Phase II Study of Olaparib in Subjects With Advanced Pancreatic Acinar Cell Carcinoma
Phase: PHASE2
Conditions: Pancreatic Acinar Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Olaparib in advanced PACC
Version Date: 12/12/2024
1
Abbreviated Title: Olaparib in advanced PACC 
NIH Protocol #: 000596
Version Date: 12/12/2024
NCT Number: NCT05286827
Title: Phase II Study of Olaparib in Subjects with Advanced Pancreatic Acinar Cell Carcinoma 
NCI Principal Investigator
Christine Alewine, M.D., Ph.D.
Laboratory of Molecular Biology (LMB) 
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 37, Room 5116
9000 Rockville Pike
Phone: 240-760-6146
Email: Christine.alewine@nih.gov
Commercial Agents: Olaparib

Abbreviated Title: Olaparib in advanced PACC
Version Date: 12/12/2024
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PRÉCIS 
Background:
•
Pancreatic Acinar Cell Carcinoma (PACC) is a rare pancreatic tumor, representing 0.5-1% 
of all pancreatic malignancies.
•
PACC is commonly advanced at presentation and median overall survival in this 
population is poor. 
•
PACC is pathologically and biochemically distinct from pancreatic adenocarcinoma. 
•
No clinical trials for PACC have ever been reported.
•
Patients are most commonly treated with combination regimens used for either pancreatic 
or colon adenocarcinoma with poor (~30%) response rates in the first-line setting.
•
PACC pathological specimens demonstrate evidence of high chromosomal instability, a 
hallmark of DNA repair deficiency.
•
Data derived from ovarian and prostate cancer patients has demonstrated that mutations in 
DNA repair genes can define subgroups of cancer patients with distinct vulnerabilities to 
DNA damage response inhibitors.
•
Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved 
for the treatment of BRCA-mutant homologous recombination repair (HRR) deficient 
cancers.
•
As PACC has multiple hallmarks of HRR deficiency, we hypothesize that PACC will be 
sensitive to PARP inhibition with olaparib.
•
Pre-clinical modeling of PACC has been very limited with no currently available animal 
models or cell lines, which precludes testing this hypothesis in the laboratory setting.
Objective:
•
To assess the anti-tumor activity of single agent olaparib, a PARP inhibitor, in participants 
with advanced pancreatic acinar cell carcinoma (PACC) 
Eligibility:
•
Participants must have advanced previously treated PACC
•
Age ≥18 years
•
Adequate organ and bone marrow function
Design:
•
This is a phase II, single arm, single center study of olaparib in participants with advanced 
previously treated PACC.
•
All participants will take olaparib by mouth twice daily for up to two years or until disease 
progression or intolerable side effects.
•
Participants will be assessed for safety (continuously) and efficacy (every 8 weeks).
•
Up to 13 evaluable participants will be enrolled.

Abbreviated Title: Olaparib in advanced PACC
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TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION ...................................................................................................................6
1.1
Study Objectives ...............................................................................................................6
1.2
Background and Rationale................................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................10
2.1
Eligibility Criteria ...........................................................................................................10
2.2
Recruitment Strategies ....................................................................................................13
2.3
Screening Evaluation ......................................................................................................13
2.4
Participant Registration and Status Update Procedures..................................................14
3
STUDY IMPLEMENTATION .............................................................................................15
3.1
Study Design...................................................................................................................15
3.2
Drug Administration .......................................................................................................15
3.3
Dose Modifications.........................................................................................................16
3.4
On Study Assessments/Evaluations................................................................................17
3.5
End of Treatment Assessments.......................................................................................19
3.6
Follow-up Period.............................................................................................................20
3.7
Study Calendar................................................................................................................21
3.8
Cost and Compensation ..................................................................................................24
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................24
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................25
4.1
Supportive Care...............................................................................................................25
4.2
Prohibited Medications ...................................................................................................25
4.3
Permitted Medications & Treatments .............................................................................27
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................27
5.1
Biospecimen Collection ..................................................................................................27
5.2
Planned Analyses ............................................................................................................28
5.3
Sample Collection Schedule ...........................................................................................29
5.4
Storage, Use, and Sharing of Specimens and Data for Secondary Research..................30
5.5
Samples for Genetic/Genomic Analysis .........................................................................31
6
DATA COLLECTION AND EVALUATION .....................................................................32

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6.1
Data Collection ...............................................................................................................32
6.2
Data Sharing Plans..........................................................................................................33
6.3
Response Criteria ............................................................................................................33
6.4
Toxicity Criteria..............................................................................................................39
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...39
7.1
Definitions.......................................................................................................................39
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................39
7.3
NCI Clinical Director Reporting.....................................................................................39
7.4
NIH Required Data and Safety Monitoring Plan............................................................39
8
MANUFACTURER PROTOCOL/SAFETY REPORTING ................................................40
8.1
Definitions.......................................................................................................................40
8.2
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................42
9
CLINICAL MONITORING..................................................................................................42
10
STATISTICAL CONSIDERATIONS ..................................................................................42
10.1
Objectives and Endpoints................................................................................................42
10.2
Sample Size Determination.............................................................................................44
10.3
Populations for Analyses ................................................................................................44
10.4
Statistical Analyses .........................................................................................................45
11
COLLABORATIVE AGREEMENTS..................................................................................46
11.1
Cooperative Research and Development Agreement (CRADA)....................................46
12
HUMAN SUBJECTS PROTECTIONS................................................................................46
12.1
Rationale For Subject Selection......................................................................................46
12.2
Participation of Children.................................................................................................46
12.3
Risk/Benefit Assessment.................................................................................................47
12.4
Consent Process and Documentation..............................................................................49
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................49
13.1
Study Discontinuation and Closure.................................................................................49
13.2
Quality Assurance and Quality Control..........................................................................50
13.3
Conflict of Interest Policy...............................................................................................50
13.4
Confidentiality and Privacy ............................................................................................50
14
PHARMACEUTICAL INFORMATION .............................................................................51
14.1
Olaparib...........................................................................................................................51
15
REFERENCES ......................................................................................................................53

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16
LIST OF ABBREVIATIONS................................................................................................57
17
APPENDICES .......................................................................................................................60
17.1
Appendix A- Performance Status Criteria ......................................................................60
17.2
Appendix B- Acceptable Birth Control Methods ...........................................................61
17.3
Appendix C- Participant Optional Olaparib Pill Diary...................................................63
17.4
Appendix D- Management of Toxicity of Olaparib........................................................66
17.5
Appendix E- Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law.............................................................................................................71

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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
•
To assess the anti-tumor activity of single agent olaparib, a PARP inhibitor, in participants 
with advanced pancreatic acinar cell carcinoma (PACC)
1.1.2
Secondary Objectives
•
To assess alternative measures of anti-tumor efficacy such as clinical outcomes and blood 
biomarkers
•
To assess the safety of olaparib in advanced PACC 
1.1.3
Exploratory Objectives
•
To acquire tumor tissue through research biopsies that can be used to establish new patient-
derived xenografts (PDX), cell line and organoid models of PACC 
•
To assess genetic alterations in PACC through genetic mapping techniques (gene copy 
number analyses and cytogenetics) and to evaluate alterations in homologous 
recombination repair (HRR) and other DNA repair pathways 
•
To assess alterations in mRNA and protein levels of HRR-related genes such as BRCA1/2, 
PALB2 and RAD51, and functionality of HRR pathway as predictive biomarkers for 
olaparib
•
To assess ID3 protein levels and protein levels of DNA repair pathway genes of interest in 
participant tumor and normal tissue
•
To assess relationship of treatment response to tumor profile

Abbreviated Title: Olaparib in advanced PACC
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1.2
BACKGROUND AND RATIONALE
1.2.1
Pancreatic Acinar Cell Carcinoma (PACC) 
PACC is a rare pancreatic tumor that accounts for 0.5-1% of all pancreatic malignancies [1]. There 
are estimated to be 250-500 cases diagnosed in the United States each year. More than half of 
patients present with advanced disease and are not candidates for surgical resection. Metastases 
are most often located in the liver (78%) [2, 3]. Recent retrospective case series have reported a 
median overall survival (OS) in this population of 15-20 months [2, 4]. PACC patients who present 
with resectable disease have a median overall survival that approaches or exceeds 5 years. 
Unfortunately, almost half of patients who present with localized disease and receive surgery will 
have recurrence [1, 2, 5, 6]. Positive lymph node status and perineural invasion are predictive of 
recurrence. Recurrence almost always manifests as hepatic metastases. In summary, ~75% of 
patients who are diagnosed with PACC will develop metastatic disease, most typically to the liver. 
PACC is pathologically distinct from pancreatic adenocarcinoma [7]. Under the microscope, 
PACC is a highly cellular tumor with little stromal response. Over 90% of tumor cells stain positive 
for trypsin and chymotrypsin. Significant serum CA 19-9 elevation is uncommon, while elevation 
of serum lipase is observed in at least 50% of patients, and elevations in alpha-fetoprotein (AFP) 
can also be seen in some cases. Those with very high lipase levels (>1000 u/dL) can develop fat 
necrosis and panniculitis from lipase hypersecretion syndrome which manifests as painful, 
erythematous subcutaneous nodules accompanied by polyarthralgia and eosinophilia [8]. Mixed 
acinar-ductal and mixed acinar-endocrine variants represent about ~10% of cases, and the acinar 
component forms the majority of cells in almost all cases. These tumors behave similarly to pure 
PACC but acinar-ductal tumors may express mucin and acinar-neuroendocrine tumors 
chromogranin and/ or synaptophysin in addition to exocrine enzymes [7]. 
No clinical trials for PACC have ever been reported. There is no standard therapy for this disease. 
All information about response to systemic treatments comes from retrospective studies [2, 4, 9]. 
PACC patients are most commonly treated with regimens used for either pancreatic or colon 
adenocarcinoma. Clinical responses to single agent chemotherapy are rare [9, 10]. Recent studies 
suggest that the response rate to first-line combination chemotherapy is 30% or less. Regimens 
containing a platinum salt with a fluoropyrimidine appear to have the most clinical benefit. The 
benefit of gemcitabine in this disease is debatable [4]. 
1.2.2
Pre-clinical models of PACC
Pre-clinical modeling of PACC has been very limited.  A rat model was described in 1980, but 
cells grown in culture rapidly lost their differentiation within a few passages [11]. A patient-
derived xenograft derived from a PACC patient liver biopsy was recently described [12]. This 
model was found to be sensitive to oxaliplatin, and resistant to other chemotherapy typically used 
to treat PACC including 5-fluorouracil, irinotecan, gemcitabine, erlotinib and doxorubicin. 
Sequencing identified an inactivating BRCA2 mutation. A cell line derived from a patient with 
acinar cell carcinoma was also reported [13], but no characterization for PACC markers lipase, 
trypsin or chymotrypsin was performed. In addition, almost no chromosomal gains or losses were 
identified, raising doubt that this is truly a PACC line. One of the scientific goals of the proposed 
study is to acquire tumor tissue through research biopsies that can be used to establish new patient-
derived xenograft (PDX), cell line and organoid models of PACC.

Abbreviated Title: Olaparib in advanced PACC
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1.2.3
Molecular characteristics of PACC tumors
Molecular characteristics of PACC tumors have suggested that they are DNA repair deficient. 
Three different studies have performed detailed genomic analysis of PACC patient tumor tissue 
[14-16]. All 3 studies agreed that no gene was mutated in >30% of tumors. Results showing 
frequent mutation (10-25% incidence) of a gene in one of these studies (e.g., JAK1) could not be 
replicated in the cohorts tested in the other studies. Activating BRAF gene fusions were identified 
in ~20% of patients in one study [14]. Two of these studies [15, 16] and an additional, earlier study 
using comparative genomic hybridization to examine chromosomal changes [17] found frequent 
copy number alterations indicative of high chromosomal instability, a hallmark of DNA repair 
deficiency. In addition, mutational signature analysis identified the defective DNA repair signature 
in 15 of 22 tumors analyzed [15]. Mutations in known DNA repair genes, DNA polymerases and 
spindle checkpoint genes could not account for this finding [16]. BRCA1/2 mutation does occur 
in PACC but at rates <10%, so cannot account for the high rates of DNA repair deficiency. Jäkel 
et al. performed epigenomic analysis to find methylation changes between tumor and normal tissue 
and then overlaid these changes upon maps of copy number alterations to identify 292 genes most 
likely to have decreased expression at the protein level in PACC [15]. Immunohistochemistry 
(IHC) analyses for 8 of these was performed on patient tumor tissues (n = 23 in Cohort 1, n = 39 
in Cohort 2) and revealed frequent downregulation of 4 of these genes: ID3 (in 89-94% of tumor 
samples), ARID1A (in 68-74%), APC (in 62-71%) and CDKN2A (in ~51%) [15].  Verification of 
decreased protein levels for the other 284 genes predicted to be down-regulated at the protein level 
(including DNA repair-related genes [18] APITD, GADD45A, HFM1, HMGB2, MAD2L2, 
MUTYH, NEIL3, PLK3, RAD54L, RPA2, SMARCAD1, TCEB3, USP1) have not yet been 
reported.  While ARID1A has long been known to participate in DNA repair, a 2017 report 
identified ID3 as a critical player in the DNA double strand break repair pathway. Specifically, it 
was reported that ID3 was required for recruitment of MDC1 to sites of DNA damage, and loss of 
ID3 resulted in profound impairment of HRR following ionizing radiation [19]. Based on these 
data, we hypothesize that some PACC tumors may be HRR deficient due to the nearly ubiquitous 
reduction in ID3. Subsequently, additional information has emerged confirming that ID3 plays a 
significant role in HRR. Bakr and colleagues found that ID3 affects DNA repair via at least two 
different mechanisms: 1) direction interaction with DNA double strand break (DSB) repair 
proteins including early complex members NBS1 and RAD50 and interaction with RECQL to 
facilitate RAD51 loading, and 2) transcriptional changes in HRR and Fanconi Anemia pathway 
genes following exposure to ionizing radiation [20]. Both of these processes were independent of 
MDC1. In addition, we have shown that ID3 knock-down increases DNA damage [21]. HR 
deficiency seen in PACC may be secondary to downregulation of ID3 due to its novel role in DDR 
processes. 
1.2.4
Poly-ADP ribose polymerase (PARP)-1 inhibitors in HRR deficient cancer
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerization (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy 
and other anti-cancer agents.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more serious 

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DSBs during the process of DNA replication. During the process of cell division, DSBs can be 
efficiently repaired in normal cells by HRR.  
Several PARP inhibitor drugs, including olaparib, have now been FDA approved for the treatment 
of BRCA-mutant HRR deficient cancers after demonstrating clinical benefit in patients with breast 
and ovarian cancers bearing these mutations [22-24]. They have also shown efficacy in BRCA 
mutant prostate and pancreatic adenocarcinoma [25, 26]. The combination of PARP inhibition 
with BRCA-mutation is synthetically lethal. PARP inhibitors prevent efficient DNA SSB repair 
and also trap the PARP enzyme on these sites of broken DNA causing a “roadblock” against 
progression of the DNA replication machinery. This stalls the replication fork and generates a 
DNA DSB. While normal cells can use HRR to fix this lesion, BRCA-mutant cells cannot 
efficiently make this type of repair. This synthetic lethal interaction between BRCA mutation and 
PARP inhibition underlies the therapeutic efficacy of these drugs in HRR deficient tumors [27, 
28]. PARP inhibitors are currently being tested for clinical efficacy against tumors bearing 
mutations in genes other than BRCA-1 and BRCA-2 that are important in the HRR pathway.
Recently, it was shown that decreased levels of ID3 confer increased sensitivity to PARP inhibition 
[20]. Cell lines of the same cancer type with lower expression of ID3 had increased sensitivity to 
PARP inhibition. Also, knock-down or knock-out of ID3 also resulted in increased anti-tumor 
efficacy of PARP inhibition in prostate, PDAC, and osteosarcoma cell lines.
Multiple clinical studies have demonstrated that sensitivity of BRCA mutant tumors to PARP-1 
inhibitor therapy correlates with sensitivity to platinum-based chemotherapy agents. This has been 
best demonstrated in ovarian cancer patients where treatment with olaparib monotherapy resulted 
in objective response rate (ORR) (CR + PR) of 61.5% (8 of 13) in platinum sensitive patients, 
41.7% (10 of 24) in platinum resistant patients, and 0% (0 of 13) platinum refractory patients [29] 
(26). Other studies have also reported decreased response to PARP inhibition therapy in platinum-
insensitive patients [30]. Reactivation of the HRR pathway through BRCA reversion mutation, 
increased RAD51 loading, or 53BP1 loss to initiate BRCA-independent HRR are cited as the most 
common platinum-resistance mechanisms. PARP inhibition ceases to be lethal once these changes 
occur.   
Direct data examining whether platinum-resistant disease with ID3 deficiency harbors similar 
resistance to PARP inhibition is unavailable. Because ID3 deficiency effects multiple events in the 
HRR pathway and also transcription of HRR pathway components, adaptations that render cells 
resistant to platinum may be insufficient to eliminate ID3-conferred PARP sensitivity. Notably, 
ID3 knock-down in the MIA-PACA PDAC cell line confers increased sensitivity to PARP 
inhibitor therapy [20] but fails to alter platinum sensitivity [21].  It is currently unclear whether 
platinum resistance is predictive of resistance to PARP inhibition in ID3-deficient tumors like 
PACC. 
1.2.5
Rationale for treating PACC with olaparib
PACC has multiple hallmarks of an HRR deficient tumor: frequent sensitivity to platinum-based 
chemotherapy regimens, high chromosomal instability, mutational signature of DNA damage 
repair deficiency, and almost universal downregulation of a gene suggested to be involved in HRR 
(ID3). Many HRR deficient tumors are sensitive to PARP inhibitors. Therefore, we hypothesize 
that PACC will be sensitive to PARP inhibition with olaparib. Since there are no appropriate pre-
clinical models of PACC, this precludes us from testing our hypothesis in the laboratory setting. 

Abbreviated Title: Olaparib in advanced PACC
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Therefore, we propose to initiate a small Phase 2 study using olaparib to treat participants with 
PACC. 
This study utilizes the same doses of olaparib and route of administration which have been 
previously approved for other indications. PARP inhibitors have a well described side effect 
profile that has not varied significantly amongst the different tumor types where it has previously 
been tested. These toxicities include increased rates of primarily low-grade nausea, fatigue, 
headache, arthralgia, diarrhea, constipation, dysgeusia, and anorexia, as well as anemia, 
neutropenia and thrombocytopenia, and venous thromboembolism which can be severe in some 
patients [22-25]. Olaparib treatment increases the risk of acute myelogenous leukemia or 
myelodysplastic syndrome. A recent metanalysis found that PARP inhibitor treatment doubles the 
risk of developing these hematologic malignancies from 0.48% to 0.73% with a mean latency since 
first drug exposure of 17.8 months [31]. We do not anticipate a differing toxicity profile when 
using olaparib in the PACC population from what has been seen previously for other populations 
of patients with advanced HRR deficient tumors. 
Because there are no standard treatments approved for PACC and the safety of olaparib is well 
described, the proposed study constitutes a rational initial step to identify a targeted treatment 
regimen effective against PACC.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria 
2.1.1.1
Histological or cytological diagnosis of pancreatic acinar cell carcinoma (PACC) as 
confirmed by NIH Laboratory of Pathology (LP).
2.1.1.2
Participants must have received one prior line of combination chemotherapy (or be 
ineligible to receive combination chemotherapy) with tumor still not amenable for 
potentially curative resection or be ineligible to receive combination chemotherapy. 
There is no limit on the number of prior therapies.
2.1.1.3
Access to medical records from past treatment
2.1.1.4
Measurable disease, per RECIST 1.1. See Section 6.3 for the evaluation of measurable 
disease.
2.1.1.5
Age ≥18 years. 
2.1.1.6
Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix A- 
Performance Status Criteria).
2.1.1.7
At least 3 weeks from previous chemotherapy or radiation therapy prior to planned start 
of treatment.
2.1.1.8
At least 30 days or 5 half-lives (whichever is greater) since receipt of any investigational 
therapy prior to planned start of treatment. 
2.1.1.9
Fully recovered from all reversible sequalae and ≥2 weeks from major surgery or from 
minor surgical procedure such as biliary or duodenal stenting prior to planned start of 
treatment.
2.1.1.10 At least 2 weeks since last use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, 

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indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors 
(e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).
2.1.1.11 At least 5 weeks since last use of phenobarbital, enzalutamide, and at least 3 weeks since 
last use of other strong (e.g., phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine and St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) CYP3A 
inducers. 
2.1.1.12 Adequate organ and marrow function as measured within 28 days prior to study treatment 
as defined below: 

leukocytes
≥3,000/mcL

absolute neutrophil count
≥1,500/mcL

hemoglobin
≥10 g/dL with no blood transfusion within 
the last 28 days

platelets
≥100,000/mcL

total bilirubin
within 1.5x normal institutional upper limit 
of normal (ULN)

Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT)
≤ 
institutional ULN unless liver metastases are 
present in which case they may be ≤5x ULN

Creatinine
must be within normal range, OR ≥51 
mL/min per the formula below)* or measured 
by 24-hour urine test
*Estimated creatinine clearance = 
(140-age [years]) x weight (kg) (x F) serum 
creatinine (mg/dL) x 72a, where F=0.85 for 
females and F=1 for males
This list includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies.
2.1.1.13 The effects of olaparib on the developing human fetus are unknown. For this reason and 
because PARP inhibitor agents are known to be teratogenic, individuals of child-bearing 
potential (IOCBP) and individual able to father a child must agree to use adequate 
contraception prior to study entry and for the duration of study participation. Specifically, 
see Appendix B- Acceptable Birth Control Methods.
2.1.1.14 Participants must agree to abstain from consuming grapefruit juice throughout the 
duration of study treatment with olaparib.
2.1.1.15 Ability of participant to understand and the willingness to sign a written informed consent 
document.
2.1.2
Exclusion Criteria
2.1.2.1
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib.
2.1.2.2
Participants unable to swallow orally administered medication or suffering from 
gastrointestinal (GI) disorders likely to interfere with absorption of study medication.

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2.1.2.3
Participants with human immunodeficiency virus (HIV) are excluded even if viral load 
(VL) is undetectable. 
2.1.2.4
Active hepatitis B (HBV) or hepatitis C virus (HCV)
2.1.2.5
Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac 
conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled 
symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, 
electrolyte disturbances, etc.), or participants with congenital long QT syndrome.
2.1.2.6
Recent (within 3 months) myocardial infarction
2.1.2.7
Unstable angina pectoris 
2.1.2.8
Symptomatic congestive heart failure
2.1.2.9
Uncontrolled major seizure disorder
2.1.2.10 Superior vena cava syndrome
2.1.2.11 Extensive interstitial bilateral lung disease on High Resolution Computed Tomography 
(HRCT) scan 
2.1.2.12 Psychiatric illness/social situations (within the last 3 months) that would limit compliance 
with study requirements or prohibits obtaining informed consent.
2.1.2.13 Uncontrolled intercurrent illness or participants considered a poor medical risk due to a 
serious, uncontrolled medical disorder, non-malignant systemic disease or active 
uncontrolled infection as documented in prior records or suggested by medical history, 
physical examination or standard clinical assessments such as imaging and laboratory 
studies.
2.1.2.14 Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features 
suggestive of MDS/AML.
2.1.2.15 Solid or liquid malignancy other than PACC unless curatively treated with no evidence 
of disease for ≥5 years, except: adequately treated non-melanoma skin cancer, curatively 
treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 
endometrial carcinoma. 
2.1.2.16 Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT).
2.1.2.17 Participants who are nursing and unwilling to stop.  
2.1.2.18 Symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain 
metastases is not required. Brain metastases are considered uncontrolled if the dose of 
corticosteroid being provided for control of brain metastases has been titrated in the 4 
weeks prior to start of treatment.  
2.1.2.19 Participants with spinal cord compression unless considered to have received definitive 
treatment for this and evidence of clinically stable disease for ≥28 days. Participants with 
unstable spinal cord compression are ineligible even if previously treated.
2.1.2.20 Participants with large volume ascites, serum albumin <2.5 mg/dL, or having received 
paracentesis within the last 4 weeks.
2.1.2.21 Participants with persistent toxicities >Grade 2 or with new Grade 2 events within the last 
2 weeks per Common Terminology Criteria for Adverse Event (CTCAE) version 5 
caused by previous cancer therapy. 

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2.2
RECRUITMENT STRATEGIES
This protocol may be abstracted into a plain language announcement posted on NIH websites and 
on NIH social media platforms. Subjects will also be drawn from patients seen in OP12 Medical 
Oncology clinic at the NIH Clinical Center as well as from referrals from outside providers. 
2.3
SCREENING EVALUATION
2.3.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the participant has signed a consent include 
the following: 
•
Email, written, in person or telephone communications with prospective participants
•
Review of existing medical records to include H&P, laboratory studies, etc. 
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
2.3.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the participant has signed the consent on this 
study. Assessments performed at outside facilities or on another NIH protocol within the 
timeframes below may also be used to determine eligibility once a participant has signed the 
consent.
All necessary laboratory values and assessment reports must be available and reviewed prior to 
signing study consent for treatment. 
The following will be completed as part of screening: 
2.3.2.1
Performed at any time prior to treatment initiation
•
Confirmation of histologic or cytologic diagnosis of PACC by the NCI LP. If archival 
tissue is unavailable or insufficient for this purpose, a fresh biopsy will be collected. 
2.3.2.2
Performed within 28 days prior to treatment initiation
•
Medical history including prior cancer therapies, surgical history, history of blood 
transfusions 
•
Physical exam including vital signs and ECOG performance status (see Appendix A- 
Performance Status Criteria) 
•
Computer tomography (CT) scan with contrast of chest, abdomen and pelvis (CAP) and 
areas of known or suspected disease involvement; F-fluorodeoxyglucose positron 
emission tomography (FDG-PET) or magnetic resonance imaging (MRI) may also be 
performed when clinically indicated as per the primary investigator’s discretion.
•
Hematology including blood smear (Complete blood count [CBC] with differential)
•
Acute care panel (sodium, potassium, chloride, bicarbonate, creatinine, glucose, blood 
urea nitrogen [BUN])
•
Hepatic panel (alkaline phosphatase, AST, ALT, total bilirubin, direct bilirubin) 

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•
Mineral panel (albumin, calcium, magnesium, phosphorus) 
•
Coagulation panel (prothrombin time [PT], partial thromboplastin time [PTT]): Activated 
partial thromboplastin time (aPTT)
•
HIV antigen/antibody testing
•
Hepatitis B surface antigen (HBsAg) and HCV with reflex viral load
•
Urinalysis
•
Serum or urine human chorionic gonadotropin (β-hCG) in IOCBP 
•
ECG  
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
2.4.1
Screen failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, and eligibility criteria.
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
reversible factors (e.g., biliary congestion amenable to decompression, recent thrombotic event, 
active infection requiring systemic treatment, low blood counts due to recent chemotherapy, 
pregnancy, or transient social issues that would impact compliance) may be rescreened.
2.4.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Cohort 1
Pancreatic acinar cell carcinoma 
Arms
Number
Name
Description
1
Arm 1
Olaparib, taken orally, twice daily
Arm Assignment
Participants in Cohort 1 will be directly assigned to Arm 1.

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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
•
This is a Phase 2, open label, single center study of olaparib in participants with previously 
treated PACC. 
•
A fixed dose of olaparib will be given orally continuously twice daily for 28-day cycles. 
•
Olaparib will be continued for up to 2 years or until disease progression, unacceptable 
toxicity, or another off-treatment reason is met (see Section 3.9.1).
3.2
DRUG ADMINISTRATION
Olaparib at the dose of 300 mg will be given orally continuously twice daily, with doses taken at 
approximately the same times each day 12 hours apart. Three tablets of 100 mg or two tablets of 
150 mg should be taken with approximately 240 mL of water. Doses may be taken with a light 
meal/snack. The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved, 
or divided.
Olaparib will be dispensed at the start of each 28-day cycle. Per the CCR policy for self-
administered oral investigational agents which will be followed in this protocol, participants will 
be provided with a pill diary (Appendix C- Participant Optional Olaparib Pill Diary), 
instructed in its use, and asked to bring it with them to each appointment.
Participants should be given clear instructions on how and when to take their study treatment. 
Participants 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 source document (e.g., medical record). All participants must 
return their bottle(s) of olaparib at the appropriate scheduled visit, when a new bottle will be 
dispensed. Participants will be instructed to notify study site personnel of missed doses. Dates of 
missed or held doses will be recorded by the participant on their participant diary (if completed) 
and by the site staff in the source documents.
If a participant misses more than 25% of olaparib doses during any cycle due to medical issues 
unrelated to drug toxicity:
•
If the drug hold is less than 4 weeks, then the participant should resume study treatment 
when recovered. The length of the cycle should be extended to allow the participant to 
complete at least 21 days of olaparib treatment within the current cycle before starting Day 
1 of the next cycle. If this occurs during Cycle 1 and the drug is held for longer than 7 days, 
new baseline staging scans should be obtained prior to restarting the drug if the participant 
had received 7 days of olaparib or less and the baseline scans were performed four weeks 
or more from the time drug is restarted.
•
If the drug hold is greater than 4 weeks:
o
During Cycle 1, the participant will be considered inevaluable for response, will be 
replaced, and will be taken off study treatment.
o
During Cycle 2 or beyond, the participant will be taken off study treatment, but will 
not be replaced or made inevaluable due to missed olaparib doses.

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•
See Section 10.3 f or additional information.
Participants must return all containers and any remaining tablets at the end of the study.
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be replaced 
if all the intact tablets can be seen and counted. Should any participant enrolled on the study miss 
a scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets or vomiting), 
the participant 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 should 
not be taken, and the participant should take their allotted dose at the next scheduled time.
It is prohibited to consume grapefruit juice while on olaparib therapy, due to P450 interactions.
3.3
DOSE MODIFICATIONS
Olaparib dosages will be modified as described and published previously for the POLO trial 
(NCT02184195, “A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study 
of Maintenance Olaparib Monotherapy in Patients with gBRCA Mutated Metastatic Pancreatic 
Cancer whose Disease Has Not Progressed on First Line Platinum-Based Chemotherapy”). The 
relevant information is included in Appendix D- Management of Toxicity of Olaparib.
For guidance on dose reductions for management AEs (including renal impairment) refer to Table 
1 and Table 2.
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors cannot 
be avoided see Table 3.
When dose reduction is necessary participants will take one 150 mg tablet and one 100 mg tablet 
twice daily or two x 100 mg tablet twice daily, or one 150 mg tablet twice daily or one 100 mg 
tablet twice daily.
Table 1: Dose reductions for study treatment to manage adverse events
Initial Dose
Following re-challenge post 
interruption: Dose reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
Table 2: Dose reduction for study treatment if participant develops moderate renal 
impairment 
Initial Dose
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft -Gault equation or based on a 24 hour urine test 
between 31 and 50 ml/min): Dose reduction 
300 mg twice daily
200 mg twice daily

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Table 3: Dose reductions for study treatment if participant has to start taking a strong or 
moderate CYP3A inhibitor
Initial Dose
Strong CYP3A inhibitor
Moderate CYP3A inhibitor
300 mg twice daily
100 mg twice daily
150 mg twice daily
3.4
ON STUDY ASSESSMENTS/EVALUATIONS
3.4.1
Timing of procedures
The following describes all tests and procedures to be conducted during the study and during the 
treatment.  Refer to Study Calendar (Section 3.7) for timing and applicable windows.  
For each time period, consider the following order of assessments:
•
Screening:  Refer to Section 2.3.2.
•
Baseline/Cycle 1:  The results of all assessments must be available and reviewed prior to 
initiation of olaparib administration to ensure results still meet standards defined in 
eligibility criteria. All participants are required to complete baseline evaluations per the 
Study Calendar (Section Error! Reference source not found.) within 7 days prior 
treatment initiation except for imaging assessments that are required to be done 21 days 
prior to treatment initiation and pregnancy test that is required to be done within 3 days 
prior to treatment initiation. Any screening tests performed within the specified time frame 
for baseline do not need to be repeated.
•
Cycle 1 Day 8 and Day 15: The results of CBC with differential, acute, mineral, and 
hepatic panels, and tumor markers must be available and reviewed within 2 calendar days 
of the blood draw. Components of these panels that are specifically relevant to monitoring 
the effects of olaparib are specified in “Clinical laboratories relevant to research” later in 
this section. The remaining laboratory values collected on these panels are part of standard 
of care assessments and unrelated to research.
•
Subsequent Cycles:  
o
Each cycle is 28 days 
o
Pre-cycle assessment may be done up to 7 days prior to the start of the cycle or by 
7 days after the planned start of the cycle if the participant has sufficient olaparib 
doses to continue the prescribed treatment. The cycle length is not changed if the 
“pre-cycle” assessment is performed late or early.
o
The results of all assessments with the exception of serum tumor markers and ECG 
must be available and reviewed prior to initiation of olaparib administration in a 
new cycle to confirm eligibility for ongoing treatment administration.  
•
Unscheduled Visits:  In the event of an unscheduled/unplanned visit (e.g., additional 
clinical assessment(s) due to toxicity), the investigator should use best clinical judgement 
as to the necessary assessments. In the event that the decision is made to continue treatment, 
all tests/assessments as required by the next visit on the Study Calendar (Section 3.7) 
should still be conducted (or repeated) within the applicable windows. If a decision is made 

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to discontinue treatment, the participant should move to the End of Treatment visit (Section 
3.5), with tests/assessments completed (or repeated) within the applicable windows.  
•
Remote/Telehealth Visits:  If participants are unable to travel to the Clinical Center for 
assessment during a specified window(s) due to extenuating circumstances such as illness, 
travel restrictions, inclement weather, etc., every effort should be made for the participant 
to complete the required evaluation with their local medical provider. Any unexpected or 
planned remote visit with participants will follow institutional approved remote platform 
requirements used in compliance with local policy (e.g., including NIH HRPP Policy 303).
Given the standard nature of the planned clinical laboratories, interlaboratory variability is 
not a concern and participants may have clinical labs drawn locally, with results sent to the 
NIH study team (e.g., via fax); in these cases, an appropriate member of the study team 
will 
follow-up 
remotely 
to 
discuss 
any 
symptoms 
and 
to 
make 
recommendations/adjustments, as necessary. Additional study drug will not be provided to 
a study participant until the specified assessments have been performed.
3.4.2
Description of Procedures
The following is a description of all procedures:
•
Symptom assessment: verbal review of participant’s current symptoms pertaining to 
eligibility on study.
•
Medical history: a review of treatment history, any ongoing medical conditions, and 
medical history pertaining to eligibility on study
•
Physical exam to determine eligibility and establish a baseline, including vital signs and 
weight:  review of organ systems, weight (kg), and vital signs (i.e., temperature, pulse, 
respirations, blood pressure). After initiation of study drug, symptom-directed physical 
examinations will be performed as clinically indicated in the investigator’s judgment.
•
Performance status (ECOG):  an assessment of activities of daily living; see Appendix A- 
Performance Status Criteria to assess safety, eligibility and to determine continuation of 
treatment per Section 3.3.
•
Laboratory assessments:  The following comprises the required tests/analytes. These 
assessments may be performed at CLIA (or equivalent) certified laboratories outside the 
Clinical Center and results forwarded to the study team for review and management. Given 
that the methodologies utilized are similar across all laboratories, no significant variability 
is expected and there is no anticipation that study data will be affected. Note: Panels 
containing the tests below may be ordered in lieu of individual tests.
o
CBC with differential panel
o
Acute care, mineral, and hepatic panels: Sodium (NA), Potassium (K), Chloride 
(CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, Alkaline 
Phosphatase, ALT, AST, Total Bilirubin, Direct Bilirubin, Albumin, Calcium, 
Note: In case a participant shows an AST or ALT ≥ 3xULN together with total 
bilirubin ≥2xULN, please refer to Appendix E- Actions Required in Cases of 
Increases in Liver Biochemistry and Evaluation of Hy’s Law, for further 
instructions. 

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o
Coagulation panel (PT, PTT): Please note that participants taking warfarin may 
participate in this study; however, it is recommended that INR be monitored 
carefully at least once per week for the first month, then at the start of every cycle if 
the INR is stable. Each coagulation test result will be recorded in CRF.
o
Urinalysis:  protein, specific gravity, glucose, and blood
o
Pregnancy test:  Serum or urine β-HCG for IOCBP
o
Serum tumor markers: Appropriate tumor markers to follow PACC include lipase, 
amylase, and/ or AFP. All three markers will be collected at baseline and end of 
treatment. Only those found to be elevated at baseline will be collected on Day 1 of 
subsequent cycles. If a participant’s tumor is known (from prior medical records) to 
make a marker not listed here, this should also be measured at baseline, the start of 
each cycle and at end of treatment.
•
Imaging scans performed for eligibility determination and response assessment:  CT scans 
(including CAP); may be adjusted to assess additional known sites of disease, as needed. 
Performed every 8 weeks (+ 7 days) (e.g., from/at end of cycle 2 and every even numbered 
cycle thereafter). If radiologic response to treatment is observed (see Section 6.3), 
confirmatory scans may be performed at 4-week interval, and in this case subsequent scans 
should continue prior to every other cycle thereafter (i.e., end of every odd numbered 
cycle). In the case of scheduling delays, dose holds, etc., response assessments should 
continue every 8 weeks (+ 7 days). 
•
Adverse events:  Adverse events (assessed using the NCI CTCAE v5.0) will be 
continuously monitored throughout the study until 30 days after the last dose of olaparib 
or start of new anticancer treatment, whichever comes first. Adverse events that occur 
beyond 30 days after the last administration will be recorded as noted in Section 6.1.
•
Review of concomitant medications: Concomitant medications will be collected 
throughout the study until 30 days after the last dose of the study drugs or start of new 
anticancer treatment, whichever comes first.
•
Olaparib administration, including dispensing and adherence review:  Study drug will be 
dispensed at each cycle and instructed to be self-administered by participants per schedule- 
see Section 3.2. Participants may be given an optional dosing diary (see Appendix C- 
Participant Optional Olaparib Pill Diary); that may be reviewed at each noted visit for 
drug adherence/accountability.
•
Contraception review:  Review of contraception to assess eligibility and to determine 
continuation of treatment  See Appendix B- Acceptable Birth Control Methods.
•
Correlative research samples:  Refer to Section 5.
3.5
END OF TREATMENT ASSESSMENTS
The participant will continue on study drug for up to 2 years or until there is evidence of tumor 
progression, intolerable toxicities, or withdraws from treatment (refer to Section 3.9.1). The “End 
of Treatment” assessments (Section 3.7) will be performed 14-30 days after completing the last 
dose of study drug or before the initiation of a new anti-cancer treatment, whichever comes first.  

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If the participant cannot return to the study center for this visit, the participant may complete 
assessments locally, including seeing a local physician for a physical exam and local clinical 
laboratories, and the study team will follow-up with the participant remotely. Imaging scans need 
only be performed at end of treatment, if not performed within the last 4 weeks. 
3.6
FOLLOW-UP PERIOD
3.6.1
30-day Follow-up Visit
The mandatory Safety Follow- up visit should be conducted approximately 30 (+ 5 days) after the 
last dose of study drug and before initiation of a new anti-cancer treatment, whichever comes first 
(see assessments, Section 3.7). In addition, the study team will confirm contact information for 
participant and a designated family member and remind participant of follow-up contact that will 
be conducted for survival status.
3.6.2
Post-Therapy Follow-up 
Overall survival will be collected until 1 year post-last dose of olaparib. Participants will be 
contacted remotely, (e.g., phone or email) approximately every 90 days. If participants are still 
being seen at the NIH, this information may be obtained from the medical records.

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3.7
STUDY CALENDAR
1 cycle = 28 days
Cycle 1
Subsequent 
Cycles
Follow-up
Procedure
Screening
Baseline/
D1
D8 and 
D15
D1
End of 
Treatment
30-day 
Follow-up
Post Therapy 
Follow-up
Section 2.3.2
Section 
Error! 
Reference 
source not 
found.
Section 3.4.1
Section 3.5
Section 3.6.1
Section 3.6.2
Window(s):
≤ 28 days
≤ 7 days
± 3 days
± 7 days
14-30 days 
after last 
treatment
+5 days
~ q90 days for 1 
year post treatment
Informed consent
X
Medical and surgical history
X
X
X
X
X
Confirmation of diagnosis/biopsy
X2
Physical exam
X
X
X
X
Vital signs, weight
X
X
X
X
Performance status
X
X
X
Symptom assessments/Adverse events
X
X
X
Concomitant medications
X
X
X
Review contraception
X
X
Ongoing survival assessment by phone, email, 
or other NIH remote platform
X
Clinical laboratories
CBC with differential
X
X
X
X
X
Chemistry panels (acute, hepatic, and 
mineral)
X
X
X
X
X

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Cycle 1
Subsequent 
Cycles
Follow-up
Procedure
Screening
Baseline/
D1
D8 and 
D15
D1
End of 
Treatment
30-day 
Follow-up
Post Therapy 
Follow-up
Section 2.3.2
Section 
Error! 
Reference 
source not 
found.
Section 3.4.1
Section 3.5
Section 3.6.1
Section 3.6.2
Window(s):
≤ 28 days
≤ 7 days
± 3 days
± 7 days
14-30 days 
after last 
treatment
+5 days
~ q90 days for 1 
year post treatment
Tumor markers
X
X
X
HIV testing
X
HBsAg and HCV with reflex viral load
X
Coagulation panel (PT, PTT)
X
X
X
Urinalysis
X
X
Serum or Urine β-hCG 
X
X
X
X
X
Radiology/ Other Assessments
ECG
X
CT CAP 
X
X1
X
Every 8 weeks
Study Drug
Dispense olaparib
X
X
Olaparib administration
Continuous PO BID daily dosing
Review Participant Dosing Diary and Drug 
Accountability (optional)
X
X
Correlative Research
                                         See Section 5.3 
PBMCs
X

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Cycle 1
Subsequent 
Cycles
Follow-up
Procedure
Screening
Baseline/
D1
D8 and 
D15
D1
End of 
Treatment
30-day 
Follow-up
Post Therapy 
Follow-up
Section 2.3.2
Section 
Error! 
Reference 
source not 
found.
Section 3.4.1
Section 3.5
Section 3.6.1
Section 3.6.2
Window(s):
≤ 28 days
≤ 7 days
± 3 days
± 7 days
14-30 days 
after last 
treatment
+5 days
~ q90 days for 1 
year post treatment
Tumor Biopsy (optional)
X
X 
(once only, C2 
preferred)
X
Archival Tissue (optional)
X
1.
Only if done >21 days prior to initiation of study therapy
2.
Any time prior to treatment initiation
Note:  Other tests/assessments should be completed as clinically indicated. For a description of all on study assessments, see Section 
3.4.

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3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs.
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the participant as 
appropriate.  The amount and form of these payments are determined by the NCI Travel and 
Lodging Reimbursement Policy. 
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete an end of treatment 
visit approximately 14-30 days following the last dose of study therapy (see Sections 3.5 and 3.7).
3.9.1
Criteria for removal from protocol therapy
•
Progressive disease 
•
Participant requests to be withdrawn from active therapy 
•
Requires use of prohibited medication (see Section 4.2)
•
Unacceptable toxicity as defined in Section 3.3
•
Investigator discretion 
•
Participant non-compliance (e.g., misses >25% of doses of olaparib in any cycle)
•
Positive pregnancy test 
3.9.2
Off-Study Criteria
•
Screen failure
•
Completed study follow-up period 
•
Participant lost to follow-up 
•
Participant requests to be withdrawn from study  
•
Investigator discretion
•
Death 
•
The study is discontinued
3.9.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for two (2) scheduled 
visits and is unable to be contacted by the study site staff. 

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The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
•
The site will attempt to contact the participant and reschedule the missed visit within two 
(2) weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, an IRB approved certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
Note: 
A 
regularly 
updated 
source 
such 
the 
one 
available 
at 
http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table should be consulted for complete 
listing of CYP3A interactions. 
The use of any natural/herbal products or other traditional remedies should be discouraged, but 
use of these products, as well as any medication or vaccine including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements that the participant is receiving at the 
time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
4.1
SUPPORTIVE CARE 
Unless otherwise indicated in Section 3.3, toxicities will be managed per current evidence-based 
practice guidelines in consultation with a medically responsible investigator if available. 
4.2
PROHIBITED MEDICATIONS
No other anti-cancer therapy (e.g., chemotherapy, immunotherapy, hormonal therapy [hormone 
replacement therapy (HRT) is acceptable], radiotherapy [unless palliative – see Section 4.3.2], 
biological therapy or other novel agent) is to be permitted while the participant is receiving study 
medication. (Note: Participants may continue the use of bisphosphonates or denosumab for bone 
disease provided the dose is stable before and during the study and they were started at least 4 
weeks prior to beginning study treatment.) 
Live virus and live bacterial (including live attenuated) vaccines should not be administered while 
the participant 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. 

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Strong or moderate CYP3A inhibitors or inducers (Table 4) should not be taken with olaparib. If 
no suitable alternative, then dose of olaparib should be reduced (see Table 3).
Table 4: Restricted concomitant medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):
Strong CYP3A inhibitors:
itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, 
telaprevir
Moderate CYP3A inhibitors:
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil 
Strong or moderate CYP3A inhibitors should not 
be taken with olaparib. If there is no suitable 
alternative concomitant medication, then the 
dose of olaparib should be reduced for the period 
of concomitant administration. The dose 
reduction of olaparib should be recorded in the 
CRF with the reason documented as concomitant 
CYP3A inhibitor use. 
•
Strong CYP3A inhibitors – reduce the 
dose of olaparib to 100 mg twice daily for 
the duration of concomitant therapy with 
the strong inhibitor and for 5 half lives 
afterwards.
•
Moderate CYP3A inhibitors - reduce the 
dose of olaparib to 150 mg twice daily for 
the duration of concomitant therapy with 
the moderate inhibitor and for 3 half lives 
afterwards.
•
After the washout of the inhibitor is 
complete, the olaparib dose can be re-
escalated.
Strong inducers:
phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s 
Wort
Moderate CYP3A inducers: bosentan, 
efavirenz and modafinil
Strong or moderate CYP3A inducers should not 
be taken with olaparib.
If the use of any strong or moderate CYP3A 
inducers are considered necessary for the 
participant’s safety and welfare this could 
diminish the clinical efficacy of olaparib.
If a participant requires use of a strong or 
moderate CYP3A inducer then they must be 
monitored carefully for any change in efficacy of 
olaparib.

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Table 4: Restricted concomitant medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):
•
CYP3A4 substrates: hormonal 
contraceptive, simvastatin, 
cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, 
sirolimus, tacrolimus and 
quetiapine
•
CYP2B6 substrates: bupropion, 
efavirenz
•
OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins 
and valsartan
•
OCT1, MATE1 and MATE2K 
substrates:  metformin
•
OCT2 substrates: serum creatinine
•
OAT3 substrates: furosemide, 
methotrexate
Effect of olaparib on other drugs
Based on limited in vitro data, olaparib may 
increase the exposure to substrates of CYP3A4, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K.
Based on limited in vitro data, olaparib may 
reduce the exposure to substrates of 2B6.
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co-
administered.
4.3
PERMITTED MEDICATIONS & TREATMENTS 
4.3.1
Anticoagulant Therapy 
Participants who are taking warfarin should be transitioned to another anticoagulant therapy for 
the duration of participation in this protocol, such as subcutaneous heparin. 
4.3.2
Palliative Radiotherapy 
Palliative radiotherapy may be used for the treatment of pain at the site of bone metastases that 
were present at baseline, provided the investigator does not feel that these are indicative of clinical 
disease progression during the study period. Study treatment should be discontinued for a 
minimum of 3 days before a participant undergoes therapeutic palliative radiation treatment. Study 
treatment should be restarted within 4 weeks as long as any bone marrow toxicity has recovered.
5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
BIOSPECIMEN COLLECTION 
Refer to Section 5.3 for sample collection and timepoints.
5.1.1
Blood
Blood samples will be collected and processed according to validated standard operating 
procedures (SOPs) to maintain sample quality and participant confidentiality. 

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5.1.1.1
PBMCs
Participant PBMCs (matched to tumor) will be stored for making of syngeneic humanized models 
if these are required for experimental drug testing. If PBMCs are not needed for this purpose, they 
may be utilized for immune monitoring.
5.1.2
Tumor Tissue (Fresh/Recent archival)
Tumor tissues (either biopsy or archival tissue) will be collected at screening. If no archival tissue 
is available, participants will be required to undergo a biopsy to confirm cancer diagnosis.
Participants may elect to provide tissue for additional research studies described below designed 
to better understand the treatment effect of olaparib on their tumor. Participants will be provided 
with the following options to provide tumor tissue for the analyses described below:
1. Participants who have had recent core or excisional biopsy of a tumor lesion (within 90 
days prior to Cycle 1/Day 1 and since completion of last anti-cancer therapy) may consent 
to use this tissue for baseline analysis for the purposes of this study even if it was collected 
for another reason. 
2. Participants may consent to undergo new interventional radiology guided needle biopsies 
of a tumor lesion for research purposes unless tumor is considered inaccessible or biopsy 
is otherwise considered not in the participant’s best interest. Core needle biopsies (1-3 
cores) with cross sectional imaging will be obtained per routine standard of care by an 
Interventional Radiologist, typically by using a 16-18G needle at the discretion of the 
provider performing the procedure. Research biopsies will be performed under local 
anesthesia and conscious sedation may be used, if warranted, and the use and risks are 
acceptable to the participant. As CT guidance will be used for a research biopsy procedure, 
research radiation exposure will be discussed with the participant. The participant will be 
reminded that all sampling for research is voluntary. No more than 3 optional research 
biopsies will be performed on this protocol for research purpose only. Consent for biopsy 
will be obtained by the interventionalist at the time of the procedure. If the participant 
refuses the optional biopsy, the refusal will be documented in the medical record.
5.2
PLANNED ANALYSES
Note: Platforms and procedures may be adjusted based upon current technology and/or 
collaborations in place at the time of actual analyses.
5.2.1
ATAC-seq 
This analysis will be performed to determine epigenetic patterns in PACC as compared to normal 
acinar cells and to determine whether olaparib treatment changes baseline epigenetics of PACC. 
Coded, linked samples will be provided to the Arda Lab for this analysis.
5.2.2
Single cell RNA analysis
We will use this technique to identify the different types of cells present in PACC tumors at 
baseline and following treatment with olaparib. Coded, linked samples will be provided to the 
Arda Lab for this analysis.

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5.2.3
Cytogenetics
Copy number changes in individual cells will be assessed by fluorescence in situ hybridization 
(FISH). Coded, linked samples will be provided to the Reid Lab for this analysis.
5.2.4
Assessment of HR pathway gene mutation status
Mutations in common HR genes will be assessed through Laboratory of Pathology COMPASS 
program. CLIA-certified analysis of mutation in ~500 oncogenes including many HR pathway 
genes is included in this analysis. More detailed sequencing (WES or WGS) may be performed 
through 19C0016 Natural History of Rare Solid Tumors protocol for co-enrolled participants (e.g., 
on samples from responding participants who lack identified abnormalities using the standard 
panel). 
5.2.5
Immunohistochemistry (IHC)
Samples will be assessed for ID3 and ARID1A protein expression. Previous literature reports these 
molecules are downregulated at the protein level in PACC. In addition, we will assess for RAD51 
foci to assess for HRR deficiency in tissue (pre-treatment and end of treatment visit/ time of 
progression), and for activation of γH2AX in on-treatment (as compared to pre-treatment) samples 
to determine effect of olaparib. These studies will be performed under the direction of Laboratory 
of Pathology collaborators Drs. David Kleiner and Stephen Hewitt.
5.2.6
PDX model making 
Fresh tissue samples not required for the above analyses will be processed by the Alewine Lab for 
PDX model development. Coded, linked specimens may be sent to collaborators at Center for 
Advanced Preclinical Research (NCI Frederick; Serguei Kozlov) for PDX establishment. 
Established PDX’s can be used for future research on PACC including assessment of drug 
sensitivity. To assess sensitivity to immunotherapy agents, humanized mouse models may be 
required. 
5.3
SAMPLE COLLECTION SCHEDULE
Test/assay
Sample type & 
amount
Handling/ 
processing1
Collection point
Location of specimen 
analysis2
ATAC-seq
Single cell RNA 
analysis
Tissue core
Fresh or 
snap-frozen
Pre-
treatment/Baseline; 
on-treatment (C2 
preferred); 
Progression
BPC/Arda Lab
Cytogenetics
BPC/Reid Lab
Mutation of HR 
pathway genes 
Tumor tissue 
(archival or 
fresh)
Formalin 
fixed 
paraffin 
Pre-
treatment/Baseline
Laboratory of 
Pathology 
(COMPASS)

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Test/assay
Sample type & 
amount
Handling/ 
processing1
Collection point
Location of specimen 
analysis2
IHC
embedded 
(FFPE)
Pre-
treatment/Baseline; 
on-treatment (C2 
preferred); 
Progression
Laboratory of 
Pathology/ Alewine 
Lab
PDX model
Tumor tissue 
(fresh only)
Immediate 
pickup
Pre-
treatment/Baseline; 
On-treatment (C2 
preferred); 
progression
Alewine Lab in 
collaboration with 
CAPR Frederick
PBMC storage 
PBMC (35 mL)
BD 
Vacutainer 
CPT tube 
syringes
Pre-
treatment/Baseline
BPC
1. Tubes and media may be substituted based on availability with the permission of the PI or laboratory 
investigator
2. The location of specimen analysis may be adjusted at the time the analyses are performed
5.4
STORAGE, USE, AND SHARING OF SPECIMENS AND DATA FOR SECONDARY RESEARCH
5.4.1
Sample Tracking and Processing
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required. 
5.4.1.1
Biospecimen Processing Core (BPC)
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube. 
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main BPC number) or, if no answer, 240-760-6190 (main 
clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov by e-mail or at 
240-858-3191.
5.4.2
Sample Storage and Disposition
Barcoded samples are stored in barcoded boxes according to stability requirements. Access to 
stored clinical samples is restricted. Unless other permission obtained, identifiable samples are 
only to be used for research purposes associated with this trial (as per the IRB-approved protocol) 
by investigators named on the protocol. It is the responsibility of the Principal Investigator to 
ensure that identifiable samples are being used in a manner consistent with IRB approval.  

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Sample barcodes are linked to participant demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of a 
sample tracking database (e.g., Labmatrix). It is critical that the sample remains linked to 
participant information such as race, age, dates of diagnosis and death, and histological 
information about the tumor to correlate results with sample characteristics.
5.4.3
Protocol Completion/Secondary Use/Sample Destruction
Any specimens that are remaining at the completion of the protocol will be stored in the conditions 
described above. The study will remain open so long as sample or data analysis continues. All 
samples and data from consenting participants will be stored until they are no longer of scientific 
value or if a participant withdraws consent for their continued use, at which time they will be 
destroyed. 
If at any time the participant withdraws consent from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request.  Following receipt of this 
request, the samples will be destroyed or returned to the participant if so requested. The 
participant’s samples and data will be excluded from future distributions, but those which have 
already been distributed for approved research use will not be able to be retrieved. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of Section 7.2.
With the permission of the participant, specimens and data collected on this study, identifiable 
through a code available to the study team, will be stored indefinitely and used for secondary 
research, including genetic research.  Furthermore, the data and/or specimens, may be shared with 
other investigators in coded (code key not available to recipient) format for secondary research. 
Any investigator conducting secondary research in human subjects will seek either additional 
regulatory approval or exemption for research as appropriate. 
Data will also be shared in public database per the study’s data sharing plan in compliance with 
NIH policies. 
In addition, specimens/data may be anonymized and further research, including genetic research, 
conducted at the site or other institutions without participant consent. Participants will be 
informed that the possibility for this type of research exists.
5.5
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.5.1
Description of the scope of genetic/genomic analysis
Identification of specific genetic/epigenetic changes for further analysis will be made by the 
investigator after taking into account various factors including the prior rate of growth of disease, 
response to treatment and tumor fraction in the available sample. DNA and RNA will be extracted 
from normal tissues and tumor samples.
5.5.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
•
As part of study efforts to provide confidentiality of participant information, this study will 
obtain a Certificate of Confidentiality which helps to protect personally identifiable 

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research information. The Certificate of Confidentiality allows investigators on this trial to 
refuse to disclose identifying information related to the research participants, should such 
disclosure have adverse consequences for subjects or damage their financial standing, 
employability, insurability or reputation. The informed consent includes the appropriate 
coverage and restrictions of the Certificate of Confidentiality.
•
Tissue and blood samples collected will be coded. DNA, RNA, and protein isolated from 
these tissues and cell lines and xenografts generated will all be similarly coded. Only 
personnel involved in this study will have access to both the code and the name of the 
participant.
•
To facilitate genetic research, and for the purpose of publication of research work, data 
from genomic studies may be deposited in appropriate public databases. Coded data will 
be deposited in a manner that the participant’s identity cannot be traced.
5.5.3
Management of results
Participants will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. (A list of current guidelines is maintained on the 
CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Participants will be contacted at this time with a request to provide a sample to be sent to a CLIA 
certified laboratory. If the research findings are verified in the CLIA certified lab, the participant 
will be offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result. If the participant does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The Principal Investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts.  Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through 30 days following the last 
dose of the study medication. After 30 days, only adverse events which are serious and related to 
the study intervention need to be recorded.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
•
Results in discontinuation from the study

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•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the 
participant’s outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_X_ Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
_X_ An NIH-funded or approved public repository. Insert name or names: clinicaltrials.gov.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.
_X_ Publication and/or public presentations.
When will the data be shared? 
_X_ Before publication.
_X_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
For the purposes of this study, participants should be re-evaluated for response every 8 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 

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(version 1.1) [32]. Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.3.1
Disease Parameters
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
•
By chest x-ray: ≥20 mm; 
•
By CT scan: 
o
Scan slice thickness 5 mm or under: as ≥10 mm
o
Scan slice thickness >5 mm: double the slice thickness 
•
With calipers on clinical exam: ≥10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 

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recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.2
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 

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next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published. [33-35] In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[36] 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.

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6.3.3
Response Criteria
6.3.3.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.3.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).
6.3.3.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The participant's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
≥4 wks. Confirmation**

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Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once ≥4 wks. 
from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note:
Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment.
6.3.4
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.5
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3.6
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of participants with partial response or 
complete response.
6.3.7
Disease Control Rate
Disease control rate (DCR) is defined as the percentage of participants with partial response, 
complete response, or stable disease.
6.3.8
Overall Survival
Overall survival (OS) is defined as the length of time from start of treatment until death from any 
cause.

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6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
participant while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis (weekly) when participants are being 
actively treated on the trial to discuss each participant. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior participants. 

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All data will be collected in a timely manner and reviewed by the Principal Investigator or a Lead 
Associate Investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines.  
The Principal Investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The Principal Investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
MANUFACTURER PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see Section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
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 

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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.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Adverse Events of Special Interest (AESI)
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in clinical 
studies. If pneumonitis is confirmed, olaparib treatment should be discontinued and the participant 
treated appropriately.
For pharmacovigilance purposes and characterization, any SAE of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca Patient 
Safety regardless of investigator’s assessment of causality or knowledge of the treatment arm. 
Investigators will be asked during the regular follow up for overall survival if the participant has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases. 
At any time after a participant has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable possibility 
that the event is causally related to the investigational product, the investigator should notify 
AstraZeneca Patient Safety.
If participants who are gaining clinical benefit are allowed to continue study treatment post data 
cut off and/or post study completion, then all SAEs must continue to be collected and reported to 
AstraZeneca Patient Safety within the usual timeframe.
Otherwise, after study treatment completion (i.e., including after any scheduled post-treatment 
follow-up safety period has ended) there is no obligation to actively report information on new 
AEs or SAEs occurring in former study patients. This includes new AEs/SAEs in participants still 
being followed up for survival but who have completed the post-treatment follow up period (30 
days).

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8.1.6.1
Overdose
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 
Olaparib must only be used in accordance with the dosing recommendations in this protocol. Any 
dose or frequency of dosing that exceeds the dosing regimen specified in this protocol should be 
reported as an overdose. The Maximum tolerated dose is 300 mg twice daily (tablet).
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately.
8.2
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement.
9
CLINICAL MONITORING
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s) and with 
applicable regulatory requirement(s). This is done through independent verification of study data 
with source documentation focusing on informed consent process and eligibility confirmation.  
Further review of drug administration and accountability, adverse events monitoring, and response 
assessment will occur as documented in a monitoring plan. 
This trial will be monitored by CCR quality management staff and/or personnel employed by a 
CCR contractor. Monitors are qualified by training and experience to monitor the progress of 
clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial 
conduct. 
10 STATISTICAL CONSIDERATIONS  
10.1 OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
Assess the anti-tumor activity of 
single agent olaparib a PARP 
inhibitor, in participants with 
advanced PACC
Objective response rate (ORR, 
CR+PR) until 1 year post-last 
dose of olaparib in the study 
population.
Determines whether olaparib 
is an active drug in this 
patient population. This will 
be considered a positive study 
if at least 3 of 13 patients 
have a response.
Secondary
Assess the safety of olaparib in 
advanced PACC 
Incidence of treatment-related 
serious adverse events from start 
of treatment to 30 days after last 
treatment as defined by Common 
Terminology Criteria for 
Adverse Events (CTCAE) v5.0. 
Descriptive endpoint to assess 
toxicity profile of the study 
drug in this population.

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Assess alternative measures of anti-
tumor efficacy such as clinical 
outcomes and blood biomarkers
Determine disease control rate, 
median duration of treatment 
response, median progression-
free survival (PFS) and median 
overall survival (OS) in the 
study population until 1 year 
after last olaparib treatment. 
Identify best response in serum 
lipase for each treated participant 
(defined as greatest decrease 
from baseline measurement 
during the treatment course).
Descriptive endpoints that 
may help to determine sample 
size needed for future Phase 3 
study.
Exploratory 
Acquire tumor tissue through 
research biopsies that can be used 
to establish new patient-derived 
xenografts (PDX), cell line and 
organoid models of PACC 
Establishment of at least 3 PDX 
models of PACC with 
availability of matched PBMCs 
collected at baseline, at cycle 2 
(preferred) and et the end of 
treatment.
PDX to be used for future 
research on PACC including 
assessment of drug 
sensitivity. PDX models 
could be used to derive new 
cell line and organoid models.
Assess genetic alterations in PACC 
through genetic mapping techniques 
and evaluate alterations in HRR and 
other DNA repair pathways
Describe genetic alterations in 
PACC anticipated to be 
important in the DNA repair 
process by analyzing participant 
baseline tumor biopsy samples 
or archival tissue for:
•
Mutation of HR pathway 
genes
•
Tumor cytogenetics changes
•
Epigenetic changes by 
ATAC-seq
Seeks to identify factors 
which make PACC a DNA 
repair deficient tumor.
Assess alterations in mRNA and 
protein levels of HRR-related genes 
such as BRCA1/2, PALB2 and 
RAD51, and functionality of HRR 
pathway as predictive biomarkers 
for olaparib
Association of alterations in 
mRNA and protein levels of 
HRR-related genes such as 
BRCA1/2, PALB2 and RAD51, 
and functionality of HRR 
pathway with radiologic 
response to olaparib
Identify biomarkers 
predictive for response to 
olaparib
Assess ID3 protein levels and 
protein levels of DNA repair 
pathway genes of interest in 
participant tumor and normal tissue
Percentage of participants with 
decreased ID3 or DNA damage 
repair pathway protein levels 
(such as ARID1A, RAD51, 
γH2AX) in tumor as compared 
to adjacent normal pancreatic 
acinar tissue. 
Identify protein level changes 
that may contribute to a 
PACC DNA repair deficiency 
phenotype.
Assess relationship of treatment 
response to tumor profile
Association of gene mutation 
profile, copy number variation, 
and ID3 protein expression with 
response to olaparib.
Gain a deeper understanding 
of how PACC responds to 
olaparib treatment

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Identify changes in ATAC-seq 
and scRNA analysis that occur 
with treatment and determine 
association with participant 
treatment response.
10.2 SAMPLE SIZE DETERMINATION
The objective response rate of BRCA mutant tumors to olaparib monotherapy in the Phase 1 setting 
in patients with advanced, previously treated disease was found to be 26.2%.  Broken down by 
histology, objective response rates were 31.1% for epithelial ovarian cancer, 12.9% in breast 
cancer, 21.7% in pancreatic adenocarcinoma, and 50.0% in prostate cancer [29]. If PACC is an 
HRR deficient tumor responsive to PARP inhibition, then we would expect to see a similar 
objective response rate in the participant population proposed here. Specifically, we would expect 
response rate to be most similar to ovarian cancer, another KRAS WT tumor with frequent HRR 
deficiency. 
With 13 participants receiving olaparib, there would be 80% power to rule out a 5% response rate 
in favor of a response rate consistent with 30%, with a one-sided 0.10 significance level exact 
binomial test. In practice, if 13 participants receive olaparib and if 2/13 (15.4%) respond, then the 
lower one-sided 90% confidence bound on 2/13 is 4.2%, which would be marginally consistent 
with 5%. In addition, the upper one-sided 90% confidence bound on 2/13 is 36%, which 
demonstrates that 2/13 could be shown to be consistent with a 30% response rate. Alternatively, if 
13 participants receive olaparib and if 3/13 (23.1%) respond, then the lower one-sided 90% 
confidence bound on 3/13 is 8.8%, which exceeds 5%. In addition, the upper one-sided 90% 
confidence bound on 3/13 is 44%, which demonstrates that 3/13 could be shown to be consistent 
with a 30% response rate.
It is expected that up to 4 years will be required to enroll up to 13 evaluable participants. Note:  
With up to 13 evaluable participants required to meet the study endpoints, a small number of 
participants will be also enrolled to account for possible inevaluable participants (2) – i.e., we 
intend to initiate study drug in up to 15 participants.  To allow for screen failures (5), a total of 20 
will be set for the purposes of the NIH accrual ceiling.
10.3 POPULATIONS FOR ANALYSES
Intention to treat any subjects who enroll onto the trial and provide consent and who receive at 
least one dose of olaparib will be included in the safety evaluation. 
10.3.1 Evaluable for toxicity
All participants will be evaluable for toxicity from the time of their first treatment with olaparib. 
10.3.2 Evaluable for objective response
Participants who have measurable disease present at baseline, have received at least one cycle of 
therapy (with at least 75% of planned doses administered), and have had their disease re-evaluated 
will be considered evaluable for response. These participants will have their response classified 
according to the definitions stated in Section 6.3.  (Note: Participants who exhibit objective disease 

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progression, or tumor or treatment-related death prior to the end of cycle 1 will also be considered 
evaluable.)
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
The fraction of all evaluable participants who experience a clinical response (CR+PR) will be 
reported along with a confidence interval. All analyses will be descriptive without formal 
hypothesis testing performed except as noted.
10.4.2 Analysis of the Primary Endpoint
The fraction of evaluable participants who experience a clinical response from olaparib will be 
reported along with an 80% and 95% two-sided confidence interval. Participants with clinical 
progression or death prior to a follow-up scan will be counted as treatment failures. Participants 
without follow-up radiologic assessment who withdraw from the study due to toxicity will be 
counted as treatment failures. Those who withdraw from study prior to follow-up radiologic 
assessment for other reasons may be replaced. 
10.4.3 Analysis of the Secondary Endpoints
Disease control rate will be calculated as the fraction of participants with CR + PR +SD (for at 
least 16 weeks) among all evaluable participants; it will be reported along with a 95% confidence 
interval.
Duration of response will be reported using the Kaplan-Meier method from the date a response is 
identified until the date a response ends (by progression or other reason) or the response is 
continuing, in which case the duration will be censored. 
PFS and OS will be determined using the Kaplan-Meier method and will be reported along with a 
95% confidence interval for the median of each. PFS will be calculated from the on-study date 
until the date of progression or death without progression as events, with participants censored if 
they do not have an event by the date of last known follow-up. OS will be calculated from the on-
study date until the date of death; participants who remain alive will be censored at the date last 
known alive.
Treatment-related changes in serum lipase, a tumor marker in PACC, will be evaluated by 
determining the difference between best on treatment level of the marker as compared to baseline 
levels, and tested for statistical significance of the change by a Wilcoxon signed rank test with a 
two-tailed p-value. If the changes are evaluated at more than one time point, the changes will be 
evaluated using unadjusted p-values with adjustment for multiple comparisons such as by the 
Hochberg method.
Analysis of safety is as described in Section 10.4.4.
10.4.4 Safety Analyses
The fraction of participants who experience a serious toxicity, by grade and type of toxicity, will 
be reported.
10.4.5 Baseline Descriptive Statistics
Standard baseline demographic characteristics will be reported.

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10.4.6 Planned Interim Analyses
None.
10.4.7 Sub-Group Analyses
None.
10.4.8 Tabulation of individual Participant Data
None.
10.4.9 Exploratory Analyses
The exploratory objectives are intended to collect data for use in planning future scientific 
investigations or clinical research. These analyses are expected to be performed first using 
descriptive techniques, reporting descriptive statistics including confidence intervals when 
appropriate. Any statistical tests performed for evaluation of exploratory objectives will be done 
without formal adjustment for multiple comparisons, but in the context of the number of tests 
performed.
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA)
This study is being conducted under CRADA #02299 with AstraZeneca.
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Individuals of any race or ethnic group will be eligible for this study. Eligibility assessment will 
be based solely on the participant’s medical status. Subjects with PACC will be eligible for 
participation in this study. No clinical treatment studies specific for PACC have previously been 
reported. As there is no established, evidence-based standard of care for this ultra-rare disease and 
it is recognized that single agent chemotherapy is ineffective, persons without prior systemic 
treatment will be permitted to enroll on study if they are unwilling or medically unfit to receive 
combination chemotherapy regimens that have been case reported as effective for this disease. 
Persons with large volume ascites, serum albumin < 2.5 mg/dL, or having received paracentesis 
within the last 4 weeks are excluded from participating in the study as these clinical features are 
predictive of disease with a life expectancy too short to benefit from olaparib. Persons with HIV 
must be excluded even if virus is under control because highly-active anti-retroviral therapies 
required for adequate treatment affect the CYP3A enzyme that is needed for metabolism of 
olaparib.
Recruitment of participants onto this study will be through standard CCR mechanisms.  No special 
recruitment efforts will be conducted.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have PACC, and because of unknown dosing or toxicities of the study agent in the 
pediatric participant.

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12.3 RISK/BENEFIT ASSESSMENT
12.3.1 Known Potential Risks
12.3.1.1 Study drug
Please refer to the risks outlined in the package insert.
12.3.1.2 Study procedures
12.3.1.2.1 Blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up to 
55 mL of research blood may be collected at any visit but no more than 121.5 ml in an 8-week 
period.
12.3.1.2.2 Urine collection
No physical risks are associated with urine collection.
12.3.1.2.3 Electrocardiogram
Some skin irritation can occur where the ECG electrodes are placed. The test is completely 
painless, and generally takes less than a minute to perform.
12.3.1.2.4 Sedation
Biopsies may be done under sedation. Potential side effects of sedation include headache, nausea, 
and drowsiness. These are generally mild and last no more than a few hours.
12.3.1.2.5 Local anesthesia
Biopsy may be done under local anesthesia. Potential side effects of local anesthesia include 
drowsiness, headaches, blurred vision, twitching muscles or shivering, continuing numbness, 
weakness or pins and needles sensation.
12.3.1.2.6 Tumor Biopsy
The risks of the optional research biopsies include pain, bleeding and infection at the biopsy site. 
In addition, as the biopsies may be collected under CT guidance, subjects in this study may be 
exposed to radiation as discussed below.
12.3.1.2.7 Imaging
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heart rate and swelling.
12.3.1.3 Risks from Radiation Exposure
On this study, participants may receive up to 4 CT-guided biopsies, and up to 8 CT scans/year. 
The total radiation dose for research purposes will be approximately 13.6 rem. The risk of getting 
cancer from the radiation exposure in this study is 1.4% and of getting a fatal cancer is 0.7%.
12.3.1.4 Non-Physical Risks of Genetic Research
12.3.1.4.1 Risk of receiving unwanted information

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Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Participants will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with participants, family members or health care providers.
12.3.1.4.2 Risk related to possibility that information may be released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the participants, family members or health care 
providers, this risk will be included in the informed consent document.
12.3.1.4.3 Risk to family or relatives
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, participants will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with participants.
12.3.2 Known Potential Benefits
The potential benefit to a participant that goes onto study is a reduction in the bulk of their tumor 
which may or may not have favorable impact on symptoms and/or survival.
No clinical trials for PACC have ever been reported and for this reason, there is no standard therapy 
for this disease currently. Current therapies for advanced PACC typically consist of repurposed 
regimens used for either pancreatic or colon adenocarcinoma based upon case reports or anecdotal 
evidence. Clinical responses to single agent chemotherapy are rare and recent studies suggest that 
the response rate to first-line combination chemotherapy is 30% or less. Recent retrospective case 
series have reported a median overall survival (OS) in this population of 15-20 months in patients 
with advanced disease.
Based upon the evidence presented in Section 1.2, we believe that PACC may represent a subtype 
of pancreatic cancer that may be uniquely susceptible to PARP inhibitor therapy. This phase 2 
study if positive, could offer additional treatment options for participants with this poorly studied 
and understood disease. Further, the results of this study could help guide the design of future 
investigations into optimal first line and maintenance regimens for advanced PACC.
12.3.3 Assessment of Potential Risks and Benefits
Olaparib, as studied in the context of treatment of multiple HRR deficient tumors has been 
generally well tolerated with an acceptable toxicity profile. The risks of hematologic, pulmonary, 
and embryonic toxicity as described above will be mitigated through frequent laboratory and 
clinical monitoring as described in Section 3.2 and dose modifications as described in Section 3.3. 
Although the risks of toxicities with olaparib therapy are well described, advanced PACC is an 
inadequately studied disease with a lack of available therapies in any line of treatment. With 
median overall survivals of 15-20 months, there is a grave need for novel treatment modalities for 
this disease and we believe that olaparib is a rational therapy which could potentially provide 
meaningful responses that could improve participant outcomes.

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12.4 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant.  Whether in person or remote, the privacy of the participant will 
be maintained. Consenting investigators (and participant, when in person) will be located in a 
private area (e.g., clinic consult room). When consent is conducted remotely, the participant will 
be informed of the private nature of the discussion and will be encouraged to relocate to a more 
private setting if needed.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic signature) on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location, but is not required. 
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants and the 

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Institutional Review Board (IRB), and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB.
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Council for Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing, and inspection by local and regulatory 
authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NCI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the collaborator(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 

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the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the investigator. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the manufacturer collaborator, 
representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect 
all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or manufacturer 
collaborator requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end 
of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION  
A determination was submitted to the FDA regarding the use of olaparib used in this study and it 
was determined that the proposed investigation is IND exempt (IND #160489).
14.1 OLAPARIB
Please see FDA-approved package insert for olaparib for complete agent information.
14.1.1 Source/Acquisition and Accountability 
The olaparib tablets used in this study will be supplied under a collaborative agreement with the 
manufacturer, AstraZeneca.  Commercial supply of olaparib will be supplied.  
14.1.2 Administration procedures
Please refer to Section 3.2.

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14.1.3 Toxicity
Please see Section 1.2.5.

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patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation 
(SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 
trial. Lancet Oncol 2017, 18(9):1274-1284.
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N, Armstrong A et al: Olaparib for Metastatic Breast Cancer in Patients with a 
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Hochhauser D, Arnold D, Oh DY et al: Maintenance Olaparib for Germline BRCA-
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16 LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event/Adverse Experience
AFP
Alpha-fetoprotein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
β-HCG
Beta-Human Chorionic Gonadotropin
BPC
Biospecimen Processing Core
BTRIS
Biomedical Translational Research Information System
BUN
Blood urea nitrogen
CAP
Chest-Abdomen-Pelvis
CAP
College of American Pathologists
CBC
Complete blood count
CC
Clinical Center
CCR
Center for Cancer Research
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
COV
Close-Out Visit
CR
Complete response
CRADA
Cooperative Research and Development Agreement
CrCl
Creatinine clearance
CRF
Case Report Form
CRIS
Clinical research information system
CRP
C reactive protein
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DCIS
Ductal carcinoma in situ
DCR
Disease control rate
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DSB
Double-strand break
dUCBT
Double umbilical cord blood transplantation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group – performance status
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FISH
Fluorescence in situ hybridization
FFPE
Formalin fixed paraffin embedded

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Abbreviation
Definition
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GI
Gastrointestinal
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
Hb
Hemoglobin
HBV
Hepatitis B virus
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HHS
Human and Health Services
HIV
Human immunodeficiency virus
HL
Hy’s Law
HR
Homologous recombination
HRCT
High Resolution Computed Tomography
HRPP
Human Research Protection Program
HRR
Homologous recombination repair
ICH
International Council for Harmonisation
IHC
Immunohistochemistry
IMV
Interim Monitoring Visit
IMP
Investigational medicinal product
INR
International normalized ratio
IOCBP
Individuals of child-bearing potential
IRB
Institutional Review Board
JCAHO
Joint Commission on Accreditation of Healthcare Organizations
LDH 
Lactate dehydrogenase
LH
Luteinizing hormone
LP
Laboratory of Pathology
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndrome
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
NCI
National Cancer Institute
NIH
National Institutes of Health
OHSRP
Office for Human Subjects Research Protection
ORR
Objective Response Rate
OS
Overall survival
PACC
Pancreatic Acinar Cell Carcinoma
PARP
Poly-ADP ribose polymerase
PBMC
Peripheral blood mononuclear cell
PD
Progressive Disease
PDX
Patient-derived xenograft

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Abbreviation
Definition
PET
Positron Emission Tomography
PHL
Potential Hy’s Law
PFS
Progression free survival
PI
Principal Investigator
PR
Partial Response
PT
Prothrombin time
PTT
Partial thromboplastin time
RDW
Red cell distribution width
RECIST
Response Evaluation Criteria in Solid Tumors
QA
Quality Assurance
RBC
Red Blood Cells
RNA
Ribonucleic Acid
SAE
Serious Adverse Event/Serious Adverse Experience
SAV
Site Assessment Visit
SD
Stable Disease
SIV
Site Initiation Visit (SIV)
SOP
Standard Operating Procedure
SSB
Single-strand break
TBL
Total Bilirubin
ULN
Upper limit of normal
VL
Viral load
WBC
White blood cells
WES
Whole exome sequencing
WGS
Whole genome sequencing

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17 APPENDICES
17.1 APPENDIX A- PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.

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17.2 APPENDIX B- ACCEPTABLE BIRTH CONTROL METHODS
Olaparib is regarded as a compound with medium/high fetal risk.
Women must be postmenopausal or have evidence of non-childbearing status. Postmenopausal is 
defined as:
•
Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
•
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
postmenopausal range for women under 50
•
radiation-induced oophorectomy with last menses >1 year ago
•
chemotherapy-induced menopause with >1 year interval since last menses
•
surgical sterilisation (bilateral oophorectomy or hysterectomy)
For women of childbearing potential: negative urine or serum pregnancy test within 28 days prior 
to study treatment and confirmed prior to treatment on Day 1. Women of childbearing potential 
and their partners, who are sexually active, must agree to the use of TWO highly effective forms 
of contraception in combination [as listed below].  This should be started from the signing of the 
informed consent and continue throughout the period of taking study treatment and for at least 6 
months after last dose of study drug(s), or they must totally/truly abstain from any form of sexual 
intercourse (see below). Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her study doctor immediately. 
Because there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with olaparib, breastfeeding must be discontinued if the mother is treated 
with olaparib.
Male participants must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing 
potential. Female partners of male participants should also use a highly effective form of 
contraception if they are of childbearing potential (as listed below). Male participants should not 
donate sperm throughout the period of taking olaparib and for 3 months following the last dose of 
olaparib.
Acceptable non-hormonal birth control methods include:
•
Total/True abstinence: When the participant refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total duration 
of the trial and for at least 6 month after the last dose of study drug for 3 months after last dose 
for male participants. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods, or declaration of abstinence solely for the duration of a trial) and 
withdrawal are not acceptable methods of contraception] 
•
Vasectomised sexual partner PLUS male condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia.
•
Tubal occlusion PLUS male condom 

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•
IUD PLUS male condom.  Provided coils are copper-banded
Acceptable hormonal methods:
•
Normal and low dose combined oral pills PLUS male condom 
•
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly efficacious 
progesterone-based pill.
•
Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom
•
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 
•
Norelgestromin / EE transdermal system PLUS male condom 
•
Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS male 
condom 
•
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom

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17.3 APPENDIX C- PARTICIPANT OPTIONAL OLAPARIB PILL DIARY
Today’s date ______________________ 
Participant Name_____________________________ Participant Study ID ___________________
Cycle #__________  Dosage of tablets dispensed (in mg)______________________________
INSTRUCTIONS TO THE PARTICIPANT: 
1.
Complete one form for each cycle (28 days). 
2.
You will take ___ olaparib tablets twice a day ~12 hours apart on every day of the cycle. You must take 
the tablets with a large glass of water. A light snack (biscuits/ toast) is also recommended to help reduce 
nausea. 
3.
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved, or divided.
4.
It is prohibited to consume grapefruit juice while on olaparib therapy
5.
If you miss a scheduled dose, you may take the scheduled dose up to 2 hours after the scheduled dose time. 
If it is more than 2 hours after the scheduled dose time, do not take the missed dose. You should then take 
the next dose at the scheduled time.
6.
Record the date, the number of tablets you took, and when you took them. 
7.
If you have any comments or notice any side effects, please record them in the Comments column. 
8.
Please bring your pill bottle and this form to your physician when you go for your next appointment. 
DAY
DATE
# Tablets and When Taken
COMMENTS (side effects or missed doses)
1
_________AM 
_________PM 
2
_________AM 
_________PM
3
_________AM 
_________PM
4
_________AM 
_________PM
5
_________AM 
_________PM
6
_________AM 
_________PM 
7
_________AM 
_________PM
8
_________AM 
_________PM

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9
_________AM 
_________PM 
10
_________AM 
_________PM
11
_________AM 
_________PM
12
_________AM 
_________PM
13
_________AM 
_________PM 
14
_________AM 
_________PM
15
_________AM 
_________PM
16
_________AM 
_________PM
17
_________AM 
_________PM 
18
_________AM 
_________PM
19
_________AM 
_________PM
20
_________AM 
_________PM
21
_________AM 
_________PM 
22
_________AM 
_________PM 
23
_________AM 
_________PM 
24
_________AM 
_________PM 

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25
_________AM 
_________PM 
26
_________AM 
_________PM 
27
_________AM 
_________PM 
28
_________AM 
_________PM 

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17.4 APPENDIX D- MANAGEMENT OF TOXICITY OF OLAPARIB
Any toxicity observed during the course of the study could be managed by interruption of the dose 
of study treatment or dose reductions. Repeat dose interruptions are allowed as required, for a 
maximum of 4 weeks on each occasion. If the interruption is any longer, the study team must be 
informed. Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg 
twice daily as a second step. If the reduced dose of 200 mg twice daily is not tolerable, no further 
dose reduction is allowed and study treatment should be discontinued. 
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
CYP3A4 inhibitors – see Table 4)
17.4.1 Management of hematological toxicity 
Table 5
Management of Hematological Toxicity 
Toxicity
Study treatment dose adjustment
CTCAEa gr 1-2
Dose interruption as judged by the investigator; appropriate 
supportive treatment and causality investigation
Repeat CTCAE gr 1-2
Dose interruption until recovery to CTCAE gr 1 and dose reduction 
to 250 mg bid as first step and 200 mg bid as second step
Toxicity
Study treatment dose adjustment
CTCAE gr 3-4
Dose interruption until recovered to CTCAE gr 1 for max of 4 weeks 
and dose reduction to 250 mg bid as first step and 200 mg bid as 
second step
Repeat CTCAE gr 3-4
Discontinue study treatment if 2 dose reductions are not able to 
manage the anemia
a
CTCAE Version 4
17.4.1.1 Management of anemia
Participants can enter the study with a haemoglobin value of > 9g/dl, this should be taken 
into account when considering the management of anemia. Adverse events of anemia 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 anemia. Common treatable causes of anemia (e.g., iron, vitamin B12 or folate 
deficiencies and hypothyroidism) should be investigated and appropriately managed.  In some 
cases, management of anemia may require blood transfusions. For cases where participants 
develop prolonged hematological toxicity (≥2 week interruption/delay in study treatment due to 
CTC grade 3 or worse anemia and/or development of blood transfusion dependence), refer to 
Section 17.4.1.3. However, if a participant develops anemia 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 a reduced dose (see Table 6) if Hb has recovered to > 9 g/dl.  Any subsequently 
required anemia related interruptions, considered likely to be dose related, or coexistent with newly 

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developed neutropenia, and or thrombocytopenia, will require a further study treatment dose 
reduction to 200 mg bid.
If a participant has been treated for anemia with multiple blood transfusions without study 
treatment interruptions and becomes blood transfusion dependent as judged by investigator, study 
treatment should be interrupted for up to a maximum of 4 weeks to allow for bone marrow 
recovery. Study treatment should be restarted at a reduced dose if bone marrow recovers.
Table 6 
Management of anemia
Haemoglobin
Action to be taken
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2)
First occurrence:
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks. Study 
treatment can be restarted if Hb has recovered to > 9g/dl.
Subsequent occurrences:
If Hb< 10 but ≥ 9 g/dl investigator judgement to continue olaparib with 
supportive treatment (e.g. transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step).
If Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
Hb < 8 g/dl
(CTCAE Grade 3)
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality. 
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥ 9 
g/dl.
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease.
17.4.1.2 Management of neutropenia, leukopenia, and thrombocytopenia
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 participant 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.
Study treatment can be restarted at the same dose if an adverse event of neutropenia or leukopenia 
have been recovered up to CTCAE grade 1 (ANC 2 1.5 x 109/L).
Any subsequent interruptions will require study treatment dose reductions to 250 mg bid as a first 
step and to 200 mg bid as a second step (see Table 7).

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An adverse event of thrombocytopenia should be managed as deemed appropriate by the 
investigator. If a participant develops thrombocytopenia CTCAE grade 3 or worse study 
treatment should be interrupted for a maximum of 4 weeks. In some cases management of 
thrombocytopenia may require platelet transfusions. Platelet transfusions should be done 
according to local hospital guidelines (see Table 7).
Table 7
Management of neutropenia, leukopenia and thrombocytopenia
Toxicity
Study treatment dose adjustment
CTCAE Grade 1-2
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation
CTCAE Grade 3-4
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce <<select 
olaparib or study treatment>> to 250 mg twice daily as a first step and 
200 mg twice daily as a second step
17.4.1.3 Management of prolonged hematological toxicities while on study treatment. 
If a participant develops prolonged hematological toxicity such as:
•
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
anemia and/or development of blood transfusion dependence
•
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L)
•
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia (Platelets < 50 x 109/L)
Weekly differential blood counts including reticulocytes and peripheral blood smear should be 
performed. If any blood parameters remain clinically abnormal after 4 weeks of dose 
interruption, the participant should be referred to hematologist for further investigations. Bone 
marrow analysis and/or blood cytogenetic analysis should be considered at this stage according 
to standard hematological practice. Study treatment should be discontinued if blood counts do 
not recover to CTC gr 1 or better within 4 weeks of dose interruption.
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 
Participant Safety. Olaparib treatment should be discontinued if participant’s diagnosis of 
MDS and/or AML is confirmed.
17.4.2 Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If 
the interruption is any longer than this the study monitor must be informed.  Where toxicity 

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reoccurs following re-challenge with study treatment, and where further dose interruptions are 
considered inadequate for management of toxicity, then the participant should be considered for 
dose reduction or must permanently discontinue study treatment.
Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse 
event occurs which the investigator considers to be related to administration of study treatment.
17.4.2.1 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 significant pulmonary 
abnormalities are identified, these need to be discussed with the Study Physician.
17.4.3 Management of nausea and vomiting
Events of nausea and vomiting are known to be associated with olaparib treatment. In clinical 
trial NCT00753545 (Assessment of efficacy of AZD2281 in platinum-sensitive relapsed serous 
ovarian cancer), 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 2 months of treatment for vomiting. 
For nausea, the incidence generally plateaus at around 9 months, and for vomiting at around 6 to 
7 months.
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines. Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e. 2 pieces of toast or a couple of biscuits). 
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.
17.4.4 Interruptions for intercurrent non-toxicity related events
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible and must be ≤4 weeks to remain on study treatment (see Section 3.2). 
All dose reductions and interruptions (including any missed doses) (see Table 8), 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 participant undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.

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Because the AEs related to olaparib may include asthenia, fatigue and dizziness, participants 
should be advised to use caution while driving or using machinery if these symptoms occur.
Table 8 
Dose reductions for study treatment
Initial Dose
Following re-challenge 
post interruption: Dose 
reduction 1
Dose reduction 2
300 mg twice daily
250 mg twice daily
200 mg twice daily
17.4.5 Renal impairment
If subsequent to study entry and while still on study therapy, a participant’s estimated CrCl falls 
below the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly. 
A dose reduction is recommended for participants who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24 hour urine test of 
between 31 and 50 ml/min) for any reason during the course of the study: the dose of olaparib 
should be reduced to 200 mg twice daily.
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in determining 
whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤30 
ml/min) or end-stage renal disease; if participants develop severe impairment or end stage disease 
is it recommended that olaparib be discontinued.

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17.5 APPENDIX E- ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER BIOCHEMISTRY AND 
EVALUATION OF HY’S LAW
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.  Specific guidance on managing liver abnormalities can be found in Section 
Error! Reference source not found. of the Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a participant meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in review 
and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug induced liver injury (DILI) caused by the investigational medicinal product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
Definitions
17.5.1 Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP).  
17.5.2 Hy’s Law (HL)
AST or ALT ≥ 3× ULN together with TBL ≥ 2×ULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, 
viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any participant who meets any of the following identification criteria in isolation or in 
combination:
ALT ≥ 3×ULN
AST ≥ 3×ULN
TBL ≥ 2×ULN

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When a participant meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the identification 
criteria are met, where this is the case the Investigator will:
Notify the AstraZeneca representative.
Request a repeat of the test (new blood draw) by the central laboratory.
Complete the appropriate unscheduled laboratory CRF module(s) with the original local laboratory 
test result.
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
Determine whether the participant meets PHL criteria (see Section Error! Reference source not 
found. for definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
Notify the AstraZeneca representative.
Determine whether the participant meets PHL criteria (see Section Error! Reference source not 
found. for definition) by reviewing laboratory reports from all previous visits.
Promptly enter the laboratory data into the laboratory CRF
Follow-up
Potential Hy’s Law criteria not met
If the participant does not meet PHL criteria the Investigator will:
Inform the AstraZeneca representative that the participant has not met PHL criteria.
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol.
Potential Hy’s Law criteria met
If the participant does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting Study treatment (See 
Section 8.4 Safety Reporting)
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an approach 
for the study participants’ follow-up and the continuous review of data.  Subsequent to this contact 
the Investigator will:
•
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 

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•
Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  << For studies using a central laboratory add: This includes 
deciding which the tests available in the Hy’s law lab kit should be used>> 
•
Complete the three Liver CRF Modules as information becomes available. 
If at any time (in consultation with the Study Physician the PHL case meets serious criteria, report 
it as an SAE using standard reporting procedures.
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be involved 
in this review together with other participant matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
If the alternative explanation is not an AE, record the alternative explanation on the appropriate 
CRF
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP:
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  
The ‘Medically Important’ serious criterion should be used if no other serious criteria apply
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ should 
be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above.
Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria are 
met.  Update the SAE report according to the outcome of the review amending the reported term 
if an alternative explanation for the liver biochemistry elevations is determined.

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Actions required when potential Hy’s Law criteria are met before and after starting study 
treatment
This section is applicable to participants << with liver metastases>> who meet PHL criteria on 
Study treatment having previously met PHL criteria at a study visit prior to starting Study 
treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the participants’ condition# compared with the 
last visit where PHL criteria were met.# 
If there is no significant change, no action is required.
If there is a significant change, notify the AstraZeneca representative, who will inform the central 
Study Team, then follow the subsequent process described in Appendix B5.
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being met 
and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), << or did the subject meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix E6.
If No: Follow the process described in Appendix E4.1.
If Yes: Determine if there has been a significant# change in the participant’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E4.
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the AstraZeneca Physician if there is any uncertainty.