Clinical trial NCT03531840
Conditions: Mesothelioma
Keywords: DNA Mismatch Repair BAP1 BRCA
Sponsor: National Cancer Institute (NCI)
Start date: 2018-07-11; Completion date: 2020-10-21
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The drug olaparib may stop cancer cells from fixing damage to their deoxyribonucleic acid (DNA). It has been approved to treat certain cancers in people that were born with a mutation in the breast cancer (BRCA) gene. It has not been approved for treating mesothelioma. But some people with mesothelioma have mutations in a gene, BRCA1 Associated Protein 1 (BAP1) related to BRCA. Researchers want to see if olaparib can work in patients with mutations in this gene. They also want to see if works on mutations in other genes or patients without any mutations. They want to see if olaparib causes mesothelioma tumors to shrink.

Objective:

To study the effect of olaparib on mesothelioma.

Eligibility:

People ages 18 and older with malignant mesothelioma that has already been treated

Design:

Participants will be screened with

Sample of tumor tissue or fluid

Medical history

Physical exam

Blood, heart, and urine tests

Scans and x-rays

Participants will give blood and tissue samples. These will be genetically tested.

The study will be done in 21-day cycles.

Participants will take tables of the study drug 2 times each day. They will get information on what food and drugs to avoid during the study. They will get information about birth control. They will keep a diary of doses and symptoms.

Participants will have blood and urine tests and scans every few weeks.

Participants will be told any important genetic testing results.

Participants will stay in the study until their disease gets worse or the participant or their doctor chooses to stop it.

About 30 days after stopping the study drug, participants will have a follow-up visit. They will have a medical history, physical exam, blood tests, and scans.

Some participants will continue to have scans every 6 weeks.

...

Detailed description:
Background:

* Malignant mesothelioma is an invasive and often fatal neoplasm that arises from mesothelium that lines several organs.
* Recent studies have identified germline mutations in the gene encoding breast cancer type 1 (BRCA1) associated protein-1 (BAP1) which can predispose to mesothelioma
* In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for the development of several other tumors including uveal melanoma, cutaneous melanoma, renal cell cancers and possibly other cancers
* In addition to BAP1, we found several novel germline variants that have previously not been associated with risk of developing mesothelioma.
* As evidenced by recent data derived from ovarian and prostate cancer patients, mutations in deoxyribonucleic acid (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) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated
* Both established and patient derived mesothelioma cell lines with mutated DNA repair genes are sensitive to olaparib.

Objective:

-Determine the efficacy with respect to objective response rate of olaparib in patients with malignant mesothelioma based on somatic or germline mutation status of DNA repair genes

Eligibility:

* Patients must have progressive, histologically or cytologically confirmed malignant mesothelioma.
* Age greater than or equal to 18 years
* Patients must have received prior platinum and pemetrexed based therapies
* Adequate organ and bone marrow function

Design:

* This is a phase II, single center study of olaparib in subjects with malignant mesothelioma
* All subjects will take olaparib by mouth twice daily until disease progression or intolerable side effects
* Subjects will be assessed for safety (continuously) and efficacy (every 6 weeks)
* Subjects will be analyzed in 3 separate comparison groups according to their mutation status

  * Comparison Group 1: Patients with a germline mutation in DNA repair genes
  * Comparison Group 2: Patients with BAP1 somatic mutations
  * Comparison Group 3: Patients with neither germline mutations nor BAP 1 somatic mutations
* Up to 30 evaluable subjects will be enrolled

Arms: arm 1: Twice daily oral olaparib
Interventions: intervention 1: Olaparib intervention 2: ClinOmics
Intervention descriptions: intervention 1: All subjects will take olaparib by mouth twice per day until disease progression or unacceptable toxicity intervention 2: Non-significant risk (NSR) device

Protocol documents:
Prot_SAP_000.pdf: 
1 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma  
CC Protocol #: 18C0097E 
Version Date:  , February 24, 2020 
NCT Number: NCT03531840 
 
Title: Phase II Study of Olaparib in Subjects with Malignant Mesothelioma 
NCI Principal Investigator: 
Raffit Hassan, M.D. 
Thoracic and GI Malignancies Branch (TGMB), CCR, 
NCI 
Building 10, Room 4-5330 
9000 Rockville Pike 
Bethesda, MD 20892 
Telephone: 240-760-6232 
E-mail: hassanr@mail.nih.gov 
 
Investigational Device: 
Device Name: 
ClinOmics 
IDE Number: 
NSR device (as determined by FDA - 
Q180160) 
Holder: 
Center for Cancer Research 
Manufacturer: 
Center for Cancer Research 
 
Commercial Agents: Olaparib 
 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
PRÉCIS 
Background: 
x Malignant mesothelioma is an invasive and often fatal neoplasm that arises from 
mesothelium that lines several organs. 
x Recent studies have identified germline mutations in the gene encoding BRCA1 associated 
protein-1 (BAP1) which can predispose to mesothelioma 
x In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for 
the development of several other tumors including uveal melanoma, cutaneous melanoma, 
renal cell cancers and possibly other cancers 
x In addition to BAP1, we found several novel germline variants that have previously not been 
associated with risk of developing mesothelioma. 
x As evidenced by recent data derived from ovarian and prostate cancer patients, mutations in 
DNA repair genes can define subgroups of cancer patients with distinct vulnerabilities to 
DNA damage response inhibitors. 
x Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or 
suspected deleterious germline BRCA mutated 
x Both established and patient derived mesothelioma cell lines with mutated DNA repair genes 
are sensitive to olaparib.  
Objective: 
x Determine the efficacy with respect to objective response rate of olaparib in patients with 
malignant mesothelioma based on somatic or germline mutation status of DNA repair genes 
Eligibility: 
x Patients must have progressive, histologically or cytologically confirmed malignant 
mesothelioma. 
x Age >18 years 
x Patients must have received prior platinum and pemetrexed based therapies 
x Adequate organ and bone marrow function 
Design: 
x This is a phase II, single center study of olaparib in subjects with malignant mesothelioma 
x All subjects will take olaparib by mouth twice daily until disease progression or intolerable 
side effects 
x Subjects will be assessed for safety (continuously) and efficacy (every 6 weeks) 
x Subjects will be analyzed in 3 separate comparison groups according to their mutation status  
o Comparison Group 1: Patients with a germline mutation in DNA repair genes 
o Comparison Group 2: Patients with BAP1 somatic mutations 
o Comparison Group 3: Patients with neither germline mutations nor BAP 1 somatic 
mutations 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
x Up to 30 evaluable subjects will be enrolled 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
TABLE OF CONTENTS  
PRÉCIS ............................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................4 
1 
INTRODUCTION ...............................................................................................................9 
1.1 
Study Objectives............................................................................................................. 9 
1.1.1 
Primary Objective ...................................................................................................... 9 
1.1.2 
Secondary Objectives................................................................................................. 9 
1.2 
Background and Rationale ............................................................................................. 9 
1.2.1 
Malignant Mesothelioma ........................................................................................... 9 
1.2.2 
Preclinical Activity of Olaparib Against Primary Mesothelioma Cell Lines .......... 10 
1.2.3 
Olaparib.................................................................................................................... 12 
1.2.4 
Study Rationale ........................................................................................................ 13 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................14 
2.1 
Eligibility Criteria......................................................................................................... 14 
2.1.1 
Inclusion Criteria ..................................................................................................... 14 
2.1.2 
Exclusion Criteria .................................................................................................... 15 
2.1.3 
Recruitment Strategies ............................................................................................. 17 
2.2 
Screening Evaluation .................................................................................................... 17 
2.3 
Registration Procedures ................................................................................................ 18 
2.3.1 
Treatment Assignment and Randomization/Stratification Procedures .................... 18 
3 
STUDY IMPLEMENTATION .........................................................................................19 
3.1 
Study Design ................................................................................................................ 19 
3.2 
Drug Administration..................................................................................................... 19 
3.3 
Dose Delays/Modifications .......................................................................................... 20 
3.3.1 
Modifications and Management of Hematologic Toxicities ................................... 20 
3.3.2 
Modifications and Management of Non-Hematologic Toxicities ........................... 22 
3.4 
Study Calendar ............................................................................................................. 24 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 28 
3.5.1 
Criteria for Removal from Protocol Therapy........................................................... 28 
3.5.2 
Follow Up ................................................................................................................ 28 
3.5.3 
Off-Study Criteria .................................................................................................... 28 
3.5.4 
Withdrawal of Informed Consent ............................................................................ 29 


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3.5.5 
Off Protocol Therapy and Off-Study Procedure ...................................................... 29 
4 
CONCOMITANT MEDICATIONS/MEASURES ...........................................................29 
4.1 
Supportive Care ............................................................................................................ 29 
4.2 
Prohibited Medications................................................................................................. 29 
4.3 
Permitted with Olaparib Dosing Changes .................................................................... 30 
4.3.1 
Strong or Moderate CYP3A inhibitors .................................................................... 30 
4.4 
Permitted with Caution ................................................................................................. 30 
4.4.1 
Strong or Moderate CYP3A inducers ...................................................................... 30 
4.4.2 
P-gp Inhibitors ......................................................................................................... 30 
4.4.3 
Effect of Olaparib on Other Drugs ........................................................................... 30 
4.5 
Permitted Medications .................................................................................................. 31 
4.5.1 
Anticoagulant Therapy............................................................................................. 31 
4.5.2 
Palliative Radiotherapy ............................................................................................ 31 
5 
BIOSPECIMEN COLLECTION .......................................................................................31 
5.1 
Correlative Studies for Research .................................................................................. 31 
5.1.1 
Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples:......... 31 
5.1.2 
Specimen Collection Table ...................................................................................... 32 
5.2 
Sample Storage, Tracking and Disposition .................................................................. 33 
5.2.1 
Blood Processing Core ............................................................................................. 33 
5.2.2 
NCI Laboratory of Pathology .................................................................................. 34 
5.2.3 
Protocol Completion/Sample Destruction ............................................................... 34 
5.3 
Samples for Genetic/Genomic Analysis....................................................................... 35 
5.3.1 
Management of Results............................................................................................ 35 
6 
DATA COLLECTION AND EVALUATION ..................................................................36 
6.1 
Data Collection ............................................................................................................. 36 
6.2 
Recording of Adverse Events ....................................................................................... 36 
6.2.1 
Time Period for Collection of Adverse Events ........................................................ 36 
6.3 
Data Sharing Plans ....................................................................................................... 37 
6.3.1 
Human Data Sharing Plan ........................................................................................ 37 
6.3.2 
Genomic Data Sharing Plan ..................................................................................... 37 
6.4 
Response Criteria ......................................................................................................... 37 
6.4.1 
Non-Pleural Mesothelioma ...................................................................................... 38 


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6.4.2 
Pleural Mesothelioma .............................................................................................. 43 
6.4.3 
Duration of Response ............................................................................................... 44 
6.4.4 
Progression-Free Survival ........................................................................................ 44 
6.4.5 
Objective Response Rate ......................................................................................... 45 
6.4.6 
Disease Control Rate................................................................................................ 45 
6.5 
Toxicity Criteria ........................................................................................................... 45 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING 
PLAN .................................................................................................................................45 
7.1 
Definitions .................................................................................................................... 45 
7.2 
OHSRP Office of Compliance and Training / IRB ...................................................... 45 
7.2.1 
Expedited Reporting ................................................................................................ 45 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review .................................... 45 
7.3 
NCI Clinical Director Reporting .................................................................................. 45 
7.4 
NIH Required Data and Safety Monitoring Plan ......................................................... 46 
7.4.1 
Principal Investigator/Research Team ..................................................................... 46 
8 
Safety Reporting Criteria to the Pharmaceutical Collaborators .........................................46 
8.1 
Definitions .................................................................................................................... 46 
8.1.1 
Adverse Event .......................................................................................................... 46 
8.1.2 
Adverse Events of Special Interest .......................................................................... 46 
8.1.3 
Serious Adverse Event ............................................................................................. 46 
8.2 
Reporting to Astra Zeneca ............................................................................................ 47 
8.2.1 
Serious Adverse Events ........................................................................................... 47 
8.2.2 
Adverse Events after the 30-day follow up period .................................................. 48 
8.2.3 
Deaths ...................................................................................................................... 48 
8.2.4 
Overdose .................................................................................................................. 49 
8.2.5 
Pregnancy ................................................................................................................. 49 
8.2.6 
Hy’s Law .................................................................................................................. 50 
9 
IDE Holder Monitoring Plan .............................................................................................50 
9.1 
Clinical Monitoring ...................................................................................................... 50 
9.2 
Laboratory Monitoring ................................................................................................. 50 
10 
STATISTICAL CONSIDERATIONS...............................................................................51 
10.1 
Statistical Hypothesis ................................................................................................... 51 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
10.1.1 Primary Endpoint ..................................................................................................... 51 
10.1.2 Secondary Endpoints ............................................................................................... 51 
10.2 
Sample Size Determination .......................................................................................... 52 
10.3 
Populations for Analyses .............................................................................................. 52 
10.3.1 Evaluable for Toxicity ............................................................................................. 52 
10.3.2 Evaluable for Objective Response, Progression Free Survival and Soluble 
Mesothelin Levels and PFS ..................................................................................... 53 
10.3.3 Evaluable Non-Target Disease Response ................................................................ 53 
10.4 
Statistical Analyses....................................................................................................... 53 
10.4.1 General Approach .................................................................................................... 53 
10.4.2 Analysis of the Primary Endpoints .......................................................................... 53 
10.4.3 Analysis of the Secondary Endpoint(s).................................................................... 53 
10.4.4 Safety Analyses ........................................................................................................ 53 
10.4.5 Baseline Descriptive Statistics ................................................................................. 54 
10.4.6 Planned Interim Analyses ........................................................................................ 54 
10.4.7 Sub-Group Analyses ................................................................................................ 54 
10.4.8 Tabulation of Individual Participant Data................................................................ 54 
10.4.9 Exploratory Analyses ............................................................................................... 54 
11 
COLLABORATIVE AGREEMENTS ..............................................................................54 
11.1 
Collaborative Research and Development Agreement (CRADA) ............................... 54 
11.2 
Intramural Material Transfer Agreement (iMTA)........................................................ 54 
11.3 
Quality Agreement ....................................................................................................... 54 
12 
HUMAN SUBJECTS PROTECTIONS ............................................................................55 
12.1 
Rationale for Subject Selection .................................................................................... 55 
12.2 
Participation of Children .............................................................................................. 55 
12.3 
Participation of Subjects Unable to Give Consent ....................................................... 55 
12.4 
Evaluation of Benefits and Risks/Discomforts ............................................................ 55 
12.4.1 Risks ......................................................................................................................... 55 
12.4.2 Image Guided Biopsy Collection ............................................................................. 56 
12.4.3 Non-Physical Risks of Genetic Research ................................................................ 56 
12.4.4 Benefits .................................................................................................................... 56 
12.5 
Risk Benefit Assessment .............................................................................................. 56 


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Version Date: 02/24/20 
12.6 
Consent Process and Documentation ........................................................................... 56 
12.6.1 Telephone Re-consent .............................................................................................. 56 
13 
PHARMACEUTICAL INFORMATION ..........................................................................56 
13.1 
Olaparib) ....................................................................................................................... 57 
13.1.1 Source ...................................................................................................................... 57 
13.1.2 Mode of Action: ....................................................................................................... 57 
13.1.3 Toxicity .................................................................................................................... 57 
13.1.4 Formulation and preparation .................................................................................... 58 
13.1.5 Stability and Storage ................................................................................................ 58 
13.1.6 Administration Procedures....................................................................................... 58 
13.1.7 Incompatibilities ...................................................................................................... 58 
13.2 
ClinOmics Platform (NSR Device) .............................................................................. 58 
13.2.1 Source ...................................................................................................................... 58 
13.2.2 Toxicity .................................................................................................................... 58 
14 
REFERENCES ..................................................................................................................59 
15 
APPENDICES ...................................................................................................................62 
15.1 
Appendix A – Performance Status Criteria .................................................................. 62 
15.2 
Appendix B -Cockcroft-Gault formula ........................................................................ 63 
15.3 
Appendix C - Participant Olaparib Pill Diary .............................................................. 64 
15.4 
Appendix D – Actions Required in Cases of Liver Biochemistry and Evaluation of 
Hy’s Law ...................................................................................................................... 67 
15.4.1 Introduction .............................................................................................................. 67 
15.4.2 Definitions................................................................................................................ 67 
15.4.3 Identification of Potential Hy’s Law Cases ............................................................. 67 
15.4.4 Follow-up ................................................................................................................. 68 
15.4.5 Actions Required for Repeat Episodes of Potential Hy’s Law ................................ 69 
 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
1
INTRODUCTION
1.1
STUDY OBJECTIVES 
1.1.1 Primary Objective 
x Determine the efficacy with respect to objective response rate of olaparib in patients with 
malignant mesothelioma based on somatic or germline mutation status of DNA repair 
genes 
1.1.2 Secondary Objectives 
x To assess the safety and tolerability of olaparib in patients with mesothelioma 
x To assess progression free survival in patients with mesothelioma treated with olaparib 
monotherapy 
x To investigate the potential of soluble mesothelin levels and levels of megakaryocyte 
potentiating factor to predict any therapeutic response  
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Malignant Mesothelioma 
Malignant mesothelioma is an invasive and often fatal neoplasm that arises from mesothelium that 
lines several organs. Common primary sites of origin of mesothelioma are the pleura (80–90%) 
and peritoneum (10–15%) and rarely the pericardium and tunica vaginalis.[1] Among the three 
main 
histologic 
subtypes 
of 
mesothelioma, 
epithelioid tumors are the most common and have a 
better prognosis than biphasic and sarcomatoid 
tumors. Mesothelioma is managed with surgery, 
usually administered in combination with other 
modalities of treatment such as chemotherapy or 
radiation. For patients with unresectable disease, 
chemotherapy using the regimen of cisplatin plus 
pemetrexed is the standard of care.[2] The prognosis 
of patients with unresectable disease is particularly 
poor with median survival ranging from 10-13 
months. 
Up to 20% of mesothelioma cases occur in patients 
without significant exposure to asbestos. Risk factors 
in this cohort are not well understood, but include 
radiation exposure, exposure to non-asbestos mineral 
fibers such as erionite, simian virus 40, and genetic 
predisposition.[1, 3, 4] Recent studies have identified 
germline mutations in the gene encoding BRCA1 
associated protein-1 (BAP1) which can predispose to 
mesothelioma.[3, 4] In addition to mesothelioma, 
germline 
BAP1 
mutations 
confer 
increased 
susceptibility for the development of several other 
Figure 1: Frequencies of 
germline mutations in DNA 
repair genes among 241 
consecutive patients with 
mesothelioma (confidential; 
unpublished) 
 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
tumors including uveal melanoma, cutaneous melanoma, renal cell cancers and possibly other 
cancers.  
Using germline DNA from 241 consecutive patients enrolled on a prospective study of natural 
history of mesothelioma, we have found that a deleterious germline mutation is present in 12% of 
mesothelioma patients (unpublished data, confidential). In addition to BAP1, we found several 
novel germline variants that have previously not been associated with risk of developing 
mesothelioma. These include mutations in CHEK2, PALB2, and BRCA2, MLH1, POT1, TP53, 
MRE11A. Figure 1 shows the distribution of germline mutations identified in our cohort. 
1.2.2
Preclinical Activity of Olaparib Against Primary Mesothelioma Cell Lines 
Olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), targets PARP which is required to 
repair single strand DNA breaks in homologous recombination (HR) repair pathway. Being a first 
clinically approved PARPi, it exploits synthetic lethality in patients carrying either BRCA1 or 
BRCA2 germline mutations. BRCA 1 associated protein (BAP1) is a deubiquitinase that functions 
as a tumor suppressor. In HR DNA repair pathway, BAP1 has been shown to interact with BRCA1.  
As evidenced by recent data derived from ovarian and prostate cancer patients, mutations in DNA 
repair genes can define subgroups of cancer patients with distinct vulnerabilities to DNA damage 
response inhibitors. Our preliminary results also show that established mesothelioma cell lines as 
well as primary mesothelioma cell lines established from patients with pleural or peritoneal 
mesothelioma are sensitive to olaparib.  
 
 
Figure 2. Expression of BAP1 in different mesothelioma cell lines. Established breast cancer 
HCC1937 was used as a control cell line that expresses BAP1 and has been shown to be 
resistant to olaparib.  
A majority of the mesothelioma cell lines with weak or no BAP1 expression were sensitive to 
olaparib (Table 1). However, there are exceptions. For example, NCI-Meso19 and NCI-Meso52 
which strongly expressed BAP1were equally sensitive to olaparib while as NCI-Meso44 which 
had no BAP1 expression was resistant to olaparib. These results suggest that sensitivity of 
mesothelioma cell lines to olaparib may be dependent on other factors besides BAP1. Since the 
sensitivity of mesothelioma tumors may not be completely dependent on BAP1 we also plan to 
enroll patients without BAP1 mutations on the study. However, the mechanisms that lead to 
decreased BAP1 protein expression are not well-known. 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
Table 1. BAP1 expression and sensitivity to olaparib in mesothelioma cell lines.  
Cell Line 
BAP1 Expression 
Olaparib IC50 
(μM)
Breast Cancer Cell Line 
HCC1937 
Strong 
>50 
Established Mesothelioma Cell Lines 
H2052 
Weak
30 
H2452 
Weak
40 
H28 
No 
18 
Patient Derived Mesothelioma Cell Lines 
NCI-Meso16 
No 
23 
NCI-Meso17 
Weak
7 
NCI-Meso18 
No 
24 
NCI-Meso19 
Strong 
24 
NCI-Meso21 
No 
30 
NCI-Meso29 
No 
27 
NCI-Meso41 
No 
31 
NCI-Meso44 
No 
>50 
NCI-Meso52 
Strong 
5 
Figure 3: Sensitivity of mesothelioma primary cell lines to olaparib. 
 
 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
 
 
1.2.3
Olaparib
Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected 
deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian 
cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an 
established safety profile and it is under investigation in several different cancers.  
Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 5’diphosphoribose [poly (ADP 
ribose] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy 
and other anti-cancer agents. 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more serious 
DNA double strand breaks (DSBs) during the process of DNA replication. During the process of 
cell division, DSBs can be efficiently repaired in normal cells by homologous recombination repair 
(HR). Tumors with HR deficiencies (HRD), such as serous ovarian cancers and SCLC cannot 
accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such 
tumor types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared 
with currently available chemotherapy regimens.  
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in tumor 
models in vivo[5, 6] and in the clinic.[7] The mechanism of action for olaparib results from the 
trapping of inactive PARP onto the single-strand breaks preventing their repair.[8, 9] Persistence of 
SSBs during DNA replication results in their conversion into the more serious DNA DSBs that 
would normally be repaired by HR repair. Olaparib has been shown to inhibit selected tumor cell 
lines in vitro and in xenograft and primary explant models as well as in genetic BRCA knock-out 
models, either as a stand-alone treatment or in combination with established chemotherapies.
Monotherapy with olaparib has shown ORR of about 30% in women with ovarian cancer, with a 
higher ORR of 40% observed in patients who carried a BRCA mutation.[10] Among patients with 
HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib yielded ORR of 
60%.[11] Combinations with chemotherapies have shown higher response rates (60-70%) in 
patients not selected for germline mutations.[12, 13]  


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of 
chemotherapy.[14-16]  
1.2.3.1 Pharmacokinetics and drug metabolism in humans 
Based on the totality of the efficacy, safety/tolerability profile and the patient convenience of a 
twice a day dosing schedule, the 300 mg twice daily tablet dose was chosen as the recommended 
Phase III monotherapy dose (Study D0810C00024). 
Following single oral (po) dosing to cancer patients using the tablet formulation, olaparib was 
rapidly absorbed with peak plasma concentrations typically observed at 1.5 hours. The population 
PK analysis characterized the absorption phase of olaparib as a sequential zero- and first-order 
absorption and showed a significant impact of olaparib tablet strength on the absorption rate 
constant. Following time to maximum plasma concentration (tmax), plasma concentrations of 
olaparib declined in a biphasic manner with an average terminal elimination half-life (t½) of 14.9 
hours (standard deviation [Sd] 8.2 hours). 
Following a single 300mg po tablet dose the mean apparent oral plasma clearance was 
approximately 47.4 L/h (Sd 3.9 L/h). Olaparib exhibited a mean volume of distribution of 158 L 
(Sd 136 L), indicating distribution into the tissues. The plasma protein binding in vitro was 
moderate and showed evidence of concentration GHSHQGHQFHDWȝJmL). 
1.2.3.2 Clinical Experience 
Olaparib monotherapy (tablet formulation) is currently approved in the United States in patients 
with germline BRCA ovarian cancer and in platinum sensitive ovarian cancer. Investigations are 
ongoing in patients with gBRCA mutated advanced breast cancer, in patients with gBRCA mutated 
breast cancer in the adjuvant treatment setting and in patients with gBRCA mutated advanced 
pancreatic cancer. Additionally, Phase I, II or III studies include investigation of cancers driven 
by other DNA homologous recombination repair deficiencies beyond BRCA mutations. The 
approved olaparib monotherapy tablet dose is 300 mg bd. 
Olaparib monotherapy is generally well tolerated at monotherapy doses up to 400 mg twice daily 
(capsule formulation) and 300 mg twice daily (tablet formulation) in patients with solid tumors. 
AE reports considered to be associated with administration of olaparib are generally mild or 
moderate (CTCAE Grade 1 or 2) hematological effects (anemia, neutropenia, lymphopenia, 
thrombocytopenia, MCV elevation), decreased appetite, nausea and vomiting, diarrhea, dyspepsia, 
stomatitis, upper abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood 
creatinine, headache and dizziness. 
In a relatively small number of patients, pneumonitis, MDS/AML and new primary malignancies 
have been reported, however totality of data from the whole development program does not 
support a conclusion that there is a causal relationship between olaparib and these events. These 
important potential risks for olaparib are being kept under close surveillance. 
1.2.4 Study Rationale 
Olaparib, a poly(ADP-ribose) polymerase inhibitor, targets PARP which is required to repair 
single strand DNA breaks in homologous recombination (HR) pathway. Being a first clinically 
approved PARPi, it exploits synthetic lethality in patients carrying either BRCA1 or BRCA2 
germline DNA repair mutations. Using germline DNA from 241 consecutive patients enrolled on 
a prospective study of natural history of mesothelioma, we have found that a deleterious germline 


14 
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mutation is present in 12% of mesothelioma patients. In addition to BAP1, we found several novel 
germline variants that have previously not been associated with risk of developing mesothelioma. 
We hypothesize that a subset of mesothelioma patients with germline or somatic alterations in 
DNA repair genes could benefit from treatment with PARP inhibitors. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically or cytologically malignant mesothelioma confirmed by 
the NCI Laboratory of Pathology. Patients with pleural, peritoneal, pericardial or tunica 
vaginalis mesothelioma are eligible.  
2.1.1.2 Archival tumor samples must be available and sufficient for diagnostic and genetic 
testing; if archival sample insufficient for testing, subject must have lesions amenable to 
biopsy and be willing to undergo biopsy. 
2.1.1.3 Patients must have measurable disease, as defined in sections 6.4.1 and 6.4.2. 
2.1.1.4 Patients must have progressive disease at study entry 
2.1.1.5 Patients must have received prior platinum and pemetrexed based therapies. Response to 
platinum is not an eligibility criterion for enrollment. 
2.1.1.6 Age >18 years. Because no dosing or adverse event data are currently available on the 
use of olaparib in patients <18 years of age, children are excluded from this study, but 
may be eligible for future pediatric trials. 
2.1.1.7 ECOG performance status < 1 (see Appendix A). 
2.1.1.8 3DWLHQWVPXVWKDYHDOLIHH[SHFWDQF\RIZHHNV 
2.1.1.9 Patients must have adequate organ and marrow function GD\VSULRUWR&'as defined 
below:  
leukocytes  
>3,000/mcL 
absolute neutrophil count 
>1,500/mcL without growth factor support 
platelets 
>100,000/mcL 
hemoglobin 
10 g/dL with no blood transfusion in the past 28 
days 
total bilirubin 
[8/1XQOHVV*LOEHUW¶V'LVHDVH 
AST(SGOT)/ALT(SGPT) 
<;LQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO;
ULN in the presence of liver metastases)  
creatinine clearance 
 51 mL/min (calculated using the -Cockcroft-
Gault formula. 
2.1.1.10 Pre-clinical data indicate that olaparib can have adverse effects on embryofetal survival 
and development. It is further not known whether olaparib or its metabolites are found in 
seminal fluid. For these reasons: 
2.1.1.10.1  Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of 2 highly effective forms of contraception in combination (male 
condom plus one of the methods listed in section 2.1.1.10.3) or must totally/truly 


15 
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abstain from any form of sexual intercourse. This should be started from the signing 
of the informed consent, throughout their participation in the study and for at least 1 
month after the last dose of olaparib. 
2.1.1.10.2 Male patients 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 patients should also use a 
highly effective form of contraception (see section 2.1.1.10.3) if they are of 
childbearing potential. Male patients should not donate sperm throughout the period 
of taking olaparib and for 3 months following the last dose of olaparib. 
2.1.1.10.3 Acceptable birth control methods: 
¾ Total sexual abstinence i.e., refrain from any form of sexual intercourse in line 
with the patients’ usual and/or preferred lifestyle. Abstinence must be for the 
total duration of the study treatment and for at least 1month (for female patients) 
or 3 months (for male patients) after the last dose of study treatment. Periodic 
abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
¾ Vasectomised sexual partner PLUS male condom. With participant assurance 
that partner received post-vasectomy confirmation of azoospermia. 
¾ Tubal occlusion PLUS male condom 
¾ Intrauterine Device PLUS male condom. Provided coils are copper-banded. 
¾ Etonogestrel implants (e.g., Implanon®, Norplant®) PLUS male condom 
¾ Normal and low dose combined oral pills PLUS male condom 
¾ Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom 
¾ Intrauterine system device (e.g., levonorgestrel-releasing intrauterine system -
Mirena®) PLUS male condom 
¾ Norelgestromin/ethinyl estradiol transdermal system PLUS male condom 
¾ Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male condom 
¾ Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only 
highly efficacious progesterone based pill. 
2.1.1.11 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who are receiving any other investigational agents. 
2.1.2.2 Patients who have received any previous treatment with a PARP inhibitor, including 
olaparib. 
2.1.2.3 Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment 
2.1.2.4 Patients with other malignancy documented as occurring within the last 1 year. 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, or other 


16 
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solid tumors including lymphomas (without bone marrow involvement) documented as 
curatively treated or under control IRU1 year. 
2.1.2.5 Patients with features suggestive of MDS/AML on peripheral blood smear. 
2.1.2.6 Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence 
of brain metastases is not required. The patient can receive a stable dose of corticosteroids 
before and during the study as long as these were started at least 4 weeks prior to 
treatment. Patients with spinal cord compression unless considered to have received 
definitive treatment for this and evidence of clinically stable disease for 28 days. 
2.1.2.7 History of allergic reactions or hypersensitivity attributed to compounds of similar 
chemical or biologic composition to olaparib or its excipients. 
2.1.2.8 Patients who have had a whole blood transfusion within 120 days prior to enrollment. 
(Packed red blood cells and platelet transfusions are acceptable, for timing refer to item 
2.1.1.9) 
2.1.2.9 3DWLHQWVZLWKSHUVLVWHQWWR[LFLWLHV&7&$(Jrade 2) with the exception of alopecia, 
caused by previous cancer therapy  
2.1.2.10 Concomitant use of known strong or moderate CYP3A inhibitors (e.g. itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, 
indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors 
(e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required 
washout period prior to starting olaparib is 2 weeks. 
2.1.2.11 Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide, 
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s 
Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required 
washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital 
and 3 weeks for other agents. 
2.1.2.12 Resting ECG with QTcF > 470 msec on 2 or more time points within a 24-hour period or 
family history of long QT syndrome  
2.1.2.13 Patients that have had major surgery within 2 weeks of starting study treatment and 
patients must have recovered from any effects of any major surgery. 
2.1.2.14 Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
2.1.2.15 Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection. Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on 
High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that 
prohibits obtaining informed consent. 
2.1.2.16 Pregnant women are excluded from this study because olaparib has the potential for 
teratogenic or abortifacient effects. Women must either be post-menopausal or must have 
DQHJDWLYHSUHJQDQF\WHVWXULQHRUVHUXP28 days prior to enrollment and confirmed 
on day 1 of cycle 1 of study therapy. 
Postmenopausal is defined as: 


17 
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 
Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
 
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
post-menopausal range for women under 50 years of age 
 
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) 
2.1.2.17 Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with olaparib, breastfeeding should be discontinued 
if the mother is treated with olaparib.  
2.1.2.18 Immunocompromised patients are excluded. 
2.1.2.19 Patients who are known to be serologically positive for human immunodeficiency virus 
(HIV). This includes HIV patients on antiretroviral therapy due to the potential for 
pharmacokinetic interactions with olaparib. 
2.1.2.20 Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the 
infection through blood or other body fluids 
2.1.2.21 Previous allogeneic hematopoietic stem cell transplant, allogeneic bone marrow 
transplant or double umbilical cord blood transplant (duCBT) 
2.1.3 Recruitment Strategies 
Information about the study will be posted on sites such as clinicaltrials.gov and the CCR 
recruitment website. In addition, information about this study will be posted on NIH social media 
platforms.  Subjects will also be drawn from patients seen at the mesothelioma clinic at the NIH 
Clinical Center as well as from referrals from outside providers.  
2.2 
SCREENING EVALUATION 
The following activities will be performed only after the subject has signed the consent for study 
# 01C0129 on which screening activities will be performed. Assessments performed at outside 
facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a patient has signed the consent. 
Screening evaluation may be completed within 28 days prior to enrollment unless otherwise noted 
x Confirmation of histologic or cytologic diagnosis of mesothelioma by the NCI Laboratory 
of Pathology. If archival tissue is unavailable or insufficient for this purpose, a fresh biopsy 
will be collected. This may be performed at any time prior to enrollment. Remaining tissue 
(fresh or archival) may be used for somatic mutational analysis. 
x Medical History including prior cancer therapies, history of blood transfusions 
x Physical exam including vital signs and ECOG performance status 
x CT scan with contrast of chest, abdomen and/or pelvis and areas of known or suspected 
disease involvement; MRI may also be performed when appropriate 
x FDG-PET scan 


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x Hematology including blood smear (See footnote in 5 in Study Calendar for detailed list 
of assessments) 
x Biochemistry assessments (See footnote 6 in Study Calendar for detailed list of 
assessments) 
x Coagulation (See footnote 8 in Study Calendar for detailed list of assessments) 
x Serum or urine ȕ-hCG in women of childbearing potential (within 28 days prior to 
enrollment and confirmed on day 1 of cycle 1) 
x Urinalysis (See footnote 7 in Study Calendar for additional instructions) 
x Electrocardiogram (Performed within 7 days prior to enrollment. See footnote 10 in Study 
Calendar for additional instructions) 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents. Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours. 
2.3.1 Treatment Assignment and Randomization/Stratification Procedures 
Cohorts 
Number 
Name 
Description 
1 
Mesothelioma 
Subjects with malignant mesothelioma 
Arms 
Number 
Name 
Description 
1 
Olaparib 
Twice daily oral olaparib 
Stratifications 
None. 
Randomization and Arm Assignment 
This is not a randomized study. Subjects 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 subjects with progressive malignant 
mesothelioma who have previously been treated. Olaparib will be continued until disease 
progression or unacceptable toxicity. As indicated in section 10, subjects will be analyzed in 3 
separate comparison groups according to their mutation status:  
x Comparison Group 1: Patients with a germline mutation in DNA repair genes 
x Comparison Group 2: Patients with BAP1 somatic mutations 
x Comparison Group 3: Patients with neither germline DNA repair mutations nor BAP1 
somatic mutations 
Germline samples for mutation status analysis will be collected and stored in a CLIA certified 
laboratory Genetics Branch (CLIA# 21D2125203). Tissue (blocks and slides) and fresh biopsies 
(if collected) will be stored in the NCI Laboratory of Pathology (CLIA#21D0716664). Genetic 
analysis will be performed retrospectively using the ClinOmics platform. 
3.2 
DRUG ADMINISTRATION 
Olaparib at the dose of 300 mg will be given orally continuously twice daily, with doses taken at 
the same times each day approximately 12 hours apart. The correct number of 100mg or 150mg 
tablets comprising the appropriate dose should be taken at the same times each day 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 21-day cycle. Per the CCR policy for self-
administered oral investigational agents (PM-8) which will be followed in this protocol, patients 
will be provided with a pill diary (Appendix C), instructed in its use, and asked to bring it with 
them to each appointment. 
Patients should be given clear instructions on how and when to take their study treatment. Patients 
will self-administer olaparib. Study site staff will make tablet counts at regular intervals during 
treatment. Compliance will be assessed by the tablet count and the information will be recorded in 
the appropriate section of the eCRF.  All patients must return their bottle(s) of olaparib at the 
appropriate scheduled visit, when a new bottle will be dispensed. Patients will be instructed to 
notify study site personnel of missed doses. Dates of missed or held doses will be recorded by the 
patient on their patient diary and by the site staff on the eCRF. 
If a patient misses more than 50% of the doses in any given cycle, the patient will be considered 
inevaluable for response per sections 10.3.2 and 10.3.3 and will be removed from the study. 
Patients 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 of the intact tablets can be seen and counted. Should any patient enrolled on the study miss a 
scheduled dose, the patient will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time. If greater than 2 hours after the scheduled dose time, the missed 
dose should not be taken, and the patient should take their allotted dose at the next scheduled time. 
Subjects should avoid grapefruit juice while on study, due to P450 interactions. 


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3.3 
DOSE DELAYS/MODIFICATIONS 
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. Study treatment can be modified per Table 2. 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. 
Table 2: Dose levels for olaparib dose modification 
Dose Level 
Olaparib tablets 
1 (Starting dose level) 
300 mg twice daily 
-1 
250 mg twice daily 
-2 
200 mg twice daily 
3.3.1 Modifications and Management of Hematologic Toxicities 
3.3.1.1 Anemia 
Table 3: Dose Delay/Modification and Management of Anemia 
Hemoglobin 
Action to be taken 
Hb < 9 but JdL  
Give appropriate supportive treatment and investigate causality.  
Investigator judgment to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks.  
If repeat Hb < 9 but JGL, dose interrupt (for max of 4 weeks) 
XQWLO+E9 g/dL and upon recovery dose reduction to 250 mg twice 
daily as a first step and to 200 mg twice daily as a second step may 
be considered. 
+EJdL 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and 
investigate causality.  
Interrupt olaparib for a maximum of 4 weeksXQWLOLPSURYHGWR+E
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. 
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 patients develop prolonged 
KHPDWRORJLFDOWR[LFLW\ 2-week interruption/delay in study treatment due to CTCAE grade 3 or 
worse anemia and/or development of blood transfusion dependence), refer to Section 3.3.1.3 for 
the management of this.  


21 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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3.3.1.2 Neutropenia, Leukopenia and Thrombocytopenia 
Table 4: Dose Modification and Management of Neutropenia, Leukopenia and 
Thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgment 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 olaparib to 250 mg twice daily as a first step and 200 mg 
twice daily as a second step 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator in consultation with the NIH CC pharmacy with close follow up and interruption of 
study drug if CTCAE grade 3 or worse neutropenia occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, study treatment should be stopped and 
appropriate management including G-CSF should be given according to local hospital guidelines. 
Please note that G-CSF should not be used within at least 24 hours after the last dose of and within 
24 hours (14 days for pegylated G-CSF) before resuming study treatment unless absolutely 
necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
)RUFDVHVZKHUHSDWLHQWVGHYHORSSURORQJHGKHPDWRORJLFDOWR[LFLW\ 2-week interruption/delay 
in study treatment due to CTCAE grade 3 or worse), refer to Section 3.3.1.3.  
3.3.1.3 Management of Prolonged Hematological Toxicities while on Study Treatment 
If a patient develops prolonged hematological toxicity such as: 
x 
-week interruption/delay in study treatment due to CTCAE grade 3 or worse anemia 
and/or development of blood transfusion dependence 
x 
-week interruption/delay in study treatment due to CTCAE grade 3 or worse 
neutropenia (ANC < 1000/mcL) 
x 
-week interruption/delay in study treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 
50,000/mcL) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any 
blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient should 
be referred to hematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard hematological 
practice. Study treatment should be discontinued if blood counts do not recover to CTCAE grade 
1 or better within 4 weeks of dose interruption. 


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Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported to the manufacturer as an SAE and full reports must be provided by the investigator to 
AstraZeneca Patient Safety. Olaparib treatment should be discontinued if patient’s diagnosis of 
MDS and/or AML is confirmed. 
3.3.2 Modifications and Management of Non-Hematologic Toxicities 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. 
Where toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced per Table 2. 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. 
3.3.2.1 Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further 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. 
3.3.2.2 Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the placebo 
treated patients and vomiting was reported in 34% of the olaparib treated patients and 14% in the 
placebo treated patients. These events are generally of mild to moderate (CTCAE grade 1 or 2) 
severity, intermittent and manageable on continued treatment. The first onset generally occurs in 
the first month of treatment for nausea and within the first 6 months of treatment for vomiting. For 
nausea, the incidence generally plateaus at around 9 months, and for vomiting at around 6 to 7 
months. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines. Alternatively, 
olaparib tablets can be taken with a light meal/snack (e.g. 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered e.g. dopamine receptor antagonist, antihistamines or 
dexamethasone. 
3.3.2.3 Renal impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls below 
WKHWKUHVKROGIRUVWXG\LQFOXVLRQmL/min), retesting should be performed promptly.  


23 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
A dose reduction is recommended for patients who develop moderate renal impairment (calculated 
creatinine clearance by Cockcroft-Gault equation of between 31 and 50 mL/min) for any reason 
during the course of the study: the dose of olaparib should be reduced to 200mg 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 patients develop severe impairment or end stage 
disease is it recommended that olaparib be discontinued. 
3.3.2.4 Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is required 
for any needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should 
be advised to use caution while driving or using machinery if these symptoms occur. 
 


24 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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3.4 
STUDY CALENDAR 
1 cycle =21 days 
Screening assessments must occur within 28 days prior to enrollment unless otherwise indicated. If screening/baseline assessments are 
performed within 7 days prior to dosing, these assessments do not need to be repeated on C1D1 unless otherwise indicated. 
Assessments after and including C1D1 may be performed up to 3 days prior to indicated time unless otherwise indicated. 
Dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, Federal holidays and inclement 
weather, etc. 
Procedure 
Screening1 
Baseline 
Cycle 1 
Subsequent 
Cycles 
Treatment 
discontinuation visit2 
Post 
Therapy 
Follow-up 
Day 1 
Day  
Day 1 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
X 
 
 
X 
 
Prior cancer therapies 
including radiotherapy 
X 
 
 
 
 
 
 
History of blood 
transfusions3 
X 
 
 
 
 
 
 
Inclusion exclusion 
criteria 
X 
 
 
 
 
 
 
Physical exam 
X 
 
X 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
Performance Score 
X 
 
X 
 
X 
 
 
Archival or fresh tissue 
for dx confirmation 
X 
 
 
 
 
 
 
Labs4 
 
 
 
 
 
 
 
Full 
hematology 
assessment5 
X 
 
X 
X 
X 
X 
 
Biochemistry6 
X 
 
X 
X 
X 
X 
 


25 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
Procedure 
Screening1 
Baseline 
Cycle 1 
Subsequent 
Cycles 
Treatment 
discontinuation visit2 
Post 
Therapy 
Follow-up 
Day 1 
Day  
Day 1 
Urinalysis7 
X 
 
X 
 
 
 
 
Coagulation8 
X 
 
X 
 
 
 
 
Serum or Urine hCG in 
women of childbearing 
potential9 
X 
 
X 
 
X 
X 
 
Electrocardiogram10 
X 
 
X 
 
 
 
 
Sample collection for 
mutational analysis 
(mandatory)11 
 
X 
 
 
 
 
 
NIH 527 release form 
 
X12 
 
 
 
 
 
Correlative Research 
Studies (See 5.1.2) 
 
 
X 
 
X 
X 
 
NIH Advance Directives 
Form13 
 
X 
 
 
 
 
 
CT CAP (MRI if 
appropriate); FDG-PET 
X 
 
Every 6 
weeks ± 
7 days 
 
 
X14 
X15 
Adverse Events 
 
 
X 
 
 
X 
 
Concomitant Medications 
 
 
X 
 
 
 
 
1. 
Screening evaluations are done within 28 days prior to enrollment with the exception of confirmation of diagnosis (within 6 months prior to 
enrollment) and ECG (within 7 days prior to enrollment) 
2. 
End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient is unable to return to the Clinical 
Center, symptom assessment may be performed via telephone and labs/scans may be performed by an outside provider; the research sample 
is not required in this circumstance. . 
3. 
Include history of blood transfusion within previous 120 days from start of study treatment and the reasons e.g. bleeding or myelosuppression. 
4. 
These tests will be performed by the NIH CC Department of Laboratory Medicine. Additional analyses may be performed if clinically 
indicated. Any clinically significant abnormal laboratory values should be repeated as clinically indicated and recorded on the eCRF. 


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5. 
Full hematology assessments for safety: hemoglobin, red blood cells (RBC), platelets, mean cell volume (MCV), mean cell hemoglobin 
concentration [MCHC], mean cell hemoglobin (MCV), white blood cells (WBC), absolute differential white cell count (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils) and absolute neutrophil count or segmented neutrophil count and Band forms should be 
performed at each visit and when clinically indicated. If absolute differentials not available please provide % differentials.  
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged hematological toxicities as defined in Section 
3.3.1.3. Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy 
for bone marrow cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts 
should be made to carry out the tests on a blood sample. If findings are consistent with MDS/AML, study drug should be discontinued and a 
full description of findings should be submitted to the manufacturer with an SAE report by the investigator. Presence or absence of blood 
cytogenetic abnormalities and flow cytometry will be documented on the clinical database.  
6. 
Biochemistry assessments for safety: sodium, potassium, calcium, magnesium, fasting glucose, creatinine, total bilirubin, gamma 
glutamyltransferase (GGT) – optional on C1D8, alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), 
urea or blood urea nitrogen (BUN), total protein, albumin and lactic dehydrogenase (LDH). In case a subject shows an AST or A/7[8/1
RUWRWDOELOLUXELQ[8/1SOHDVHUHIHUWR Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions. 
7. 
Urinalysis by dipstick should be performed at screening/baseline and then only if clinically indicated. Microscopic analysis should be 
performed by the NIH Clinical Center Department of Laboratory Medicine if required. 
8. 
Coagulation: activated partial thromboplastin time (APTT) and international normalized ratio (INR) will be performed at screening/baseline 
and if clinically indicated unless the patient is receiving warfarin. Patients taking warfarin may participate in this study; however, it is 
recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week for the first month, then monthly if the 
INR is stable. 
9. 
Two pregnancy tests on blood or urine samples will be performed for pre-menopausal women of childbearing potential one within 28 days 
prior to the start of study treatment and the other on Day 1 of the study prior to commencing treatment. Tests will be performed by the NIH 
Clinical Center Department of Laboratory Medicine. If results are positive the patient is ineligible/must be discontinued from the study. In 
the event of a suspected pregnancy during the study, the test should be repeated. 
10. ECGs are required within 7 days prior to starting study treatment and when clinically indicated. Twelve-lead ECGs will be obtained after the 
patient has been rested in a supine position for at least 5 minutes in each case. The Investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected. ECGs will be recorded at 25 mm/sec. All ECGs 
should be assessed by the investigator as to whether they are clinically significantly abnormal / not clinically significantly abnormal. If there 
is a clinically significant abnormal finding, the Investigator will record it as an AE on the eCRF. The original ECG traces must be stored in 
the patient medical record as source data 
11. Please refer to sections 5.1.2 and 5.3. 


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12. As indicated in section 5.3.1, patients will be offered the opportunity to identify a designee to receive actionable genetic results. If the patient 
refuses, this must be documented in the medical record. 
13. As indicated in section 12.3DOOVXEMHFWVDJHZLOOEHRIIHUHGWKHRSSRUWXQLW\WRFRPSOHWHDQ1,+advance directives form. This should 
be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the 
form is strongly recommended, but is not required. 
14. Performed only if patient removed from study therapy for reason other than progressive disease 
15. Follow up scans will continue every 6 weeks until disease progression. Scans performed outside the NIH Clinical Center are acceptable. 
 


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3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit or 
phone call approximately 30 days following the last dose of study therapy. 
3.5.1 Criteria for Removal from Protocol Therapy 
x Progressive disease 
x Participant requests to be withdrawn from active therapy (see section 3.5.4) 
x Requires use of prohibited medication 
x Unacceptable Toxicity as defined in section 3.3 
x Investigator discretion 
x Patient non-compliance 
x Positive pregnancy test 
3.5.2 Follow Up 
By discontinuing from study treatment, the patient is not withdrawing from the study. Patients 
should be followed for progression (if discontinuation in the absence of progression) as per the 
Study Calendar.  
Any patient discontinuing investigational product should be seen at 30 days post discontinuation 
for the evaluations outlined in the Study Calendar at the Treatment discontinuation visit. The 
patient’s tumor status should be assessed clinically and, if appropriate, disease progression should 
be confirmed by radiological assessment. After discontinuation of study medication, the principal 
Investigator/Sub-Investigator will perform the best possible observation(s), test(s) and 
evaluation(s) as well as give appropriate medication and all possible measures for the safety of the 
patient. In addition, they will record on the eCRF the date of discontinuation, the reasons, 
manifestation and treatment at the time of discontinuation. Patients will be required to attend the 
treatment discontinuation visit. The patient should return all study medication. 
After discontinuation of the study medication at any point in the study, all ongoing AEs or SAEs 
must be followed as directed in section 6.2.1). All new AEs and SAEs occurring during the 30 
calendar days after the last dose of study medication must be reported (if SAEs, they must be 
reported to AstraZeneca within 24 hours as described in Section 8.2.1) and followed to resolution 
as above. Patients should be seen at least 30 days after discontinuing study medication to collect 
and / or complete AE information. For guidance on reporting adverse events to the manufacturer 
after the 30-day follow up period see Section 8.2.2. 
Any patient who has not yet shown objective radiological disease progression at withdrawal from 
olaparib should continue to be followed as per RECIST as detailed in Study Calendar. 
3.5.3 Off-Study Criteria 
x Completed study follow-up period 
x Patient non-compliance 
x Participant requests to be withdrawn from study (see section 3.5.4) 


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x Death 
x Participant lost to follow-up 
x The study is discontinued 
 
3.5.4 Withdrawal of Informed Consent 
Patients are free to withdraw from the study at any time (investigational product and assessments), 
without prejudice to further treatment. 
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
x to further participation in the study including any further follow up  
x withdrawal of consent to the use of their study generated data 
x withdrawal to the use of any samples 
3.5.5 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Note: 
A 
regularly 
updated 
source 
such 
the 
one 
available 
here 
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 use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the case report form (CRF). 
4.1 
SUPPORTIVE CARE 
Unless otherwise indicated in sections 3.3.1 and 3.3.2, 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 (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy (unless palliative – see 4.5.2), biological 
therapy or other novel agent) is to be permitted while the patient is receiving study medication. 
(Note: Patients may continue the use of bisphosphonates or denosumab for bone disease and 
corticosteroids for the symptomatic control of brain metastases 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 patient is receiving study medication and during the 30-day follow up period. An increased 


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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. 
4.3 
PERMITTED WITH OLAPARIB DOSING CHANGES 
4.3.1 Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A 
inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not be taken 
concomitantly 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.  
x Strong CYP3A inhibitors – reduce the dose of olaparib to 100mg twice daily for the 
duration of concomitant therapy with the strong inhibitor and for 5 half-lives of the CYP3A 
inhibitor and any metabolites of the inhibitor that are also CYP3A subfamily enzyme 
inhibitors. 
x Moderate CYP3A inhibitors - reduce the dose of olaparib to 150mg twice daily for the 
duration of concomitant therapy with the moderate inhibitor and for 3 half-lives of the 
CYP3A inhibitor and any metabolites of the inhibitor that are also CYP3A subfamily 
enzyme inhibitors. 
x After the washout of the inhibitor is complete, the olaparib dose can be re-escalated to the 
dose that had been or would be administered without concomitant use of an inhibitor. 
4.4 
PERMITTED WITH CAUTION 
4.4.1 Strong or Moderate CYP3A inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (e.g. bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib. 
If the use of any strong or moderate CYP3A inducers are considered necessary for the patient’s 
safety and welfare this could diminish the clinical efficacy of olaparib. 
If a patient requires use of a strong or moderate CYP3A inducer then they must be monitored 
carefully for any change in efficacy of olaparib. 
4.4.2 P-gp Inhibitors 
It is possible that co-administration of P-gp inhibitors (e.g. amiodarone, azithromycin) may 
increase exposure to olaparib. In addition, olaparib is an inhibitor of P-gp. Caution should therefore 
be observed when olaparib is used concomitantly with substrates, inhibitors, and inducers of P-gp. 
4.4.3 Effect of Olaparib on Other Drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
UGT1A1, P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
Based on limited in vitro data, olaparib may reduce the exposure to substrates of 2B6.  


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The efficacy of hormonal contraceptives may be reduced if co administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins are 
co-administered. 
Examples of substrates include: 
x CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
x CYP2B6 – bupropion, efavirenz 
x CYP2C9 – warfarin  
x CYP2C19 - lansoprazole, omeprazole, mephenytoin 
x CYP1A2 – duloxetine, melatonin 
x P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
x OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
x OCT1, MATE1, MATE2K – metformin 
x OCT2 - serum creatinine 
x OAT3 -furosemide, methotrexate 
4.5 
PERMITTED MEDICATIONS 
4.5.1 Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
international normalized ratio (INR) be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable. Subcutaneous heparin and low molecular weight heparin 
are permitted. 
4.5.2 Palliative Radiotherapy  
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that 
were present at baseline, provided the investigator does not feel that these are indicative of clinical 
disease progression during the study period. Study treatment should be discontinued for a 
minimum of 3 days before a patient undergoes therapeutic palliative radiation treatment. Study 
treatment should be restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples:  
The levels of serum mesothelin as well as megakaryocyte potentiating factor, which is released 
into serum from the processing of mesothelin precursor protein will be assessed in order to 
determine correlation with therapeutic response.  
5.1.1.1 Sample Collection  
Samples will be prior to the first olaparib dose of each cycle and at the end of treatment.  


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All blood samples will be taken by either direct venipuncture or an indwelling venous access. At 
each sample collection time, blood (2mL) will be drawn into a 3.5-mL serum separator tube (tiger 
top tube) labeled as follows:  
x Subject ID Number  
x Study Number  
x Time and date of collection  
5.1.1.2 Sample Processing 
manner Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples 
(the Friday before is preferred). 
x For sample pickup, page 102-11964. 
x For immediate help, call 240-760-6180 (main blood processing core number) or, if no 
answer, 240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
Upon arrival in the CPP, each sample should be processed in the following:  
Allow blood to clot for 10 minutes and centrifuge to separate the serum within 30 minutes of 
collection. If unable to process within 30 minutes, then whole blood tubes may be stored upright 
in refrigerator (4-8°C) for up to 48 hours prior to processing. Processing of samples within 30 
minutes is strongly preferred. Stability studies will establish if degradation of soluble mesothelin 
in whole blood during 0.5 to 48 hours is significant and therefore if the data from these samples 
should be included in the analysis.  
Transfer the serum into two pre-labeled cryotubes and immediately freeze by placing on dry ice. 
Transfer frozen serum samples into a – 80°C freezer for storage.  
5.1.1.3 Sample Storage  
All samples will be stored by Dr. Figg’s Clinical Pharmacology Program. 
5.1.2 Specimen Collection Table 
 
Test/assay 
Volume 
blood 
(approx) 
Type of tube 
Collection 
point (+/- 
KUV 
Specimen 
Storage 
Location of 
specimen 
analysis 
MPF and 
mesothelin 
2 mL 
3.5 mL serum 
separator 
(tiger top) 
Day 1 of each 
cycle (pre-dose) 
and at end of 
treatment  
(Deliver to 
Dr. Figg’s 
lab) 
Hassan Lab  
Mandatory 
Mutational 
Analysis 
NA 
NA 
Baseline if 
tissue (fresh or 
archival) 
collected at 
Entire 
collected 
specimen 
stored in 
Retrospectively 
analyzed using 
platform in a 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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Test/assay 
Volume 
blood 
(approx) 
Type of tube 
Collection 
point (+/- 
KUV 
Specimen 
Storage 
Location of 
specimen 
analysis 
(Tumor 
Biopsy) 
OR 
screening is 
insufficient 
the 
Laboratory 
of 
Pathology 
(Ordered 
in CRIS) 
ClinOmics 
Core 
(Archival 
Tumor 
Sample) 
NA 
 
Baseline if 
tissue (fresh or 
archival) 
collected at 
screening is 
insufficient  
Laboratory 
of 
Pathology  
Retrospectively 
analyzed  in 
the ClinOmics 
Core 
Mandatory 
Mutational 
Analysis 
(Blood) 
8.5 mL 
Sodium 
citrate 
Baseline  
Molecular 
Pathology 
– Deliver 
blood 
STAT to 
building 
10/Room 
3S245 
(open 7:30 
AM – 4:30 
PM) 
Ordered in 
CRIS 
(indicate 
for storage 
only) 
Retrospectively 
analyzed in the 
ClinOmics 
Core 
 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
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. 
5.2.1 Blood Processing Core 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. 


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Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80qC according 
to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material. 
5.2.2 NCI Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not placed in 
paraffin blocks is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, 
the slides and tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled.  
5.2.3 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed. Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 
samples, provided they have an IRB-approved protocol and patient consent or an exemption from 
OHSRP. 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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The PI will record any loss or unanticipated destruction of samples as a deviation and report to the 
IRB per the requirements of section 7.2.  
5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
All genetic testing on the protocol will be stored in a CLIA certified laboratory for later analysis 
using the ClinOmics platform. 
A blood sample will be collected and stored for later mandatory germline mutational analysis of 
DNA repair genes (via whole exome sequencing) as indicated in section 5.1.2. 
In addition, leftover tumor tissue from the confirmation of diagnosis may be used for mutational 
analysis. If insufficient, additional archival tissue may be requested or a fresh tumor biopsy 
obtained. Collection of tumor biopsy should be guided by ultrasound, CT scan, or other method 
according to the location of the selected lesion using a 18-gauge needle to provide cores ideally 
of at least 20 mm in length or equivalent size. At least 2, ideally 4 core biopsies will be obtained. 
Fine needle aspiration and biopsy of bone lesions are not acceptable. All biopsies collected under 
this protocol will undergo review and storage in the NCI Laboratory of Pathology.  
All CLIA samples will be stored and tracked by the CLIA laboratories Pathology for tissue 
(CLIA#21D0716664) and Genetics Branch for blood (CLIA# 21D2125203) according to their 
detailed CLIA SOP manuals. The research laboratory must be bypassed. The freezers are locked, 
temperature monitored using state of the art equipment according to the CLIA documents. Samples 
are stripped of identifiers and given an ID according to the CLIA documents. No personal 
identifiers will be utilized. 
Though the intent is to analyze samples as soon as possible, logistical issues may cause delay. 
Therefore, genetic analysis may be performed on stored blood and tissue samples. 
5.3.1 Management of Results 
All genetic testing performed on this study will be done in CLIA certified laboratory, the 
ClinOmics Core though the testing may not be performed in real time.  
At the time of consent, subjects will be informed that genetic findings will arise from this study 
and that information on somatic findings will be provided as well as germline secondary findings. 
The type of findings to be returned will be discussed as well as the delay in testing. 
Participants will be asked complete and sign an NIH-527 Release form at the time of consent. The 
completion of the form is optional, but a note will be made in the medical record to document 
refusal. In the event that the participant dies or becomes incapacitated in the time frame between 
providing a sample for germline analysis and results being available, actionable results will be 
provided to the individual specified on the release form. 
The treating investigator will disclose somatic findings as well as germline findings in which no 
mutation of clinical utility has been identified to subjects remaining on study at the time the 
germline analysis is performed.  
.. 
Germline potential clinically actionable findings for the purpose of this study will be flagged as 
germline mutations that are high confidence pathogenic or likely pathogenic cancer related or 
American College of Medical Genetics (ACMG) list of genes. The ACMG guidelines for 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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reporting findings that is current at the time of primary analysis. (A list of current ACMG 
guidelines 
is 
maintained 
on 
the 
CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Germline 
potential clinically actionable variants will be evaluated by the Genetics Branch Genetics Core 
comprised of a Clinical Geneticist and genetic counsellors.  Those deemed to be clinically 
actionable will be confirmed by COLOR or another CLIA/CAP commercial laboratory from a 
new DNA sample taken from the patient. Subjects (or designees) will be informed if a clinically 
actionable gene variant is discovered through a consult with the Genetics Branch who will 
provide appropriate genetic counseling. The results of the verified actionable germline variant 
with a consult note will be uploaded into CRIS as part of the medical records. 
If the subject or designee 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 secondary 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 an in-house password protected 
electronic system (C3D) 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. All data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with NIH security standards. 
Primary and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.2 
RECORDING OF ADVERSE EVENTS 
6.2.1 Time Period for Collection of Adverse Events 
Adverse Events will be collected from initiation of study therapy, throughout the treatment period 
through the 30-day follow up period/treatment continuation visit. Adverse events occurring after 
the 30-day follow up period will only be recorded if they meet the definition of adverse event of 
special interest (section8.1.2) or it the adverse event is serious and is deemed related to olaparib.  
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.  
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: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  


37 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
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x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
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 patient’s 
outcome. 
6.3 
DATA SHARING PLANS 
6.3.1 Human Data Sharing Plan 
What data will be shared? 
The PI will share human data generated in this research for future research as follows: 
• Coded, linked data in an NIH-funded or approved public repository. 
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
• 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: 
• An NIH-funded or approved public repository: clinical trials.gov. 
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 
When will the data be shared? 
• Before publication. 
• At the time of publication or shortly thereafter. 
6.3.2 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. 
6.4 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks (2 
cycles). In addition to a baseline scan, confirmatory scans should also be obtained no less than 4 
weeks following initial documentation of objective response. 
Response and progression will be assessed by the investigator on the basis of physical 
examinations, computed tomography (CT) or Magnetic Resonance (MR) scans, and potentially 
other modalities according to standard of care. 
For peritoneal mesothelioma, the international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)[17] will be used. Changes in 


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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.  
For pleural mesothelioma, modified RECIST for MPM (malignant pleural mesothelioma)[18] 
should be used as described in section 6.4.2.  
6.4.1 Non-Pleural Mesothelioma 
6.4.1.1 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:  
x By chest x-ray: >20 mm;  
x By CT scan:  
o Scan slice thickness 5 mm or under: >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
x With calipers on clinical exam: >10 mm. 
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 
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non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 


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Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.4.1.2 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 t10 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 


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independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. 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 patient 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.[19-21] 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.[22] 
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. 


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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. 
6.4.1.3 RECIST version 1.1 Response Criteria 
6.4.1.3.1 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. 
6.4.1.3.2 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 patient 
to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
6.4.1.3.3 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 patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
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: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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Non-Target Lesions 
New Lesions 
Overall Response 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
6.4.2 Pleural Mesothelioma 
Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.[18] Therefore, 
modified criteria were defined in 2004 adjusting target lesion measurements to the specific needs 
of this disease. 
6.4.2.1 Modified RECIST Criteria for MPM 
Target lesion:  
Pleural lesions measurable at baseline and defined as tumor thickness measurements perpendicular 
to the chest wall or mediastinum in two positions at three separate levels on transverse cuts of CT 
scan. The sum of those 6 measurements define a pleural unidimensional measure. For 
reproducibility of lesion identification in follow up scans, cuts were taken at least 1 cm apart and 
close to anatomical landmarks in the thorax. Reassessments should be done at same position at the 
same level and by the same reader. Nodal, subcutaneous, and other measurable lesion were 
measured as per RECIST criteria. All unidimensional measurements were added to obtain total 
tumor measurement. 
Evaluation of target lesions  
x 
Complete Response (CR): Disappearance of all target lesions with no evidence of tumor 
elsewhere.  
x 
Partial Response (PR): At least a 30% decrease in the total tumor measurement  
x 
Confirmed response (PR and CR): require a repeat scan at least 4 weeks apart  
x 
Progressive Disease (PD): At least a 20% increase in the total tumor measurement, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). (Note: the appearance of one or more new lesions is also considered 
progression).  
x 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study.  
6.4.2.2 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Response 
for 
this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
6.4.3 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.  
6.4.4 Progression-Free Survival 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. Patients that have not progressed or died will be 
censored at the date of the last tumor assessment. 


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6.4.5 Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients with partial response or 
complete response. 
6.4.6 Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with stable disease, partial 
response or complete response 
6.5 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient 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 here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB  
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 here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found 
here.   
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 


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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 when patients are being actively treated on 
the trial to discuss each patient.  
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 patient 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.  
 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL 
COLLABORATORS 
 
DEFINITIONS 
8.1.1 Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs 
8.1.2 Adverse Events of Special Interest 
Adverse events of special interest [AESI] are events of scientific and medical interest specific to 
the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI may be serious or non-serious. 
Adverse Events of Special Interest for olaparib are the Important Potential Risks of MDS/AML, 
new primary malignancy (other than MDS/AML) and pneumonitis. 
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE [e.g. non-melanoma skin 
cancer] or SAE, and regardless of investigator’s assessment of causality or knowledge of the 
treatment arm. 
8.1.3 Serious Adverse Event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 


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x 
Requires in-patient hospitalization or prolongation of existing hospitalization  
x 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
REPORTING TO ASTRA ZENECA  
The following essential information must be provided to AstraZeneca SAE reports (initial and 
follow-up):  
o 
Include AE cover sheet provided by AstraZeneca and tracking number 
(ESR-17-12714) 
o 
CC study number 
o 
Patient study number  
o 
Age 
o 
Sex 
o 
Investigational Medical Product (IMP) dose, start & stop date 
o 
SAE onset & stop date 
o 
Event term as reported by the investigator and/or the CTCAE V5 term  
o 
CTCAE grade  
o 
Investigator’s assessment of seriousness, according to ICH definitions 
o 
Investigator’s assessment of causality  
o 
SAE Outcome 
o 
Date of death, if applicable 
 
Note: The Study tracking number must be provided in the header of the cover note and also in the 
e-mail Subject. If possible, the study tracking number may also be included in the SAE form. 
 
Reports are sent to: 
AEMailboxClinicalTrialTCS@astrazeneca.com or Fax to TCS: 1-302-886-4114) 
 
8.2.1 Serious Adverse Events 
If any SAE occurs in the course of the study, then Investigator will inform AstraZeneca within one 
day i.e., immediately but no later than 24 hours of when he or she becomes aware of it. 
Adverse Events (AEs) for malignant tumors reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the malignant 
tumor, the AE may not fulfill the attributes for being assessed as Serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, which do not spread remotely after a routine treatment that does not require 


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hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell carcinoma 
and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumor event in question is a new malignant 
tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is being treated 
by the IP under study and is not the development of new or progression of existing metastasis to 
the tumor under study). Malignant tumors that – as part of normal, if rare, progression – undergo 
transformation (e.g., Richter's transformation of B cell chronic lymphocytic leukemia into diffuse 
large B cell lymphoma) should not be considered a new malignant tumor. 
An AstraZeneca representative will work with the Investigator to ensure that all the necessary 
information is provided to the AstraZeneca Patient Safety data entry site within 1 calendar day 
of initial receipt for fatal and life-threatening events and within 5 calendar days of initial receipt 
for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca of any follow-up information on a previously reported SAE within one calendar day 
i.e., immediately but no later than 24 hours of when he or she becomes aware of it. 
8.2.2 Adverse Events after the 30-day follow up period 
For Pharmacovigilance purposes and characterization, any case of MDS/AML or new primary 
malignancy occurring after the 30-day follow up period should be reported to AstraZeneca Patient 
Safety whether it is considered a non-serious AE [e.g. non-melanoma skin cancer] or SAE, and 
regardless of investigator’s assessment of causality or knowledge of the treatment arm. 
Investigators will be asked during the regular follow up for overall survival if the patient has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases. 
At any time after a patient has completed the study therapy, 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 patients who are gaining clinical benefit are allowed to continue study treatment post data cut 
off and/or post study completion, then all SAEs must continue to be collected and reported to 
Patient Safety within the usual timeframe. 
Otherwise, after study treatment completion (i.e. after any scheduled post treatment follow-up 
period has ended) there is no obligation to actively report information on new AEs or SAEs 
occurring in former study patients. This includes new AEs/SAEs in patients still being followed 
up for survival but who have completed the post treatment follow up period (30 days). 
8.2.3 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study follow-up 
period after the administration of the last dose of study treatment, must be reported as follows: 
x 
Death clearly the result of disease progression should be documented in the DEATH 
eCRF but should not be reported as an SAE. 
x 
Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours of Investigator 


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awareness of the event. The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main and 
contributory causes of death. This information can be captured in the ‘death eCRF’. 
x 
Deaths with an unknown cause should always be reported as a SAE. A post mortem 
maybe helpful in the assessment of the cause of death, and if performed a copy of the 
post-mortem results should be forwarded to AstraZeneca within the usual SAE 
timeframes (see sections 8.2.1 and 8.2.2). 
8.2.4 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.  
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the Investigator 
or other site personnel inform AstraZeneca immediately, or no later than 24 hours after 
Investigator awareness of the event. 
AstraZeneca will work with the Investigator to ensure that all relevant information is provided to 
the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.2.1. 
For other overdoses, reporting must occur within 30 days. 
8.2.5 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
8.2.5.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, olaparib should be discontinued 
immediately. 
The outcomes of any conception occurring from the date of the first dose of study medication until 
1 month after the last dose of study medication must be followed up and documented. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled as 
AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs AstraZeneca within 1day i.e., immediately but no later than 24 hours of becoming aware 
of it. 


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AstraZeneca will work with the Investigator to ensure that all relevant information is provided to 
the AstraZeneca Patient Safety data entry site within 1 or 5 calendar days for SAEs (see Section 
8.2.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.2.5.2 Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should if possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 3 months after the 
last dose should be followed up and documented. 
8.2.6 Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
RFFXUUHQFHVRI$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1PD\QHHGWREH
reported as SAEs. Please refer to Appendix D for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law. 
9 
IDE HOLDER MONITORING PLAN 
As the IDE holder for device trials, FDA regulations require the CCR to maintain a monitoring 
program. This is done in two parts. 
9.1 
CLINICAL MONITORING 
The CCR’s program allows for confirmation of: study data, specifically data that could affect the 
interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, 
ICH E6, and SOPs; and human subjects protection. This is done through independent verification 
of study data with source documentation focusing on: 
x Informed consent process 
x Unanticipated adverse device effect reporting 
x Adverse device effect monitoring 
x Eligibility confirmation 
x Drug administration and accountability 
x Response assessment. 
The clinical portion of the trial will be monitored by 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 
9.2 
LABORATORY MONITORING 
The program will also include laboratory monitoring for compliance with IDE regulations 
(§812.46) including device labeling as required under §812.5. Monitors will review data focusing 
on: 
x Informed consent documentation 


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x Laboratory specimen data related to the collection, processing and storage of biological 
samples used in the NSR device analysis 
The laboratory portion of the trial will be monitored by an NIH contractor for laboratory 
monitoring. 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 STATISTICAL HYPOTHESIS 
The primary objective of this pilot study is to obtain preliminary estimates of the overall response 
rates to olaparib in patients with malignant mesothelioma according to their individual comparison 
group:  
x Comparison Group 1 - Patients with a germline mutation in DNA repair genes (estimated 
at 10-12% of all patients);  
x Comparison Group 2 - Subjects with BAP1 somatic mutations (estimated at 50-60% of all 
patients) and  
x Comparison Group 3 - Patients with neither germline DNA repair mutations nor BAP1 
somatic mutations (estimated at 30-40% of all patients). 
10.1.1 Primary Endpoint  
The primary efficacy endpoints are the objective response rates to olaparib overall, as well as in 
the three comparison groups of patients. These will be assessed approximately 6 months after 
enrollment of last subject. 
10.1.2 Secondary Endpoints 
Secondary objectives include: determining safety and tolerability of olaparib in patients with 
mesothelioma; estimation of progression free-survival (PFS), identifying biomarkers of response 
to olaparib, and evaluating serum mesothelin and MPF as biomarkers of anti-tumor efficacy. 
Objective 
Endpoints 
Assess safety and tolerability 
x Numbers of DLTs identified by type and grade – 
assessed approximately 21 days after enrollment of 
last subject. 
Assess PFS 
x Kaplan Meier analysis of progression free survival in 
all patients combined – assessed approximately 6 
months after enrollment of last subject depending on 
outcomes noted. 
Investigate 
potential 
soluble 
mesothelin levels and MPF 
x 
Comparison of responders vs. non-responders with 
respect to biomarker baseline level changes over time – 
assessed approximately 6 months after enrollment of 
last subject depending on outcomes noted. 
x 
Preliminary evaluation of mesothelin and MPF with 
respect to objective response – assessed approximately 6 
months after enrollment of last subject depending on 
outcomes noted. 


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Objective 
Endpoints 
x 
Preliminary evaluation of mesothelin and MPF with 
respect to progression free survival – assessed 
approximately 6 months after enrollment of last 
subject depending on outcomes noted. 
 
10.2 SAMPLE SIZE DETERMINATION 
The primary objective of this pilot study is to obtain preliminary estimates of the overall response 
rates to olaparib in patients with malignant mesothelioma according to their individual comparison 
group:  
x Comparison Group 1 - Patients with a germline mutation in DNA repair genes (estimated 
at 10-12% of all patients) 
x Comparison Group 2 - Patients with BAP1 somatic mutations (estimated at 50-60% of all 
patients)  
x Comparison Group 3 - Patients with neither germline DNA repair mutations nor BAP1 
somatic mutations (estimated at 30-40% of all patients). 
All patients will be enrolled without consideration of their mutation status, and then the results 
will be retrospectively categorized and evaluated by mutation type. These results will be used to 
determine if there are any further patients to be enrolled following an amendment taking into 
consideration the preliminary results obtained. 
It would be desirable if overall there was at least approximately a 20% response rate. The study 
will initially plan to enroll 30 evaluable patients in order to estimate the overall response rate with 
a maximum two-sided 90% confidence interval width of +/- 16%. If the observed response rate 
were 15-20%, the confidence interval width overall would be approximately +/-10-15%. Thus, 30 
patients are adequate for an overall assessment of response. If during the initial 20 patients 
evaluated, there are 0-1 responses noted, then no further patients will be enrolled as soon as this 
can be determined since the upper one-sided 90% confidence interval bound on 1/20 is 18.1%, 
which is below the approximate response rate of interest.  Because accrual is proceeding rapidly 
on the study and continued enrollment is desirable at this time, up to 25 total patients may be 
enrolled (5 additional patients) while awaiting the response evaluations among the first 20 patients.  
It is expected that 30 evaluable patients can be enrolled in approximately 12-18 months. As patient 
non-compliance with study drug dosing will prevent them from being evaluable, the accrual ceiling 
must be adjusted accordingly. Estimating an average of 3 cycles of study therapy and a non-
compliance rate of 10% per cycle the accrual ceiling will be set at 40 patients. 
10.3 POPULATIONS FOR ANALYSES 
10.3.1 Evaluable for Toxicity  
All patients will be evaluable for toxicity from the time of their first treatment with olaparib. 


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10.3.2 Evaluable for Objective Response, Progression Free Survival and Soluble Mesothelin 
Levels and PFS  
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, have taken at least 50% of the doses per given cycle, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their response 
classified according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
10.3.3 Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, have taken at least 50% of the 
doses per given cycle, and have had their disease re-evaluated will be considered evaluable for 
non-target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
Response rates will be determined in all patients and in the three comparison groups, based on all 
evaluable patients, and reported along with appropriate confidence intervals. 
10.4.2 Analysis of the Primary Endpoints 
After enrollment, when the mutation determination is possible, the response rates will be assessed 
according to each of the three categories of mutation and the results reported accordingly. The 
proportions responding in each category will be presented along with 95% confidence intervals. 
The results obtained will be used to determine if there are any further patients to be enrolled 
following an amendment taking into consideration the preliminary results obtained. 
10.4.3 Analysis of the Secondary Endpoint(s) 
The secondary objectives will be assessed using the following measures.  
Descriptive tabulations of toxicity will be provided. 
Kaplan-Meier analysis of PFS will be performed, including reporting PFS at relevant time points, 
along with 95% confidence intervals. 
Responders vs. non-responders will be compared with respect to serum mesothelin and MPF 
baseline levels or changes over time (see section 5.1 for biomarkers to be reported), with results 
compared between response categories using two-tailed Wilcoxon rank sum tests. 
Serum mesothelin and MPF at baseline will be categorized into two groups of approximately equal 
size and tested for their association with PFS using Kaplan-Meier curves and two-tailed log-rank 
tests. Changes in serum mesothelin and MPF will be determined up until the end of treatment, and 
landmark analyses will be used to assess their association with PFS. 
10.4.4 Safety Analyses 
Safety of the agent will be assessed by reporting the grade of adverse events noted in each patient 
and reporting the proportion with grade 3 and grade 4 adverse events. Safety data will be presented 


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in individual listings. Summaries will also be prepared. The safety data will consist of the reporting 
of all adverse events, vital signs, physical examination data, and appropriate laboratory safety data. 
10.4.5 Baseline Descriptive Statistics 
Limited demographic and clinical characteristics of all patients will be reported. 
10.4.6 Planned Interim Analyses 
If during the initial 20 patients evaluated, there are 0-1 responses noted, then no further patients 
will be enrolled as soon as this can be determined. since the upper one-sided 90% confidence 
interval bound on 1/20 is 18.1%, which is below the approximate response rate of interest. Because 
accrual is proceeding rapidly on the study and continued enrollment is desirable at this time, up to 
25 total patients may be enrolled (5 additional patients) while awaiting the response evaluations 
among the first 20 patients. . 
10.4.7 Sub-Group Analyses 
None will be performed. 
10.4.8 Tabulation of Individual Participant Data 
Toxicity data may be reported on a per-patient basis if adequate events are noted, or may be 
summarized. 
10.4.9 Exploratory Analyses 
No exploratory analyses are planned. 
 
11 COLLABORATIVE AGREEMENTS  
11.1 COLLABORATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
The study agent, olaparib, will be provided under a CRADA (# 02299) between NCI and the 
manufacturer, AstraZeneca. 
11.2 INTRAMURAL MATERIAL TRANSFER AGREEMENT (IMTA) 
Rather than amending the above mentioned CRADA to include the current study, an internal MTA 
(#43420-27) was executed to make the study agent supplied under the CRADA available for the 
current study. 
11.3 QUALITY AGREEMENT 
As a supplement to address items required by the sponsor that were not addressed in the CRADA 
or the MTA, a quality agreement was executed between the Raffit Hassan, M.D. and AstraZeneca 
to establish the obligations and the responsibilities of each party relating to the quality assurance 
requirements of the manufacture, analysis, packing and/or release by AstraZeneca of products and 
the supply to the investigator. 


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12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
This study will be open to all individuals with malignant mesothelioma regardless of gender, 
ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. The 
selection criteria reflect all available nonclinical and clinical safety experience with olaparib. 
Further, the selection criteria address the potential pharmacokinetics issues that may confound the 
reliable assessment of the study objective related to the pharmacokinetic drug-drug interaction.  
The treatment of men as well as women is justified because of the severity of the underlying 
neoplastic disease. Men and women who use appropriate contraception or women who are not of 
child-bearing potential will be enrolled into this study. The proportion of men and women enrolled 
into the dose-escalation cohorts of this study depends only on the availability of subjects at the 
NIH Clinical Center. 
12.2 PARTICIPATION OF CHILDREN 
Children will not participate in this study for the reasons indicated in the eligibility criteria. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4.4), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate. For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
12.4.1 Risks 
12.4.1.1 Study Drug 
Potential risks of the study include the possible occurrence of any of a range of side effects as 
listed in section 13.1.3 and the consent document. The procedure for protecting against or 
minimizing risks will be to medically evaluate patients on a regular basis, provide premedications 
and supportive therapies as described earlier.  
12.4.1.2 Research Blood Collection 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.  


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12.4.2 Image Guided Biopsy Collection 
The risks of the research biopsy collected at baseline include pain, bleeding and infection at the 
biopsy site. In addition, as the biopsy may be collected under CT guidance, subjects in this study 
may be exposed to approximately 0.80 rem. This amount is below the guideline of 5 rem per year 
allowed for adult research subjects by the NIH Radiation Safety Committee. 
12.4.3 Non-Physical Risks of Genetic Research 
These risks are noted in the consent document.  
12.4.4 Benefits 
The potential benefit to a patient (including those who have lost the capacity to consent) 
participating in the study is a reduction in the bulk of his/her tumor, which may or may not have a 
favorable impact on symptoms and/or survival. 
12.5 RISK BENEFIT ASSESSMENT 
Patients with advanced and/or metastatic mesothelioma, are in continuous need of improved 
therapy options. This is especially true for patients who have progressed on standard therapy such 
as the patient population that will be eligible for this trial. Pre-clinical and clinical data (see 
sections 1.2.2 and 1.2.3) suggest that olaparib may improve outcomes in patients with 
mesothelioma, particularly in those with mismatch repair defects. A number of clinically 
appropriate strategies to minimize risk to patients have been built into the protocol through the 
means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, 
the potential benefits of olaparib for mesothelioma patients retaining the ability to consent and 
those who lose capacity to consent during the course of the trial outweigh the risks associated with 
the proposed entry-into-human trial with olaparib. 
12.6 CONSENT PROCESS AND DOCUMENTATION 
The procedures and tests involved in this study and the associated risks, discomforts and benefits 
of these processes including the disclosure of genetic results (see section 5.3.1), will be carefully 
explained to the patient, and a signed informed consent document will be obtained prior to entry 
onto the study. 
12.6.1 Telephone Re-consent  
Reconsent by telephone is permitted on this study. Telephone consent will be obtained per 
OHSRP/IRBO and CCR policies and procedures.. 
13 PHARMACEUTICAL INFORMATION 
There will be no IND obtained for the use of the commercial agent (olaparib) used in this study.  
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drug is already 
approved and marketed and the investigation is not intended to support a significant change in 
advertising; and the investigation does not involve a route of administration or dosage level in use 
in a patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 


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13.1 OLAPARIB) 
13.1.1 Source 
The olaparib tablets used in this study will be supplied under a collaborative agreement with the 
manufacturer, AstraZeneca. 
13.1.2 Mode of Action:  
Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ diphosphoribose polymerase 
(PARP-1, PARP-2, and PARP-3). In tumors that are deficient in the homologous recombination 
DNA repair pathway (example, BRCA mutants), inhibition of PARP by olaparib causes 
accumulation of DNA double-strand breaks and genomic instability. Olaparib may also enhance 
the effects of DNA damage caused by ionizing radiation and chemotherapy. 
13.1.3 Toxicity  
13.1.3.1 Serious Adverse Events 
A review of the AstraZeneca Patient Safety database (which includes AstraZeneca-sponsored, 
investigator-sponsored/collaborative group monotherapy studies and Managed Access Program 
reports) as of 15 June 2016 identified a total of 1413 SAEs (1093 unblinded, 320 blinded) received 
IURPSDWLHQWVLQRODSDULEPRQRWKHUDS\VWXGLHV6$(UHSRUWVRISDWLHQWVWUHDWHGZLWK
olaparib/placebo monotherapy) were anemia (n=143), abdominal pain (n=40), vomiting (n=47), 
nausea (n=42) and dyspnea (n=41). The most commonly reported SAEs from these monotherapy 
studies were similar for the tablet and capsule formulation.
13.1.3.2 Frequent Adverse Events 
• Most common adverse reactions and laboratory abnormalities in clinical trials were anemia, 
nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, 
decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, 
myalgia, back pain, dermatitis/rash, abdominal pain/discomfort, increase in creatinine, mean 
corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in 
absolute neutrophil count, and decrease in platelets.  
• The following adverse reactions and laboratory abnormalitLHVKDYHEHHQLGHQWLILHGLQWR
<20% of the 223 patients receiving olaparib: cough, constipation, dysgeusia, peripheral edema, 
back pain, dizziness, headache, urinary tract infection, dyspnea, and rash.  
• The following adverse reactions and laboratory abQRUPDOLWLHVKDYHEHHQLGHQWLILHGLQWR
<10% of the 223 patients receiving olaparib and not included in the table: leukopenia, 
stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, 
depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, 
pruritus, hypertension, venous thrombosis (including pulmonary embolism), and hot flush. 
13.1.3.3 Warnings and Precautions 
• Myelodysplastic syndrome/Acute Myeloid Leukemia: (MDS/AML) occurred in patients 
exposed to olaparib, and some cases were fatal. Monitor patients for hematological toxicity at 
baseline and monthly thereafter. Discontinue if MDS/AML is confirmed.  
• Pneumonitis: occurred in patients exposed to olaparib, and some cases were fatal. Interrupt 
treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed.  


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• Embryo-Fetal toxicity: olaparib can cause fetal harm. Advise females of reproductive potential 
of the potential risk to a fetus and to avoid pregnancy.  
13.1.4 Formulation and preparation  
Olaparib tablets are supplied as green, film-coated tablets in 100 mg and 150 mg strengths. The 
100 mg strength is also available as a yellow, film-coated tablet. 
x 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped  
x 150 mg are 14.5 mm x 7.25 mm oval-shaped  
Olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures. Each dosing container will contain 32 tablets. Olaparib sufficient for 1 21-day cycle + 3 
additional days in case of vomiting will be dispensed to patients on Day 1 at the beginning of each 
subsequent cycle until the patient completes the study, withdraws from the study or closure of the 
study.  
Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and 
iron oxide black. The yellow tablet film coating only differs from the green film coating with the 
omission of iron oxide black. 
13.1.5 Stability and Storage  
All study drugs should be kept in a secure place under appropriate storage conditions. Store in a 
secure location below 30° C (86° F). Sites are not permitted to re-package tablets. Once the bottle 
is opened, olaparib tablets must be used within 3 months of the opening date; unused tablets should 
be discarded. Instruct patients not to open a bottle until they are ready to use it.  
13.1.6 Administration Procedures 
Please refer to section 3.2. 
13.1.7 Incompatibilities 
CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the 
inhibitor cannot be avoided, the dose may be reduced as allowed by protocol. 
CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a moderate 
CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy.  
13.2 CLINOMICS PLATFORM (NSR DEVICE) 
13.2.1 Source 
The platform was developed in house by the Center for Cancer Research and is available for use 
by investigators at the NCI. Testing will be performed in the NCI Laboratory of Pathology 
(CLIA#21D0716664) and/or ClinOmics (CLIA# 21D2125203) 
13.2.2 Toxicity 
None.  However, participants may experience non-physical risks of genetic research as described 
in section 12.4.3. 
 
 


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14 REFERENCES  
 
1. 
Robinson BW, Lake RA: Advances in malignant mesothelioma. N Engl J Med 2005, 
353(15):1591-1603. 
2. 
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier 
U, Boyer M, Emri S, Manegold C et al: Phase III study of pemetrexed in combination 
with cisplatin versus cisplatin alone in patients with malignant pleural 
mesothelioma. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2003, 21(14):2636-2644. 
3. 
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, 
Trusa S et al: Germline BAP1 mutations predispose to malignant mesothelioma. Nat 
Genet 2011, 43(10):1022-1025. 
4. 
Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski 
MF, Reva B et al: The nuclear deubiquitinase BAP1 is commonly inactivated by 
somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 
2011, 43(7):668-672. 
5. 
Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, 
Smith GC, Martin NM, O'Connor M et al: Poly(ADP-ribose) polymerase-1 inhibitor 
treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and 
delays tumor relapse in combination with carboplatin. Cancer Res 2009, 69(9):3850-
3855. 
6. 
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, 
Derksen PW, de Bruin M, Zevenhoven J, Lau A et al: High sensitivity of BRCA1-
GHILFLHQWPDPPDU\WXPRUVWRWKH3$53LQKLELWRU$='DORQHDQGLQ
combination with platinum drugs. Proc Natl Acad Sci U S A 2008, 105(44):17079-
17084. 
7. 
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland 
H, Lau A, O'Connor MJ et al: Inhibition of poly(ADP-ribose) polymerase in tumors 
from BRCA mutation carriers. N Engl J Med 2009, 361(2):123-134. 
8. 
Helleday T: The underlying mechanism for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Mol Oncol 2011, 5(4):387-393. 
9. 
Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, 
Pommier Y: Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer 
Res 2012, 72(21):5588-5599. 
10. 
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, 
Huntsman D, Clemons M, Gilks B et al: Olaparib in patients with recurrent high-
grade serous or poorly differentiated ovarian carcinoma or triple-negative breast 
cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 
2011, 12(9):852-861. 


60 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
11. 
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung 
N, Armstrong A et al: Olaparib for Metastatic Breast Cancer in Patients with a 
Germline BRCA Mutation. N Engl J Med 2017, 377(6):523-533. 
12. 
Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, Colombo N, 
Spacek J, Vuylsteke P, Hirte H et al: Olaparib combined with chemotherapy for 
recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet 
Oncol 2015, 16(1):87-97. 
13. 
Lee JM, Hays JL, Annunziata CM, Noonan AM, Minasian L, Zujewski JA, Yu M, 
Gordon N, Ji J, Sissung TM et al: Phase I/Ib study of olaparib and carboplatin in 
BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker 
analyses. J Natl Cancer Inst 2014, 106(6):dju089. 
14. 
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, 
Dillon KJ, Hickson I, Knights C et al: Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy. Nature 2005, 434(7035):917-921. 
15. 
McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara S, O'Connor 
MJ, Tutt AN, Zdzienicka MZ et al: Deficiency in the repair of DNA damage by 
homologous recombination and sensitivity to poly(ADP-ribose) polymerase 
inhibition. Cancer Res 2006, 66(16):8109-8115. 
16. 
Menear KA, Adcock C, Alonso FC, Blackburn K, Copsey L, Drzewiecki J, Fundo A, Le 
Gall A, Gomez S, Javaid H et al: Novel alkoxybenzamide inhibitors of poly(ADP-
ribose) polymerase. Bioorg Med Chem Lett 2008, (14):3942-3945. 
17. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer 2009, 
45(2):228-247. 
18. 
Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in 
malignant pleural mesothelioma. Annals of oncology : official journal of the European 
Society for Medical Oncology / ESMO 2004, 15(2):257-260. 
19. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, 
Higano C, Bubley GJ, Dreicer R et al: Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2008, 
26(7):1148-1159. 
20. 
Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer 
E, Sagae S, Greven K, Vergote I et al: Re: New guidelines to evaluate the response to 
treatment in solid tumors (ovarian cancer). Journal of the National Cancer Institute 
2004, 96(6):487-488. 
21. 
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, 
Freidlin B, Halabi S, Hudes G et al: Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: recommendations from the 


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Prostate-Specific Antigen Working Group. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 1999, 17(11):3461-3467. 
22. 
Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK, 
Friedlander M, Jakobsen A, Vermorken JB: Re: new guidelines to evaluate the 
response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer 
Intergroup. Journal of the National Cancer Institute 2000, 92(18):1534-1535. 
 


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


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15.2 APPENDIX B -COCKCROFT-GAULT FORMULA  
 
Creatine Clearance (mL/min) =  (140 - age) x weight in kg (x 0.85 for females) 
(serum creatinine [mg/dL] x 72) 


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Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
15.3 APPENDIX C - PARTICIPANT OLAPARIB PILL DIARY 
Today’s date ________________________________  
Patient Name_______________________________ Patient Study ID ______________________ 
Cycle #__________  
INSTRUCTIONS TO THE PATIENT:  
1. Complete one form for each cycle (21 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. You should avoid drinking grapefruit juice while on study. 
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. If you miss more than half of the doses (21 tablets) in any cycle, we will have to remove you from the study. 
7. Record the date, the number of tablets you took, and when you took them.  
8. If you have any comments or notice any side effects, please record them in the Comments column.  
9. 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  
 


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Version Date: 02/24/20 
DAY DATE 
# Tablets and When Taken 
 
COMMENTS (side effects or missed doses) 
7 
 
_________AM  
_________PM 
 
8 
 
_________AM  
_________PM 
 
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 
 


66 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
DAY DATE 
# Tablets and When Taken 
 
COMMENTS (side effects or missed doses) 
20 
 
_________AM  
_________PM 
 
21 
 
_________AM  
_________PM  
 
 
Patient’s Signature: ________________________________________ Date: _________________________  
 
 
The Study Team will complete this section:  
1. Date patient started protocol treatment______________  
2. Date patient was removed from study therapy _____________ 
 3. Total number of pills taken this cycle (Days 1-21)___________ 
 
Physician/Nurse Signature ____________________________________________________________________  
 


67 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
15.4 APPENDIX D – ACTIONS REQUIRED IN CASES OF LIVER BIOCHEMISTRY AND EVALUATION 
OF HY’S LAW 
15.4.1 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. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates 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. 
15.4.2 Definitions 
15.4.2.1 Potential Hy’s Law (PHL) 
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Normal (ULN) together with 7RWDO%LOLUXELQ7%/[8/1DWDQ\SRLQWGXULQJWKHVWXG\
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
15.4.2.2 Hy’s Law (HL) 
$67RU$/7[ULN together with 7%/[8/1ZKHUHQRRWKHUUHDVRn, 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 timeframe within which the elevations 
in transaminases and TBL must occur. 
15.4.3 Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
x 
$/7[8/1 
x 
$67[8/1 
x 
7%/[8/1 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 


68 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
x 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
x 
Promptly enter the laboratory data into the laboratory CRF 
15.4.4 Follow-up 
15.4.4.1 Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
15.4.4.2 Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
x 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated  
x 
Investigate the etiology of the event and perform diagnostic investigations.  
x 
Complete the three Liver CRF Modules as information becomes available  
x 
If at any time the PHL case meets serious criteria, report it as an SAE using standard 
reporting procedures 
15.4.4.3 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 Investigator 
will follow the instructions below. 
If there is an 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: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes 
If there is no explanation that would explain the ALT or AST and TBL elevations other than the 
IMP: 
x 
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 


69 
Abbreviated Title: Ph 2 Olaparib in Mesothelioma 
Version Date: 02/24/20 
 
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: 
x 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
x 
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 
15.4.5 Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is 
based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being met 
and answer the following question: 
x 
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g. chronic or progressing malignant disease, severe infection 
or liver disease? 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met 
x 
If there is no significant change no action is required 
x 
If there is a significant change, follow the process described in Section 15.4.4.2 of this 
Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of whether 
there has been a significant change will be at the discretion of the Investigator; this may be in 
consultation with the Study Physician if there is any uncertainty. 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 1 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Raffit Hassan, MD
STUDY TITLE:
Phase II Study of Olaparib in Subjects with Malignant 
Mesothelioma
STUDY SITE:
NIH Clinical Center
Cohort:
Standard 
Consent Version:
02/24/2020 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Raffit Hassan, M.D. by phone at 240-760-6232 or email raffit.hassan@nih.gov 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time 
needed to ask any questions and discuss this study with NIH staff, and with your family, friends, 
and personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason. In either 
case, you will not lose any benefits to which you are otherwise entitled. However, to be seen at 
the NIH, you must be taking part in a study or are being considered for a study. If you do choose 
to leave the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Olaparib is a drug that may stop cancer cells from repairing damage to their DNA.  Olaparib has 
been approved by the FDA for use in certain types of ovarian cancer and breast cancer, including 
persons with ovarian cancers that were born with a mutation in the BRCA gene.  While it has not 
been approved for use in mesothelioma, we are studying olaparib in mesothelioma as an 
investigational agent because we have found in our lab that some patients with mesothelioma 
have mutations in a gene named BAP-1, that is in the same family as BRCA.  In addition, because 
olaparib is designed to target cancers that have mutations in genes that help to repair DNA, we 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
will test whether participants with mutations in such genes other than BAP-1 might also be 
treated with olaparib. We will determine whether olaparib caused tumors in persons with 
mesothelioma to shrink.  Participants will be divided into 3 different groups for comparison. 
These groups are: 
1) Persons that have germline mutations in genes repair DNA damage. Germline means that 
you were born with the mutation and that it is found in most cells in your body.
2) Persons with BAP-1 mutation in the tumor.  This type of mutation, called a somatic 
mutation, is one that was acquired after birth and is only found in the tissues where the 
mutation occurred.
3) Persons with mesothelioma that are in not in group 1 or group 2. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to participate because you have been diagnosed with malignant 
mesothelioma that has previously been treated with platinum and pemetrexed.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 40 participants will be enrolled in the study.
DESCRIPTION OF RESEARCH STUDY
Before You Begin the Study
Before beginning the study, you will need to have tests and/or procedures to help your doctor 
verify whether you can participate. This is called screening. Most of the exams, tests, and 
procedures you will have are part of the usual approach for your cancer. However, there are 
some extra procedures that you will need to have if you take part in this study.  If you have 
already had some of these examinations very recently, your doctor may decide not to repeat 
them. Briefly, these tests, which are performed under a separate protocol, include:
•
Confirmation of diagnosis - You must provide a sample tumor tissue for an evaluation 
from the NCI Laboratory of Pathology.  The tissue may be from a previous surgery, 
biopsy or collection from a tumor effusion (fluid around the tumor).  If none is available, 
we will ask you to have a biopsy or a collection of effusion material to provide a fresh 
sample).  Please see page 7, Tumor biopsies and effusions for a description of the 
procedure.
•
Medical history and physical examination
•
Routine blood and urine tests including pregnancy test in women who can have children.  
Pregnant women will not be allowed on study.
•
Scans and x-rays
•
Electrocardiogram (ECG) – a test of your heart
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
During the Study
Once the doctor has decided you are eligible and you have signed the consent for this study, we 
will collect a blood sample for the germline genetic testing described above.  We will also test 
the tumor tissue we collected at screening for mutations in DNA repair.  If there is not enough 
tissue leftover to do this, we will need to collect additional tissue.  
You will start the study therapy before we have the results of the genetic testing as the 
information is only needed to compare the 3 groups at the end. In fact, the results may not be 
available to use for several months.  At the beginning of each 21-day cycle, you will be given a 
21-day supply of olaparib tablets.  Tablets should be taken twice a day every day with water.  
You should try to take each dose about 12 hours apart and take them at around the same time 
each day.  You may have a meal or a light snack with each dose.  You will continue to take 
olaparib until your disease gets worse or for any of the other reasons listed on page 9, Stopping 
Therapy.
There are some medications that may interact with the olaparib used on this study; therefore, 
please be sure to inform the study team of all the medications and supplements that you are 
taking while on study therapy as you may not be able to take some of these with your study 
medication.  You may not drink grapefruit juice or eat grapefruits while you are taking the study 
therapy.
You will be given a pill diary to take track of when you take each dose of olaparib along with 
any symptoms you might experience.  Please bring the diary and any remaining pills with you 
for each study visit.
We will perform routine tests to monitor your organ function while you are taking olaparib.  
During the first cycle, you will have a blood test before you start taking the olaparib and about 
one week after you have taken your first dose.  After cycle 1, blood tests will be done once per 
cycle (every 3 weeks).  Other tests, including urine tests and pregnancy testing if you are a 
woman who can have children will be done once every 3 weeks.  We will perform scans every 2 
cycles (every 6 weeks) to find out whether your tumors are shrinking or not.
Blood will also be collected for research studies at the beginning of each cycle.
Genetic testing
It is important to note that even though the laboratory we are using to perform genetic tests is 
certified, the test we are using is investigational.  Investigational means that the test is not 
approved by the U.S. Food and Drug Administration (FDA) and is still being tested in research 
studies.  The FDA does allow the use of such tests in clinical trials like this one.
Though we are focused on finding the mutations that are part of the research, the tests may 
include genes that are not related to the ones we are looking for.  These are called secondary 
findings.
Since the analyses that we perform in our laboratory are not approved, the genetic changes that 
we find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic 
results of testing on your tissue and blood that is performed in our research lab. However, in the 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
unlikely event that we discover a finding believed to be clinically important based on medical 
standards at the time we first analyze your results, we will contact you and ask you to have an 
additional tube of blood drawn to verify the findings we have seen in our lab. If the results are 
verified, you or the person you named in the form will also be offered genetic education and 
counseling at NIH (at our expense) to explain the results.  
If you or your designee does not want to come to NIH, we will help you (or your designee) find a 
local genetic healthcare provider who can explain it to you or your designee (at your or your 
designee’s expense).
This analysis may not be performed for up to several months after the samples have been 
collected.  Because of this, you may be deceased or have diminished mental capacity at the time 
results are available.  Therefore, we will give you the option to complete a form to name a person 
(a designee) that you would like to receive information about findings that may have 
implications for your family. If the result is in your tumor, but not in the blood test, your doctor 
will provide you with the results of this testing and any possible treatment options.  Your doctor 
will also inform you if we did not find a change in the genes that might be important to your or 
your family’s health in the germline (blood test). 
Note:  Not finding a variation in a gene or genes in the germ line or your cancer or pre-cancerous 
tumor does not necessarily mean that your genes are “normal”. This can be because we are not 
able to detect all changes that affect the function of a gene with sequencing.  This is one of the 
limitations of genetic testing.  
When You Are Finished Taking the Drugs
Approximately 30 days after you have had your last dose of study drug, you will be asked to 
return to the NIH for a follow up visit to have the following tests:
•
Medical history and physical exam
•
Routine blood tests
•
Research blood test
•
Scans (unless you stopped taking olaparib because your tumors got larger)
If you cannot return to the Clinical Center for this visit, we will contact you by telephone and ask 
that you send us the results of the scans and blood tests needed at this timepoint.
If after this visit, your disease remains stable or improves, you will continue come back to the 
Clinical Center for a follow up clinic visit and be scanned every 6 weeks until your disease 
worsens. If you cannot come back for these visits, you may have the scans done locally and send 
them to us.
BIRTH CONTROL
Female Participants
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant you will need to either abstain from any form of sexual 
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Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
intercourse (if this is your usual or preferred lifestyle) or use a male condom in addition to a 
highly effective form of birth control (see list below) before starting study treatment, during 
study treatment, and for one month after you finish study treatment.  
Male Participants
Males 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. 
Your female partners should also use a highly effective form of birth control (in addition to the 
condom) if she can have children. You should not donate sperm throughout the period of taking 
olaparib and for 3 months following the last dose of olaparib.
Male and Female Participants
If you think that you or your partner is pregnant, you should tell your study doctor or nurse at 
once.  
Highly effective forms of birth control include: 
•
intrauterine device (IUD)
•
intravaginal device
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
The drug used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health.
There is also a risk that you could have other side effects from sampling procedures.
Here are important things to know about side effects:
1. The study doctors do not know who will or will not have side effects.
2. Some side effects may go away soon, some may last a long time, and some may never go 
away.
3. Some side effects may make it hard for you to have children.
4. Some side effects may be mild.  Other side effects may be very serious and even result in 
death.
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem:
•
If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect.
•
Your study doctor will work with you to treat your side effects.
•
Your study doctor may adjust the study drugs to try to reduce side effects.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
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CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Risks of Olaparib
The tables below show the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you.
COMMON, SOME MAY BE SERIOUS
In 100 people receiving olaparib, 10 or more may have:
•
Loss of appetite
•
Dizziness
•
Headache
•
Changes in taste of food
•
Vomiting 
•
Nausea
•
Diarrhea
•
Tiredness/weakness
•
Indigestion/heartburn
•
Cough
•
Pain in the stomach area under the ribs
•
Shortness of breath 
•
Decreased number of a type of blood cell that helps to clot blood which may lead to 
bruising and bleeding
•
Anemia which may cause tiredness or may require blood transfusion
•
Decrease in the total number of white blood cells and in certain white blood cells 
(neutrophils) that protect from infection, which can be associated with fever
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving olaparib, from 1 to 9 may have:
•
Rash
•
Sores in mouth which may cause difficulty swallowing
•
Decrease in the number of white blood cells that support the immune system 
(lymphocytes), which can be associated with higher risk of infection
•
Increased blood level of creatinine (a substance normally eliminated by the kidneys into 
the urine) 
RARE, AND SERIOUS
In 100 people receiving olaparib, fewer than 1 may have:
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 7 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
RARE, AND SERIOUS
In 100 people receiving olaparib, fewer than 1 may have:
•
Allergic reactions
•
Itchy rash on swollen, reddened skin
The study drug may affect your ability to drive or use machines.  If you feel dizzy, weak or tired 
while taking your study treatment, take special care when driving or using tools or machines.
Other Possible Risks
Other side effects have been seen in previous studies, but it is not yet known if these were related 
to olaparib, or if they were unrelated events possibly due to the patient’s cancer or other cause.  
Assessing the full range of side effects of olaparib is an important part of this study.
•
Inflammation of the lungs that may cause difficulty breathing and can be life-threatening
•
A pre-cancerous condition (myelodysplastic syndrome or MDS) where the bone marrow 
isn’t as good at producing blood cells as it was before. This condition may transform into 
AML, a type of leukemia (bone marrow cancer) where many abnormal and immature white 
blood cells are made while normal functioning blood cells are not made.
•
A new cancer other than AML resulting from treatment of a prior cancer 
Risks Associated with Research Sampling
Blood collections: 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Tumor biopsies and effusions 
Tumor biopsies and tumor effusions: local anesthesia of the skin will be given prior to any tumor 
biopsy or effusion collection, in order to prevent painful sensations.  However, you may still 
experience pain or discomfort at the biopsy site.  Irritation, redness, swelling and/or bleeding 
may also occur.  There is a risk of abnormal healing, fever, infection or of an allergic reaction to 
the anesthetic agent used to anesthetize the skin at the biopsy site.  Once the sample has been 
obtained, a stitch may be used to close the wound and facilitate healing. 
In some cases, we may use CT scans to help guide us during your biopsy.  This introduces the 
added risk of research radiation.  This research study may involve exposure to radiation from up 
to 1 CT guided tumor biopsy for research.  This radiation exposure is not required for your 
medical care and is for research purposes only. The amount of radiation you will receive in this 
study is 0.80 rem which is below the guideline of 5 rem per year allowed for research subjects by 
the NIH Radiation Safety Committee.  The average person in the United States receives a 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the 
earth's air and soil.  If you would like more information about radiation, please ask the 
investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 8 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
Psychological or Social Risks Associated with Loss of Privacy
1.
Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.  
2.
Release of genetic information:  
•
Your privacy is very important to us and we will use many safety measures to protect 
your privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic 
information is unique to you, you do share some genetic information with your children, 
parents, brothers, sisters, and other blood relatives. Consequently, it may be possible that 
genetic information from them could be used to help identify you. Similarly, it may be 
possible that genetic information from you could be used to help identify them. 
•
While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, 
telephone number, or social security number, people may develop ways in the future that 
would allow someone to link your genetic or medical information in our databases back 
to you. For example, someone could compare information in our databases with 
information from you (or a blood relative) in another database and be able to identify you 
(or your blood relative). It also is possible that there could be violations to the security of 
the computer systems used to store the codes linking your genetic and medical 
information to you.
•
There also may be other privacy risks that we have not foreseen.
Since some genetic variations can help to predict future health problems for you and your 
relatives, this information might be of interest to health care providers, life insurance companies, 
and others.  However, Federal and State laws provide some protections against discrimination 
based on genetic information.  For example, the Genetic Information Nondiscrimination Act 
(GINA) makes it illegal for health insurance companies, group health plans, and most employers 
to discriminate against you based on your genetic information.  However, GINA does not 
prevent companies that sell life insurance, disability insurance, or long-term care insurance from 
using genetic information as a reason to deny coverage or set premiums.  GINA also does not 
apply to members of the United States military, individuals covered by the Indian Health 
Service, or veterans obtaining health care through the Veteran’s Administration.  Lastly, GINA 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 9 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
does not forbid insurance medical underwriting based on your current health status though the 
Affordable Care Act limits consideration of pre-existing conditions by insurers.
POTENTIAL BENEFITS OF PARTICIPATION
The aim of this study is to see if study therapy will cause your tumors to shrink.   We do not 
know if you will receive personal, medical benefit from taking part in this study.  These potential 
benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that 
are caused by the cancer.  Because there is not much information about the drug’s effect on your 
cancer, we do not know if you will benefit from taking part in this study, although the knowledge 
gained from this study may help others in the future who have cancer.  
ALTERNATIVE APPROACHES OR TREATMENTS
Instead of being in this study, you have these options:
•
Getting treatment or care for your cancer without being in a study
•
Taking part in another study
•
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:
•
if he/she believes that it is in your best interest
•
if your disease comes back during treatment
•
if you do not comply with study requirements (e.g. you miss too many doses in a cycle)
•
if you have side effects from the treatment that your doctor thinks are too severe
•
if you come pregnant
•
if you need to take any of the medicines that are not allowed on the study
•
if the investigator decides to end the study
•
if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to AstraZeneca or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 10 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
CONFLICT OF INTEREST 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using a drug developed 
by AstraZeneca through a joint study with your researchers and the company.   The company 
also provides financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  
We may put your research data in a large database for broad sharing with the research 
community. These databases are commonly called data repositories. These data repositories 
might or might not be located at the NIH. The information in this database could include but is 
not limited to genetic information, ethnicity and sex.  If your individual research data is placed 
in one of these repositories, it will not be labeled with your name or other information that 
could be used to easily identify you, and only qualified researchers will be able to look at your 
data. These researchers must receive prior approval from individuals or committees to access 
the data.
Your summary genomic data is being placed in an unrestricted database, so researchers will be 
able to access summary information about all the participants included in the study (including 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 11 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
you), or summary information combined from multiple studies, without applying for permission. 
The risk of anyone identifying you with this information is very low.
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will You Receive Compensation for Participation in The Study?
Some NIH Clinical Center studies offer compensation for participation in research. The 
amount of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will You Receive Reimbursement or Direct Payment by NIH As Part of Your 
Participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
•
If some tests and procedures performed outside the NIH Clinical Center, you 
may have to pay for these costs if they are not covered by your insurance 
company.
•
Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.
•
Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 12 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will Your Medical Information Be Kept Private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:
•
The National Cancer Institute and other government agencies, like the Food and Drug 
Administration (FDA), which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board
•
Qualified representatives from AstraZeneca, the pharmaceutical company who produces 
olaparib.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release 
any information about your research involvement without your written permission.  However, if 
you sign a release of information form, for example, for an insurance company, the NIH will 
give the insurance company information from your medical record.  This information might 
affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 13 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The Certificate does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self 
or others including, for example, child abuse and neglect, and by signing below you consent to 
those disclosures. Other permissions for release may be made by signing NIH forms, such as the 
Notice and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy 
Act allows release of information from your medical record without your permission, for 
example, if it is requested by Congress. Information may also be released for certain research 
purposes with due consideration and protection, to those engaged by the agency for research 
purposes, to certain federal and state agencies, for HIV partner notification, for infectious disease 
or abuse or neglect reporting,  to tumor registries, for quality assessment and medical audits, or 
when the NIH is involved in a lawsuit.  However, NIH will only release information from your 
medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Raffit 
Hassan, M.D., Raffit.Hassan@nih.gov, 240-760-6232. You may also call the NIH Clinical 
Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/24/2020
Page 14 of 14
CC ICF template v 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally 
authorized to make research decisions on behalf of the adult participant unable to consent and have the 
authority to provide consent to this study. As applicable, the information in the above consent was described 
to the adult participant unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language 
facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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