), body weight, height
•
Haematology /Clinical chemistry/Urinalysis
•
Coagulation test
−
activated partial thromboblastin time (APTT) will be performed at baseline and
if clinically indicated
−
international normalized ratio (INR) will be performed at baseline and if
clinically indicated unless the patient is receiving warfarin. Patients taking
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warfarin may participate in this study; however, it is recommended that 
prothrombin time (INRand APTT) be monitored carefully at least once per 
week for the first month, then monthly if the INR is stable 
•
Physical examination
•
CT (or MRI if CT is contraindicated) of chest, abdomen and pelvis
•
Research Core Needle Biopsy (CNB) from metastatic site will be optional during the
screening period.
•
ECG (within 7 days prior to the start of the study treatment)
•
Menopausal status; serum or urine pregnancy test for women of childbearing potential.
The pregnancy test should be performed within 28 days prior to the start of study
treatment and confirmed on day 1 prior to dosing.
•
Baseline sign and symptoms will be captured during screening period.
•
Archival paraffin embedded tumor tissue sample will be requested
The Principal Investigator/Sub-Investigator should adhere to the study plan, procedures and 
perform tests/observations in accordance with the protocol. 
4.2 
Treatment period 
The visit schedule is based on 28-day cycles. 
Patients will attend the clinic every two weeks on days 1 (1st day of treatment) and 15 
following the commencement of study treatment and then every 4 weeks (day 1 of every 
cycle) until discontinuation of treatment. The following assessments will be performed at time 
points specified in the study schedule (see Table 2): 
•
Vital signs: These will include weight, temperature, pulse rate, BP.
•
ECOG Performance Status: Day 1 of every cycle and until objective radiological
disease progression, at discontinuation of study treatment visit and then 30 days post
last dose
•
Haematology and clinical chemistry: Cycle 1 Days 1 and 15 and then Day 1 of every
cycle.
•
Physical examination: Cycle 1 Days 1 and 15 and then Day 1 of each cycle. Further
assessments after day 1 are not required to be captured on an eCRF, however any
significant changes from baseline must be reported as an AE.
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• CT of chest, abdomen and pelvis (or MRI if CT is contraindicated) performed until 
objective disease progression. RECIST assessments to be scheduled every 8 weeks (±1 
week) for the first 40 weeks and then every 12 weeks (±1 week).  
• ECG at baseline and any time if clinically indicated  
• Urinalysis at baseline and any time if clinically indicated 
• Serum or urine pregnancy test for women of childbearing potential (prior to treatment 
on day 1 of 1st day of study treatment).  If the test is positive then a confirmatory test 
should be performed 
• AE and concomitant medications (including any blood transfusions) at every visit 
• Mandatory blood sample for biomarker analysis at cycle 1 day 1 (pre-dose) and 
disease progression (Section 5.3.1) 
Once patients have discontinued study treatment, other treatment options will be at the 
discretion of the investigator. 
4.3 
Follow-up period 
4.3.1 
Treatment discontinuation visit due to objective radiological disease 
progression 
Patients should be discontinued from study treatment if they have objective radiological 
disease progression according to RECIST 1.1 criteria. A follow-up visit should be conducted 
30 days after the last dose of study treatment.  Any serious and/or non-serious AEs ongoing at 
the time of the Discontinuation Visit or which have occurred during the defined 30-day 
follow-up period must be followed-up (in accordance with Section 6.2).  Appropriate safety 
evaluations should be repeated and/or additional tests performed at any time when clinically 
indicated, or at the discretion of the investigator, until resolution, unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease.  If the 
patient is lost to follow-up, then this should be noted in the eCRF.  The assessments to be 
carried out at the 30-day follow up visit are detailed in the study schedule (Table 2). 
Following radiological disease progression patients will be followed for OS. 
4.3.2 
Treatment discontinuation visit due to any other discontinuation criteria 
Patients should be discontinued from study treatment if any discontinuation criteria are 
fulfilled (see Section 3.6).  A follow up visit should be scheduled as indicated above. The 
assessments to be carried out at the 30-day follow up visit are detailed in the study schedule 
(Table 2). 
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4.3.3 
Survival 
Assessments for survival should be made every 8 weeks following objective radiological 
disease progression.  Survival information may be obtained via telephone contact with the 
patient, patient’s family or by contact with the patient’s current physician.  Survival data will 
be collected up to the time of the final overall survival (OS) analysis.  In addition, patients 
should be contacted in the week following the data cut-off for the primary PFS and final 
survival analyses to provide complete survival data. 
Patients will be followed up as per Table 2 to the point of the final analysis.  At this point 
investigators will be notified that no further data collection for the study is required.  
Monitoring and recording of SAEs will continue as per Section 6.4.  
The status of patients at the time of an overall survival analysis should be obtained by the site 
personnel by checking the patient’s notes, hospital records, contacting the patients general 
practitioner and checking publicly available death registries. In the event that the patient has 
actively withdrawn consent to the processing of their personal data the vital status of the 
patient can be obtained by site personnel from publicly available resources where it is possible 
to do so under applicable local laws (see Section 3.7). 
4.3.4 
Subsequent Treatment 
Following objective progression patients will be assessed every 8 weeks for survival (see 
Section 4.3.3). Outcome from subsequent therapy is not an objective of this trial.  
4.4 
Patient management post final analysis 
At this time point, the clinical study database will close to new data.  Patients who are 
receiving treatment can either choose to discontinue from the study or where the investigator 
believes patients are gaining clinical benefit; patients may continue to receive study treatment.  
All patients will receive follow up care in accordance with standard local clinical practice. 
SAEs will continue to be reported to AstraZeneca Patient Safety Department, for any patients 
who continue on olaparib until 30 days after study treatment is discontinued, in accordance 
with Section 6.4.  Additionally as stated any SAE or non-serious adverse event, that is 
ongoing at the end of the study, must be followed up to resolution unless the event is 
considered by the investigator to be unlikely to resolve, or the patient is lost to follow-up.  If 
an investigator learns of any SAEs, including death, at any time after a patient has completed 
the study, and he/she considers there is a reasonable possibility that the event is causally 
related to the investigational product, the investigator should notify AstraZeneca, Patient 
Safety. 
Drug accountability should continue to be performed until the patient stops study treatment 
completely 
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5. 
STUDY ASSESSMENTS   
 Electronic Case Report Forms will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the electronic Case Report Forms as 
specified in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms. A copy of the completed 
electronic Case Report Forms will be archived at the study site. 
5.1 
Efficacy assessments 
5.1.1 
CT and MRI scans tumor assessments (RECIST 1.1) 
Following the baseline assessment, subsequent tumor assessments according to RECIST 1.1 
should be performed every 8 weeks (±1 week) for the first 40 weeks and then every 12 weeks 
(± 1 week) thereafter, up to objective disease progression by RECIST.  
For those patients with no evidence of disease at baseline, following a clinical complete 
response to chemotherapy, progression is defined by the detection of new lesions on follow up 
radiological assessments (RECIST 1.1). 
 
The imaging modalities used for RECIST assessment will be CT (MRI where CT is 
contraindicated) scans of the chest, abdomen and pelvis with other regions as clinically 
indicated. The same imaging modality should preferably be used for each restaging visit. 
Radiological examinations performed in the conduct of this study should be retained at site as 
source data. 
It is important to follow the assessment schedule as closely as possible. If scans are performed 
outside of scheduled visit ± 1 week window interval and the patient has not progressed, every 
attempt should be made to perform the subsequent scans at their scheduled time points.  
Patients will be evaluated until objective radiological disease progression by RECIST 1.1 as 
per the study schedule (seeTable 2), and then followed for second progression and survival, 
regardless of whether study treatment is discontinued or delayed and/or protocol violations, 
unless they withdraw consent. 
5.1.2 
Tumor Evaluation 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
progression free survival (PFS) times.  (The RECIST 1.1 guidelines for measurable, non-
measurable, target and non-target lesions and the objective tumor response criteria (complete 
response, partial response, stable disease, no evidence of disease or progression of disease).  
The methods of assessment of tumor burden used at baseline - CT or MRI scans of chest, 
abdomen and pelvis, with other regions as clinically indicated for the assessment of disease 
must be used at each subsequent follow-up assessment, see Section 4.3.  
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Study Code:  ISS22810097 
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Following the baseline assessment, efficacy for all patients will be assessed by objective 
tumor assessments every 8 weeks (±1 week) for the first 40 weeks then every 12 weeks (±1 
week), according to the planned study scheduleTable 2 until objective radiological disease 
progression as defined by RECIST. If a patient discontinues treatment (and/or receives a 
subsequent cancer therapy) prior to progression then the patient should still continue to be 
followed until objective radiological disease progression as defined by RECIST 1.1. 
Categorization of objective tumor response assessment will be based on the RECIST criteria 
of response: complete response (CR), partial response (PR), stable disease (SD), progression 
of disease (PD), no evidence of disease (NED) and not evaluable (NE).  Target lesion (TL) 
progression will be calculated in comparison to when the tumor burden was at a minimum (ie, 
smallest sum of diameters previously recorded on study).  In the absence of a best response of 
progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline 
tumor measurements obtained before allocation. 
For patients with non-measurable disease only at baseline, categorization of objective tumor 
response assessment will be based on the RECIST criteria of response: CR (complete 
response), PD (progression of disease) and Non CR/Non PD. Patients with no disease at 
baseline will be assessed according to RECIST 1.1 criteria for new lesions with responses of 
No Evidence of Disease (NED) or progression of disease. 
If the investigator is in doubt as to whether disease progression has occurred on study therapy, 
particularly with response to NTL (non-target lesion) or the appearance of a new lesion, it is 
advisable to continue treatment until the next scheduled assessment or sooner if clinically 
indicated and reassess the patient’s status.  If repeat scans confirm disease progression, then 
the date of the initial scan should be declared as the date of disease progression.  
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. 
Following progression, patients should continue to be followed up for survival every 8 weeks 
as outlined in the study plan. It is important to follow the assessment schedule as closely as 
possible. Please refer to the study plan and CT/MRI scans in section 5.1.1. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the Study Schedule (see Table 2). 
These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated.  
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Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
The following laboratory variables will be measured: 
Table 3 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin  
S-Sodium 
B-Red blood cells [RBC] 
S-Potassium 
B-Platelets 
S-Magnesium (baseline only and if clinically 
indicated) 
B-Mean cell volume [MCV] 
S-Calcium  
B-Mean cell haemoglobin concentration [MCHC]  
S-Creatinine 
B-Mean cell haemoglobin [MCH] 
S-Total bilirubin 
B-White blood cells [WBC]  
S-Gamma glutamyltransferase [GGT]  
B-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. 
S-Aalkaline phosphatase [ALP] 
S-Aspartate transaminase [AST] 
S- alanine transaminase [ALT] 
S-Urea or blood urea nitrogen [BUN] 
S-Total protein 
S-Albumin 
S-Lactate dehydrogenase (LDH) 
 
 
Urine Tests 
 
Urinalysis (Dipstick, baseline only and if clinically 
indicated) 
 
U-Hb/Erythrocytes/Blood 
 
U-Protein/Albumin 
 
U-Glucose 
 
Urinalysis (Microscopic analysis, baseline only 
and if clinically indicated) 
 
 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 5.2. 
For blood volume see Section 5.4.1. 
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5.2.2 
Physical examination 
For timing of individual measurement refer to study schedule (Table 2). 
A physical examination will be performed and include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen and neurologic systems. Additional systems 
to be examined as clinically indicated. 
5.2.3 
ECOG 
ECOG Performance Status is a widely used, 5-level, clinician reported outcome of the 
patient’s performance status. Below is a description of the clinician’s grading system for the 
ECOG Performance Status. This measure will be applied according to the study schedule (see 
Table 2). 
Table 4 
ECOG Performance Status a 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
a 
As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
  
5.2.4 
ECG 
5.2.4.1 
Resting 12-lead ECG 
ECGs are required during screening within 7 days prior to starting study treatment and when 
clinically indicated afterwards.  
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected.  
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal / not clinically significantly abnormal.  If 
there is a clinically significant abnormal finding, the investigator will record it as an AE on the 
eCRF.  The original ECG traces must be stored in the patient medical record as source data. 
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5.2.5 
Vital signs 
Height will be assessed at screening only. 
Weight will be assessed at screening and as clinically indicated at any other time.  
Any changes in vital signs should be recorded as an AE, if applicable. 
5.2.5.1 
Pulse and blood pressure 
Blood pressure and pulse rate will be measured preferably using a semi-automatic BP 
recording device with an appropriate cuff size. 
5.2.5.2 
Body temperature 
Body temperature will be measured in degrees Celsius using an automated thermometer. 
5.2.6 
Other safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in the Study Schedule (see Table 2). 
These tests will be performed by the hospital’s local laboratory.  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. 
5.2.6.1 
Serum or urine pregnancy test 
Pregnancy tests on blood or urine samples will be performed for pre-menopausal women of 
childbearing potential as per the study schedule.  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. 
5.2.7 
Bone marrow or blood cytogenetic samples  
Bone marrow or blood cytogenetic samples may be collected only if clinically indicated for 
patients with prolonged haematological toxicities as defined in Section 6.6.1.  
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.  Full reports must be 
provided by the investigator for documentation on the Patient Safety database. 
5.3 
Biomarkers 
Tumor and blood samples will be collected for the biomarker work as detailed in the 
Laboratory manual.  
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For blood volume see Section 5.4.1. 
5.3.1 
Biomarker samples 
The biomarker samples will be collected as described in Table 5. 
Table 5  
Samples for Biomarker Research 
Sample Type 
Visits 
Research biopsy  
Screening; after progression  
 
 
Archival tumor sample (paraffin or 
cytology) – Requested, if available 
 Screening 
Blood samples for biomarker analysis  
Cycle 1 Day 1 and disease progression  
 
The samples and data from this research will be coded and not labelled with any personal 
details.  Each sample will be identified with the study and patient enrollment number.  In this 
way biomarker data may be correlated with clinical data, samples destroyed in the event of 
withdrawal of consent and regulatory audit enabled.  However, only the investigators will be 
able to link the biomarker sample to the individual patient.  The coded samples will be 
provided to the research laboratories performing the biomarker analyses. Investigators will not 
provide biomarker results to patients, their family members, any insurance company, an 
employer, clinical study investigator, general physician or any other third party unless 
required to do so by law.  The patient’s samples will not be used for any other purpose other 
than those described in the protocol. 
5.3.1.1 
Guidance for BRCA testing of patients with unknown BRCA status. 
Patients who meet the eligibility criteria of family history will be referred to a genetic 
counsellor only if their underlying genetic status is unknown. Genetic testing will be ordered 
as per patient eligibility for testing as per standard of care. If the result shows that the patient 
has a deleterious/suspected deleterious BRCA mutation, the patient will not be eligible to the 
study.  ` 
5.3.1.2 
Collection of blood sample for exploratory assay(s) 
All patients will be required to provide a mandatory 12 ml blood sample that will be stored in 
Dr. Donghui Li’s laboratory for subsequent assessment of current and future assay(s). 
Residual blood (or its derivatives) may be used to evaluate future HRD companion diagnostic 
tests and for additional exploratory work, to elucidate the mechanism of response, understand 
the mode of action of study treatment, and improve the understanding of pancreas cancer and 
disease recurrence. 
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5.3.2 
Exploratory Biomarker Research on Archival Tumor Samples (Paraffin block 
or tissue cytology slides) (Requested, if available) 
These samples will be collected from the site pathologist during the screening period.  An 
adequately sized (minimum of 2 mm x 2 mm) archival tumor tissue paraffin block from a core 
biopsy from the primary tumor or a metastatic site is preferred. Alternatively, 10-20 pre-cut 
sections mounted on glass slides prepared from the block can be provided. If the only 
diagnostic test was cytologic, a paraffin block or three unstained slides of tumor tissue should 
be tested for correlative studies as detailed in the laboratory manual. 
Collection of an archival tumor sample is requested if available for all patients. Surplus tissue 
may be used for additional exploratory work, to elucidate the mechanism of response, 
understand the mode of action of study treatment, and improve the understanding of disease 
progression. 
Please refer to Investigator Laboratory Manual for further details of archival tissue collection, 
shipping and storage. 
5.3.3 
Exploratory Blood samples for biomarker analysis (Mandatory) 
All consenting patients will be required to provide a blood sample at Cycle 1 Day 1 and 
disease progression for exploratory biomarker research. 
Patients will be required to provide: 
• 1x 6ml blood sample for preparation of serum at cycle 1 day 1 and disease 
progression. 
• 1x 6ml blood sample for preparation of plasma at cycle 1 day 1 and disease 
progression.  
Please refer to Investigator Laboratory Manual for further details of biomarker blood sample 
collection, shipping and storage.  
5.4 
Biological sampling procedures  
5.4.1 
Volume of blood 
The volume of blood that will be drawn from each patient will vary, dependent upon the 
length of time that the patient remains in the trial.  The total volume of blood to be drawn 
from each patient in the study, assuming they complete screening, 6 cycles of treatment, a 
treatment discontinuation visit and the 30-day follow-up visit, is 255mL. 
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  The number of samples/blood volumes is therefore patient to 
site-specific change.  Extra blood samples may also be collected if, for example, additional 
samples are required for repeat safety assessments. 
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The total volume of blood that will be drawn from each patient in this study is as follows: 
Table 6  
Volume of blood to be drawn from each patient 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
5 
21 
105 
 
Haematology 
5 
21 
105 
 
Coagulation 
3 
1 
3 
Whole blood sample for genetic testing 
(retrospective/prospective) 
Whole blood sample for assessment of 
current and future BRCA mutation 
assay(s) (if indicated) 
9 
 
9 
1 
 
1 
9 
 
9 
Serum Pregnancy test (site may use urine 
instead) 
Site dependent 
Site may use 
urine instead 
 
Serum sample for exploratory biomarkers, 
cycle 1 day 1 (mandatory) 
6 
1 
6 
Plasma sample for exploratory 
biomarkers, cycle 1 day 1 (mandatory) 
6 
1 
6 
Serum sample for exploratory biomarkers, 
disease progression (mandatory) 
6 
1 
6 
Plasma sample for exploratory 
biomarkers, disease progression 
(mandatory) 
6 
1 
6 
Total 
 
 
255 
5.4.2 
Handling, storage and destruction of biological samples 
The samples will be used up or disposed of after analyses or retained for further use as 
described here. 
HR dysfunction expression signature by microarray will be evaluated from fresh RNA 
extracted from pretreated biopsies performed in the screening period from core needle biopsy 
from liver, omentum, lung or lymph node (Peng scientific co-PI / MDACC et al). Total RNA 
will be extracted from the frozen tissues by using a mirVana RNA isolation labeling kit 
(Ambion, Inc). Five hundred naograms of total RNA will be used for labeling and 
hybridization using Illumina HumanHT 12v4 (24 rxn) chips according to the manufacturer’s 
protocols (Illumina). All microarray experiments will be conducted in the MDACC 
Sequencing and Microarray Core Facility, where the protocol for microarray analysis has been 
standardized to produce robust and reliable microarray data. Microarray data analyses will be 
consulted with MDACC bioinformatics Shared Resource. Briefly, as described in our previous 
publication36, the microarray data will be normalized using the quantile normalization method 
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in the LIMMA (Linear Models for Microarray Data) package in the R language environment. 
The expression level of each gene will be transformed into a log2 base before further analysis. 
Based on cluster analysis of the gene expression array data (Cluster 3.0), we will investigate if 
the HR-defective gene signature correlates with clinical response to PARPi. We will select the 
most significant genes in the HR-defective gene signature associated with PARPi response for 
further study. We will also test if a subset of the gene signature can be identified as predictive 
markers, which will allow for a more clinically-appropriate PCR-based analysis.  
5.4.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria),  
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with sponsor and appropriate labelling, 
shipment and containment provisions are approved. 
5.4.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
If required, sponsor will ensure that remaining biological samples are returned to the site, 
according to local regulations or at the end of the retention period, whichever is the sooner. 
5.4.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, sponsor is 
not obliged to destroy the results of this research. 
Archival tumor sample: If consent to use the sample is withdrawn this will not impact 
eligibility to study. The patient may continue in the study if the patient is already on study 
treatment. 
Blood samples for biomarker analysis: Although mandatory, the patient may continue in the 
study if the patient is already on study treatment. 
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The Principal Investigator: 
• Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to sponsor 
• Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• Ensures the laboratory (ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented 
and the signed document returned to the study site 
• Ensures that the patient and sponsor are informed about the sample disposal. 
Sponsor ensures the central laboratory (ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
An adverse event 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. 
6.2 
Recording of adverse events 
6.2.1 
Time period for collection of adverse events 
Adverse Events will be collected from first protocol specific intervention (start of study 
medication) throughout the treatment period up to and including the 30-day follow-up period.  
All ongoing and any new AEs/SAEs identified during the 30 calendar days follow up period, 
after the last dose of study medication must be followed to resolution. After any interim 
analysis, any ongoing AEs/SAEs need to be unlocked and followed for resolution. 
 SAEs will be recorded from first protocol specific intervention (start of study medication). 
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Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate.    
  
The Investigator or designee will be responsible for verifying and providing source 
documentation for all adverse events and assigning attribution for each event for all subjects 
enrolled on the trial. 
6.2.2 
Follow-up of unresolved adverse events 
Any SAEs or non-serious adverse event that is ongoing at the time of the 30-day follow up, 
must be followed up to resolution unless the event is considered by the investigator to be 
unlikely to resolve, or the patient is lost to follow up.  
6.2.3 
Variables  
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 (yes or no) 
− 
Action taken with regard to investigational product 
− 
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 hospitalisation 
− 
Date of discharge 
− 
Probable cause of death 
− 
Date of death 
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− 
Autopsy performed 
− 
Causality assessment in relation to Study procedure(s) 
− 
Causality assessment in relation to Other medication 
− 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.3.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.3. 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 when it satisfies the criteria 
shown in Section 6.3. 
Severity of AE 
For each episode on an adverse event, all changes to the CTCAE grade attained as well as the 
highest attained CTC grade should be reported. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.3.  An AE of severe 
intensity need not 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. 
The grading scales found in the National Cancer Institute (NCI) CTCAE version 4.0 will be 
utilised for all events with an assigned CTCAE grading.  For those events without assigned 
CTCAE grades the recommendation is that the CTCAE criteria that convert mild, moderate 
and severe events into CTCAE grades should be used. 
A copy of the CTCAE version can be downloaded from the NCI website. 
6.2.4 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
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6.2.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the CRF.  
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. 
6.2.6 
Adverse events based on examinations and tests 
The reporting of laboratory/vital signs/ECG abnormality as AE should be avoided unless one 
of the following is met: 
− 
Any criterion for an SAE is fulfilled 
− 
Causes study treatment discontinuation 
− 
Causes study treatment interruption 
− 
Causes study treatment dose reduction 
− 
The investigator believes that the abnormality should be reported as an AE 
If deterioration in a laboratory value/vital sign 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, anaemia versus low haemoglobin 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 laboratory value, 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. 
6.2.7 
Hy’s Law 
Cases where a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN may need 
to be reported as SAEs if related to the study medication as per study PI. 
6.2.8 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  The development of local 
regional recurrence or distant metastasis to the primary cancer under study should be 
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considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 
New cancers 
The development of a new primary cancer (including skin cancer) should be regarded as an 
AE and will generally meet at least one of the serious criteria (see Section 6.3).  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. 
Lack of efficacy 
When there is deterioration in the cancer, for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless 
AstraZeneca or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration 
should be considered to be a lack of efficacy and not an AE. 
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 DEATH 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 (see Section 6.3 for further details).  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-mortem 
results should be forwarded to  AstraZeneca within the usual timeframes. 
6.3 
Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or AstraZeneca, it results in any of the following outcomes: 
• Death 
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• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
• Important medical events as defined above may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office. 
 
• (Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last study treatment/intervention, unless the 
participant withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of 
the event has stabilized, or there has been acceptable resolution of the event. 
 
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• Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
Reporting to AstraZeneca: 
 
All SAEs must be reported to AstraZeneca (by the investigator or designee) in a timely 
fashion of study personnel learning of its occurrence. 
6.4 
Overdose 
There is currently no specific treatment in the event of overdose of olaparib and possible 
symptoms of overdose are not established.   
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 CRF 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 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
For overdoses associated with SAE, standard reporting timelines apply (see Section 6.4).  For 
other overdoses, reporting should be done within 30 days. 
6.5 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
6.5.1 
Maternal exposure 
Women of childbearing potential must agree to use adequate contraception.  Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to AstraZeneca. 
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If a patient becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
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 discontinued from the study. 
If any pregnancy occurs, then the Investigator or other site personnel informs the appropriate 
AstraZeneca representatives within 1day i.e., immediately but no later than 24 hours 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 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
6.5.2 
Paternal exposure  
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days 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 30 days after the 
last dose should be followed up and documented. 
To capture information about a pregnancy from the partner of a male patient, the male 
patient’s partner consent must be obtained to collect information related to the pregnancy and 
outcome; the male patient should not be asked to provide this information.  
 
6.6 
Management of toxicity of olaparib 
Non-hematological toxicities that are clinically significant and definitely, probably or possible 
related to olaparib. Note all reductions are final, there will be no re-escalation. Maximal dose 
reduction allowed is 200 mg bid. 
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6.6.1 
Management of haematological toxicity olaparib  
Table 7  
Management of Haematological Toxicity from Olaparib 
Toxicity 
Study treatment dose adjustment 
CTCAEa gr 1 or 2 
Appropriate supportive treatment and causality investigation 
Repeat CTCAE gr 2 
Dose interruption until recovery to CTCAE gr 1 and resume at same dose. 
For repeat gr. 2 or higher, dose reduction to 250 mg bid as first step. For 
repeat toxicities reduce to 200 mg bid  
CTCAE gr 3-4 
Dose interruption until recovered to CTCAE gr 1 and dose reduction to 
250 mg bid as first step. For repeat toxicities reduce to 200 mg bid. 
Maximal dose interruption allowed is 4 weeks. 
Repeat CTCAE gr 3-4 
Discontinue study treatment if already at 200 mg bid dosage. 
a 
CTCAE Version 4 
Note: These dose reductions will not apply to Anemia. Please refer to 6.6.1.1 for the same. 
6.6.1.1 
Management of anaemia 
Adverse events of anaemia CTCAE grade 1 or 2 (Hb > 8 g/dl) 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 anaemia.  Common treatable causes 
of anaemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) should be 
investigated and appropriately managed.  In some cases management of anaemia may require 
blood transfusions.  However, if a patient develops anaemia CTCAE grade 3 (Hb < 8g/dl) 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/dl.  Any subsequently required 
anaemia 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 anaemia with multiple blood transfusions without study 
treatment interruptions and becomes blood transfusion dependant as judged by investigator, 
study treatment should be interrupted for up to a maximum of 4 weeks to allow for bone 
marrow recovery.  Study treatment should be restarted at a reduced dose. 
6.6.1.2 
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 (7 
days for pegylated G-CSF) of the last dose of study treatment unless absolutely necessary.  
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Study treatment can be restarted if an adverse event of neutropenia or leukopenia has been 
recovered up to CTCAE grade 1 (ANC ≥ 1.5 x 109/L).   
Dose modifications for neutropenia are described in Table 7 above. 
6.6.1.3 
Management of thrombocytopenia 
An adverse event of thrombocytopenia should be managed as deemed appropriate by the 
investigator. In some cases management of thrombocytopenia may require platelet 
transfusions.  Platelet transfusions should be done according to local hospital guidelines. 
Management of prolonged haematological toxicities while on study treatment. 
If a patient develops prolonged haematological toxicity such as: 
• ≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
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 haematologist for further investigations.  Bone 
marrow analysis and/or blood cytogenetic analysis should be considered at this stage 
according to standard haematological 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.  Olaparib treatment should be discontinued if patient’s diagnosis of MDS 
and/or AML is confirmed. 
6.6.2 
Management of non-haematological toxicity Olaparib 
6.6.2.1 
Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormality 
occurs, an interruption in study treatment 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 study treatment can be restarted, if deemed appropriate by the 
investigator.  If drug-induced pneumonitis is observed, olaparib will be discontinued.  
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6.6.2.2 
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 for nausea and within the first 6 months of treatment for 
vomiting. For nausea, the incidence generally plateaus at around 9 months, and for vomiting at 
around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea 
or vomiting and as required thereafter, in accordance with local treatment practice guidelines. 
As per international guidance on antiemetic use in cancer patients (ESMO, NCCN), generally 
a single agent antiemetic should be considered e.g. dopamine receptor antagonist, 
antihistamines, dexamethasone. 
6.6.2.3 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept 
as short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution 
of intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with AZ study physician. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF. 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery 
study treatment can be restarted when the wound has healed.  No stoppage of study treatment 
is required for any biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment.  Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur.  
6.7 
Study governance and oversight 
6.7.1 
Data Monitoring  
The MD Anderson IND Office will organize on-site monitoring of this study at MDACC to be 
conducted as per the Monitoring Plan. The frequency of these visits at the site may depend on 
accrual or other factors (eg: site issues, etc). A clinical monitor will make regularly scheduled 
trips to the investigational site to review the progress of the trial. Site monitoring of the study 
is the responsibility of the Investigator and GI Medical Oncology (GIMO) Department. The 
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study monitor will advise the Investigator regarding the practical conduct of the study and 
maintaining compliance with the protocol, GCP and all applicable regulatory requirements. 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a GIMO 
representative will review the protocol and CRFs with the Investigator and his staff. 
Throughout the course of the study, the study monitor will oversee the conduct and the 
progress of the study by frequent contacts with the Investigator. This will include telephone 
calls and on-site visits.  
During the on-site visits, the CRFs will be reviewed for completeness with corresponding 
source documents. As part of the data audit, source documents will be made available for 
review by the study monitor. The study monitor will also perform drug accountability checks 
and may periodically request review of the Investigator study file to ensure completeness of 
documentation in all respects of clinical study conduct. 
Monitoring visits will be arranged in advance with site personnel at a mutually acceptable 
time. Sufficient time must be allowed by the site personnel for the monitor to review CRFs 
and relevant source documents. The Investigator should be available to answer questions or 
resolve data clarifications. The Investigator or appointed delegate will receive the study 
monitor during these on-site visits, cooperate in providing the documents for inspection, and 
respond to inquiries.  
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
AstraZeneca’s Pharmaceutical Development, R&D Supply Chain will supply olaparib to the 
Investigator as film-coated tablets as shown below. 
Investigational product 
Dosage form and strength 
Olapariba 
Tablet –100mg and 150 mg  
 
 
a 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
 
7.2 
Dose and treatment regimens 
Study treatment is available as film-coated tablet containing 150 mg or 100 mg of olaparib. 
For all centres, olaparib will be packed in high-density polyethylene (HDPE) bottles with 
child-resistant closures.  The study treatment will be dispensed to patients.  Each dosing 
container will contain sufficient medication for at least each treatment period plus overage.  
The planned dose of 300 mg bid will be made up of two (2) x 150 mg tablets bid with 100 mg 
tablets used to manage dose reductions.  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 
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or divided.  Olaparib tablets can be taken with a light meal/snack (eg, two pieces of toast or a 
couple of biscuits). Multiple bottles of olaparib may be required for dispensing in order to 
make up the desired dose.  
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (eg, as a result of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum 
of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and the patient should take their allotted dose at the 
next scheduled time. 
Once patients have been discontinued from study treatment, other treatment options will be at 
the discretion of the investigator. 
7.3 
Labelling 
Labels for olaparib will be prepared in accordance with Good Manufacturing Practice (GMP) 
and local regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for 
labelling.  Label text will be translated into local language.  
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions and may 
only be dispensed by investigator or pharmacist qualified designee. The investigational 
product label on the olaparib bottle and the IB specifies the appropriate storage conditions.  
7.5 
Compliance 
The administration of all study drug should be recorded in the appropriate sections of the 
eCRF. 
Patients should be given clear instructions on how and when to take their olaparib.  Patients 
will self-administer olaparib.  Study site staff will make tablet counts at regular intervals 
during treatment.  Compliance will be assessed by the tablet count and the information will be 
recorded in the appropriate section of the eCRF.  After the tablet count has been performed, 
the remaining tablets will not be returned to the patient, but will be discarded by 
Investigational Pharmacy.  All patients must return their bottle(s) of olaparib at the 
appropriate scheduled visit, when a new bottle will be dispensed.  Patients will be instructed to 
notify study site personnel of missed doses.  Dates of missed or held doses will be recorded by 
the site staff on the eCRF. 
Patients must return all containers and any remaining tablets at the end of the study. 
7.6 
Accountability 
The study treatment provided for this study will be used only as directed in the study protocol. 
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The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery, destruction and return should be 
signed.  Any discrepancies must be accounted for on the appropriate forms. 
7.7 
Concomitant and other treatments  
Any medications (with the detailed exceptions) 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 addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded.  This includes any blood transfusions. 
The reasons for the use, doses and dates of treatment should be recorded in the patient’s 
medical records  
All medications (prescriptions or over the counter medications) continued at the start of study 
medication 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. 
7.7.1 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy, 
radiotherapy, biological therapy or other novel agent) is to be permitted while the patient is 
receiving study medication.  Hormone replacement therapy (HRT) is acceptable. 
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. 
7.7.2 
CYP3A4/5 restrictions  
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. 
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.  A phase I study to assess the effect of steady state itraconazole (a CYP3A4 
Inhibitor) on the pharmacokinetics of olaparib following oral dosing of the tablet formulation 
has been conducted  in patients with advanced solid tumours. Following a single oral 
administration of olaparib (100 mg tablet), AUC increased by 2.7-fold  in combination with 
itraconazole compared with olaparib administered alone. Cmax also increased by 1.4-fold and 
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tmax was delayed by about 0.5 hour when olaparib was dosed in combination with 
itraconazole.  (Astrazeneca internal report reference D0816C00007).  A phase I study was also 
conducted in patients to investigate  the effect of steady rifampicin, a potent CYP Inducer, on 
the pharmacokinetics of olaparib following a single oral dose (300 mg) of the tablet 
formulation. Results showed that olaparib Cmax  decreased in the presence of rifampicin by 
about 71%. There was also an 87% reduction in AUC for olaparib in combination with 
rifampicin compared with olaparib alone. (Astrazeneca internal report reference 
D0816C00008). 
 
In vitro data have also shown that the principal enzyme responsible for the formation of the 3 
main metabolites of olaparib is CYP3A4/5 and consequently, to ensure patient safety, the 
following potent inhibitors of CYP3A4/5 must not be used during this study for any patient 
receiving olaparib. While this is not an exhaustive list, it covers the known potent inhibitors, 
which have most often previously been reported to be associated with clinically significant 
drug interactions: 
• ketoconazole, itraconazole, ritonavir, idnavir, saquinavir, telithromycin, clarithromycin 
and nelfinavir  
For patients taking any of the above, the required wash-out periods prior to starting olaparib is 
one week. 
In addition, to avoid potential reductions in exposure due to drug interactions, the following 
CYP inducers should be avoided: 
• Phenytoin, rifampicin, rifapentin, rifabutin, carbamazepine, phenobarbitone, 
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 phenobarbitone 5 weeks, and for any of the others, 3 weeks. 
Olaparib can inhibit CYP3A4 and UGT1A1 in vitro. These findings suggest that olaparib has 
the potential to cause clinically significant interactions with other CYP3A4 substrates or 
UGT1A1 substrates in the liver or gastrointestinal tract. Therefore, caution should be 
exercised when substrates of CYP3A4 are combined with olaparib, in particular those with a 
narrow therapeutic margin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus and quetiapine). Substrates of UGT1A1 should also 
be given with caution in combination with olaparib (e.g. irinotecan, nintedanib, ezetimibe, 
raltegravir or buprenorphine). 
 
 
7.7.3 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form. 
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7.7.4 
Anti-emetics/ Anti-diarrheal 
Should a patient develop nausea, vomiting and/or diarrhoea, then these symptoms should be 
reported as AEs (see section 6.2) and appropriate treatment of the event given. 
7.7.5 
Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; 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. 
7.7.6 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. 
Treatment with bisphosphonates or RANKL inhibitor for the prevention of skeletal related 
events in patients with bone metastasis is permitted and must be started at least 5 days prior to 
allocation. 
7.7.7 
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer after discontinuation of treatment will be 
collected.  Response to subsequent therapies and PFS on those therapies will also be collected. 
The choice of subsequent systemic anticancer treatment will be entirely at the discretion of the 
investigator. 
8. 
STATISTICAL ANALYSIS AND SAMPLE SIZE 
DETERMINATION  
8.1 
Statistical considerations 
The primary endpoint is the objective response (i.e. CR or PR) achieved during the treatment. 
Simon's optimal two-stage design [Simon, 1989] will be implemented for the study.  With an 
type I error rate α of 0.058 and a β error rate of 0.19, and assuming P0 (OR rate of standard 
drug treatment) and P1 (OR rate of new study treatment) are 5% and 20%, respectively, it is 
estimated that up to 34 patients will be enrolled in the study, with 15 patients in the first stage 
and 19 patients in the second stage.  In the first step, if 0 or 1 response is observed among the 
first 15 patients treated, the study will be stopped for futility. However, if two or more 
responses are observed, then 19 additional patients will be enrolled onto the trial. The study 
drug will be considered of interest if ≥ 4 responders out of the 34 patients are observed. Based 
on this design, we estimate a 83% probability of early termination under the null hypothesis 
(i.e. ORR ≤ 5%).  The expected sample size under the null hypothesis is 18.3. If the 
alternative hypothesis is true (i.e. ORR ≥ 20%), then the probability of early termination is 
16.7%.  
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Further enrollment will continue during the interim analysis unless 0 or 1 responder has been 
reported by the time of enrollment of the 15th subject being analyzed. In this event, enrollment 
will be suspended and the first 15 subjects will be followed to further assess their responses. 
During this follow-up period, as soon as two or more responders among the 15 patients are 
observed, the enrollment will resume. If 0 or 1responder is observed after the 15 subjects have 
been fully assessed, the trial will be terminated for futility. 
After the first 6 evaluable patients have completed 24 weeks of study treatment, and every 3 
patients thereafter, a response/toxicity summary should be submitted to the IND Medical 
Monitor for review and approval.   Enrollment will continue per protocol. 
Toxicity monitoring 
Unacceptable toxicities will also be monitored closely for the phase II portion of the study 
using the method of Thall et al. Denote the probability of unacceptable toxicity by TE, where 
unacceptable toxicity is defined as treatment related grade 3 or higher toxicities.  We assume 
TE ~ beta (0.3, 0.7).  We will stop the enrollment if at any point Pr(PE > 0.30 | data)  >0.85. 
That is, we will stop the trial if, at any time during the study, we determine that there is more 
than 85% chance that the unacceptable toxicity rate is more than 30%. This toxicity 
monitoring rule will be applied after the first 6 patients have been enrolled and evaluated. The 
corresponding stopping boundaries are to stop the trial if (number of patients with 
unacceptable toxicities / number of patients) ≥4/(6-8), 5/(9-10), 6/(11-13), 7/(14-16), 8/(17-
19), 9/(20-21), 10/(22-24), 11/(25-27), 12/(28-30), 13(31-33). The operating characteristics 
are listed in table 7. 
Table 7: OCs for unacceptable toxicity monitoring 
 
True Prob(unacceptable tox)  
Pr(stop) 
mean # Pts (25%, 50%, 75%) 
0.1  
0.006 
33.8 (34, 34, 34) 
0.2  
0.085 
32.0 (34, 34, 34) 
0.3  
0.367 
26.1 (13, 34, 34) 
0.4  
0.754 
17.6 (7, 13, 33) 
0.5  
0.959 
11.1 (6, 7, 13) 
 
Multc Lean V2.1 was used for the toxicity monitoring design. 
 
8.2 Statistical Analysis 
8.2.1 Statistical analysis for the primary endpoint 
For the primary analysis, patients who are eligible for the trial and receive any dose of 
olaparib will be included in estimating the response rate.  Response outcome in the first 24 
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weeks will be used for primary analysis.  If a patient does not achieve an objective response in 
the first 24 weeks, the patient will be considered as a non-responder.  At any restaging, if 
there is progression per RECIST or if patient response cannot be assessed for any reason, that 
patient will be counted as a non-responder.  The objective response rate and its corresponding 
exact 95% confidence interval (CI) will be estimated. If an objective response rate of 20% or 
more is observed in one cohort with at least 5 patients treated, then treatment is warranted in 
further study in that cohort. 
8.2.2 Statistical analysis for the secondary endpoints 
The Progression free survival (PFS) is defined as the time from the date of study entry to the 
date of progression or to the date of death from any cause, whichever occurred first, or to the 
last follow-up date if patients are alive without disease progression. If a patient did not have 
an event, PFS will be censored at the last date of contact. Overall survival (OS) is defined as 
the time from date of study entry to the date of death from any cause or to the date of last 
follow-up if patients are alive. If a patient is not known to have died, the OS will be censored 
at the last date of contact.  
The Kaplan-Meier method will be used to estimate the probability of OS and the probability 
of PFS. The Log rank test and Cox proportional hazards models will be used to determine the 
association of OS or PFS with patient characteristics.      
The CA 19-9 clinical response is defined as the percentage reduction before and after 8 weeks 
of treatment. The mean, standard deviation, median and range will be summarized for the 
percentage reduction of CA 19-9.  
8.2.3 Statistical analysis for all the other demographic and clinical parameters  
For categorical variables, frequencies and percentages will be tabulated. For continuous 
variables, ranges, medians, means and standard deviations will be calculated. Distributions for 
categorical variables will be compared by the Chi square test or by Fisher exact test. Test for 
normality will be done by Shapiro-Wilk normality test. The comparisons of continuous 
variables will be performed by either t test or Wilcoxon rank sum test, and by ANOVA or 
Kruskal-Wallis test. All statistical tests will be analyzed to a significance level of 0.05.  
8.2.4. Safety analysis 
All patients who received at least one dose of olaparib will be included in the safety analysis. 
Safety and tolerability will be assessed in terms of adverse events (AEs), deaths, laboratory 
data, vital signs and ECG. AEs and other categorical events will be tabulated using 
frequencies and percentages. Summaries will be tabulated by severity. Continuous safety 
outcomes will be summarized using descriptive statistics including mean, standard deviation, 
median and range. 
8.2.5. Statistical analysis for exploratory correlative studies:  
 
To visualize expression patterns of the 230 study HRD signature genes, hierarchical clustering 
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analysis will be performed based on Pearson correlation (or other distance measures) and will 
use average linkage algorithms, and the corresponding heat-map and dendrogram will be 
plotted. ANOVA will be use per gene to identify differentially expressed genes, with Beta-
Uniform Mixture (BUM) model to control the false discovery rate (FDR) at 0.05 to adjust 
for multiple testing. In addition, Fisher’s exact test and two sample t test will be used to 
compare incidence of ATM loss and gene expressions between responders and non-
responders. 
 
The incidence of ATM loss will be examined in the study population.  Multivariable logistic 
regression will be used to evaluate the incidence of ATM loss after adjusting for the effects of 
covariates. Historical data suggest that the incidence of ATM loss in the study population is 
25%.32 We will confirm these findings and also use Kaplan Meier method to compare survival 
between the ATM high and loss groups and Cox regression to measure PFS and OS in the 
study subgroups.  
9. 
STUDY AND DATA MANAGEMENT  
9.1 
Training of study site personnel 
Before the first patient is entered into the study, Principal Investigator will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the investigational 
staff and also train them in any study specific procedures.  
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.2 
Monitoring of the study 
During the study, monitor representative will have regular contacts with the study site, 
including visits to: 
− 
Provide information and support to the Investigator(s) 
− 
Confirm that facilities remain acceptable 
− 
Confirm that the investigational team is adhering to the protocol, that data are 
being accurately and timely recorded in the CRFs, that biological samples are 
handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed 
− 
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant 
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to the study) including verification of informed consent of participating 
patients. This will require direct access to all original records for each patient 
(eg, clinic charts) 
− 
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the 
patient. 
The monitor representative will be available between visits if the Investigator(s) or other staff 
at the centre needs information and advice about the study conduct. 
9.2.1 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between and the Principal Investigator should be in place before any study-
related procedures can take place, or patients are enrolled. 
9.2.2 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).  
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The study is expected to start in Q2 2015 & end by Q3 2016. 
9.4 
Data management  
Data management of the trial conducted at MDACC will be performed by Department of 
Gastrointestinal Medical Oncology.   
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the CTCAE v4.   
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
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The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
When all data have been coded, validated, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
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 at MDACC 
10.2 
Patient 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. 
MDACC investigators will not provide individual genotype results to patients, any insurance 
company, any employer, their family members, general physician or any other third party, 
unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an investigator might know a patient’s identity and also have access to his 
or her genetic data. Also Regulatory authorities may require access to the relevant files, 
though the patient’s medical information and the genetic files would remain physically 
separate. 
10.3 
Ethics and regulatory review 
An Institutional Review Board (IRB)/Ethics Committee should approve the final study 
protocol, including the final version of the Informed Consent Form and any other written 
information and/or materials to be provided to the patients.  The investigator will ensure the 
distribution of these documents to the applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to sponsor before enrollment of any patient into the study.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
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Sponsor should approve any modifications to the Informed Consent Form that are needed to 
meet local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
 AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant. 
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the investigational product.   AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
• Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
• Ensure each patient is notified that they are free to discontinue from the study at any 
time 
• Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each patient provides signed and dated informed consent before conducting any 
procedure specifically for the study 
• Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
• Ensure a copy of the signed Informed Consent Form is given to the patient 
• Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the informed consent form that is approved by an Ethics Committee. 
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10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
Sponsor will distribute any subsequent amendments and new versions of the protocol to each 
Principal Investigator(s). For distribution to Ethics Committee see Section 10.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, Sponsor and 
the centre’s Ethics Committee are to approve the revised Informed Consent Form before the 
revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 
10.6 
Audits and inspections 
Authorised representatives a regulatory authority, or an Ethics Committee may perform audits 
or inspections at the centre, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements.  
 
 
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11. 
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