untitled h1
untitled h2

Ph 2 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
untitled h1
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 1
untitled h1
precis 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.
untitled h1
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
untitled h1
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
untitled h1
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 Abbreviated Title: Ph 2 Olaparib in Mesothelioma
Version Date: 02/24/20
- Up to 30 evaluable subjects will be enrolled 3
untitled h1
abbreviated title ph 2 olaparib

| TABLE OF CONTENTS                                                                                                                              |                                                                                                                                                   |                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                                                       |                                                                                                                                                   |                                                                                                   |
| TABLE OF CONTENTS............................................................................................................................4 |                                                                                                                                                   |                                                                                                   |
| l                                                                                                                                              | INTRODUCTION .                                                                                                                                    |                                                                                                   |
| Study Objectives                                                                                                                               |                                                                                                                                                   |                                                                                                   |
| 1.1                                                                                                                                            | Primary Objective ............................................................................................................................. 9 |                                                                                                   |
| 1.1.1                                                                                                                                          |                                                                                                                                                   |                                                                                                   |
| 1.1.2                                                                                                                                          | Secondary Objectives                                                                                                                              |                                                                                                   |
| 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                                                                                                                                          |                                                                                                   |
| 1.2.4                                                                                                                                          | Study Rationale                                                                                                                                   |                                                                                                   |
| 2                                                                                                                                              | ELIGIBILITY ASSESSMENT AND ENROLLMENT..........................................................14                                                 |                                                                                                   |
| 2.1                                                                                                                                            | Eligibility Criteria                                                                                                                              |                                                                                                   |
| 2.1.1                                                                                                                                          | Inclusion Criteria .                                                                                                                              |                                                                                                   |
| 2.1.2                                                                                                                                          | Exclusion Criteria .                                                                                                                              |                                                                                                   |
| 2.1.3                                                                                                                                          | Recruitment Strategies .                                                                                                                          |                                                                                                   |
| 2.2                                                                                                                                            | Screening Evaluation                                                                                                                              |                                                                                                   |
| 2.3                                                                                                                                            | Registration Procedures                                                                                                                           |                                                                                                   |
| 2.3.1                                                                                                                                          | Treatment Assignment and Randomization/Stratification Procedures .................. 18                                                            |                                                                                                   |
| 3                                                                                                                                              | STUDY IMPLEMENTATION .........................................................................................................19                  |                                                                                                   |
| 3.1                                                                                                                                            | Study Design .                                                                                                                                    |                                                                                                   |
| 3.2                                                                                                                                            | D Drug Administration                                                                                                                             |                                                                                                   |
| Dose Delays/Modifications                                                                                                                      |                                                                                                                                                   |                                                                                                   |
| 3.3                                                                                                                                            | 3.3.1                                                                                                                                             | Modifications and Management of Hematologic Toxicities ....................................... 20 |
| 3.3.2                                                                                                                                          | Modifications and Management of Non-Hematologic Toxicities ............................. 22                                                       |                                                                                                   |
| 3.4                                                                                                                                            | S Study Calendar .                                                                                                                                |                                                                                                   |
| 3.5                                                                                                                                            | Criteria for Removal from Protocol Therapy and Off Study Criteria ........................... 28                                                  |                                                                                                   |
| 3.5.1                                                                                                                                          | Criteria for Removal from Protocol Therapy                                                                                                        |                                                                                                   |
| 3.5.2                                                                                                                                          | Follow Up                                                                                                                                         |                                                                                                   |
| OFF-Study Criteria .                                                                                                                           |                                                                                                                                                   |                                                                                                   |
| 3.5.3                                                                                                                                          |                                                                                                                                                   |                                                                                                   |
| 3.5.4                                                                                                                                          | Withdrawal of Informed Consent ................................................................................................... 29             |                                                                                                   |  
4 Abbreviated Title: Ph 2 Olaparib in Mesothelioma  
| Version Date: 02/24/20                                                                                              |                                                                                                                       |
|---------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|
| Off Protocol Therapy and Off-Study Procedure ................................................................... 29 |                                                                                                                       |
| 3.5.5                                                                                                               |                                                                                                                       |
| 4                                                                                                                   | CONCOMITANT MEDICATIONS/MEASURES ...................................................................29                |
| SUPPORTIVE CARE                                                                                                     |                                                                                                                       |
| 4.1                                                                                                                 |                                                                                                                       |
| 4.2                                                                                                                 | Prohibited Medications                                                                                                |
| 4.3                                                                                                                 | Permitted with Olaparib Dosing Changes .                                                                              |
| Strong or Moderate CYP3A inhibitors                                                                                 |                                                                                                                       |
| 4.3.1                                                                                                               |                                                                                                                       |
| 4.4                                                                                                                 | Permitted with Caution                                                                                                |
| 4.4.1                                                                                                               | Strong or Moderate CYP3A inducers                                                                                     |
| P-gp Inhibitors                                                                                                     |                                                                                                                       |
| 4.4.2                                                                                                               |                                                                                                                       |
| 4.4.3                                                                                                               | Effect of Olaparib on Other Drugs                                                                                     |
| 4.5                                                                                                                 | Permitted Medications                                                                                                 |
| 4.5.1                                                                                                               | Anticoagulant Therapy                                                                                                 |
| 4.5.2                                                                                                               | Palliative Radiotherapy                                                                                               |
| S                                                                                                                   | BIOSPECIMEN COLLECTION                                                                                                |
| 5.1                                                                                                                 | Correlative Studies for Research                                                                                      |
| Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples:........ 31                                    |                                                                                                                       |
| 5.1.1                                                                                                               | Specimen Collection Table                                                                                             |
| 5.1.2                                                                                                               |                                                                                                                       |
| 5.2                                                                                                                 | Sample Storage, Tracking and Disposition .                                                                            |
| 5.2.1                                                                                                               | Blood Processing Core                                                                                                 |
| 5.2.2                                                                                                               | NCI Laboratory of Pathology                                                                                           |
| 5.2.3                                                                                                               | Protocol Completion/Sample Destruction .                                                                              |
| 5.3                                                                                                                 | Samples for Genetic/Genomic Analysis                                                                                  |
| Management of Results                                                                                               |                                                                                                                       |
| 5.3.1                                                                                                               |                                                                                                                       |
| 6                                                                                                                   | DATA COLLECTION AND EVALUATION                                                                                        |
| 6.1                                                                                                                 | DATA COLLECTION                                                                                                       |
| 6.2                                                                                                                 | Recording of Adverse Events                                                                                           |
| 6.2.1                                                                                                               | Time Period for Collection of Adverse Events ..................................................................... 36 |
| DATA Sharing Plans .                                                                                                |                                                                                                                       |
| 6.3                                                                                                                 |                                                                                                                       |
| 6.3.1                                                                                                               | Human Data Sharing Plan                                                                                               |
| 6.3.2                                                                                                               | Genomic Data Sharing Plan                                                                                             |
| Response Criteria                                                                                                   |                                                                                                                       |
| 6.4                                                                                                                 |                                                                                                                       |
| 6.4.1                                                                                                               | Non-Pleural Mesothelioma .                                                                                            |  
S  
| 6                                                                                                                                                 |                                                                                                                     |             |
|---------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|-------------|
| Abbreviated Title: Ph 2 Olaparib in Mesothelioma                                                                                                  |                                                                                                                     |             |
| Version Date: 02/24/20                                                                                                                            |                                                                                                                     |             |
| 6.4.2                                                                                                                                             | Pleural Mesothelioma .                                                                                              |             |
| 6.4.3                                                                                                                                             | D Duration of Response                                                                                              |             |
| 6.4.4                                                                                                                                             | Progression-Free Survival                                                                                           |             |
| 6.4.5                                                                                                                                             | Objective Response Rate                                                                                             |             |
| 6.4.6                                                                                                                                             | Disease Control Rate                                                                                                |             |
| Toxicity Criteria                                                                                                                                 |                                                                                                                     |             |
| 6.5                                                                                                                                               |                                                                                                                     |             |
| 7                                                                                                                                                 | NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING                                                             |             |
| PLAN ..........................................................................................................................................45 |                                                                                                                     |             |
| 7.1                                                                                                                                               | Definitions                                                                                                         |             |
| 7.2                                                                                                                                               | OHSRP Office of Compliance and Training / IRB ................................................................ 45   |             |
| 7.2.1                                                                                                                                             | Expedited Reporting                                                                                                 |             |
| 7.2.2                                                                                                                                             | IRB Requirements for PI Reporting at Continuing Review ......................................... 45                 |             |
| 7.3                                                                                                                                               | NCI Clinical Director Reporting                                                                                     |             |
| 7.4                                                                                                                                               | NIH Required Data and Safety Monitoring Plan ................................................................... 46 |             |
| Principal Investigator/Research Team ............................................................................................. 46             |                                                                                                                     |             |
| 7.4.1                                                                                                                                             |                                                                                                                     |             |
| Safety Reporting Criteria to the Pharmaceutical Collaborators                                                                                     |                                                                                                                     |             |
| 8                                                                                                                                                 | 8.1                                                                                                                 | Definitions |
| A Adverse Event                                                                                                                                   |                                                                                                                     |             |
| 8.1.1                                                                                                                                             | Adverse Events of Special Interest .                                                                                |             |
| 8.1.2                                                                                                                                             |                                                                                                                     |             |
| 8.1.3                                                                                                                                             | Serious Adverse Event                                                                                               |             |
| 8.2                                                                                                                                               | Reporting to Astra Zeneca                                                                                           |             |
| 8.2.1                                                                                                                                             | Serious Adverse Events .                                                                                            |             |
| 8.2.2                                                                                                                                             | Adverse Events after the 30-day follow up period ......................................................... 48       |             |
| 8.2.3                                                                                                                                             | D DEATHS .                                                                                                          |             |
| 8.2.4                                                                                                                                             | OVERDOSE .                                                                                                          |             |
| Pregnancy                                                                                                                                         |                                                                                                                     |             |
| 8.2.5                                                                                                                                             |                                                                                                                     |             |
| 8.2.6                                                                                                                                             | Hy's Law                                                                                                            |             |
| 9                                                                                                                                                 | IDE Holder Monitoring Plan .                                                                                        |             |
| 9.1                                                                                                                                               | Clinical Monitoring                                                                                                 |             |
| Laboratory Monitoring                                                                                                                             |                                                                                                                     |             |
| 9.2                                                                                                                                               |                                                                                                                     |             |
| 10                                                                                                                                                | STATISTICAL CONSIDERATIONS                                                                                          |             |
| 10.1                                                                                                                                              | Statistical Hypothesis .                                                                                            |             |  
| Abbreviated Title: Ph 2 Olaparib in Mesothelioma                        |                                                    |                                                          |
|-------------------------------------------------------------------------|----------------------------------------------------|----------------------------------------------------------|
| Version Date: 02/24/20                                                  |                                                    |                                                          |
| 10.1.1 Primary Endpoint                                                 |                                                    |                                                          |
| 10.1.2 Secondary Endpoints .                                            |                                                    |                                                          |
| 10.2                                                                    | Sample Size Determination                          |                                                          |
| 10.3                                                                    | Populations for Analyses .                         |                                                          |
| 10.3.1                                                                  | Evaluable for Toxicity .                           |                                                          |
| Evaluable for Objective Response, Progression Free Survival and Soluble |                                                    |                                                          |
| 10.3.2                                                                  | Mesothelin Levels and PFS                          |                                                          |
| Evaluable Non-Target Disease Response                                   |                                                    |                                                          |
| 10.3.3                                                                  |                                                    |                                                          |
| 10.4                                                                    | Statistical Analyses                               |                                                          |
| 10.4.1                                                                  | General Approach .                                 |                                                          |
| Analysis of the Primary Endpoints                                       |                                                    |                                                          |
| 10.4.2                                                                  |                                                    |                                                          |
| 10.4.3                                                                  | Analysis of the Secondary Endpoint(s)              |                                                          |
| 10.4.4                                                                  | SS                                                 |                                                          |
| 10.4.5                                                                  | Baseline Descriptive Statistics                    |                                                          |
| Planned Interim Analyses .                                              |                                                    |                                                          |
| 10.4.6                                                                  | SUB-Group Analyses .                               |                                                          |
| 10.4.7                                                                  |                                                    |                                                          |
| 10.4.8                                                                  | Tabulation of Individual Participant Data          |                                                          |
| 10.4.9 Exploratory Analyses                                             |                                                    |                                                          |
| COLLABORATIVE AGREEMENTS .                                              |                                                    |                                                          |
| 11                                                                      | 11.1                                               | Collaborative Research and Development Agreement (CRADA) |
| 11.2                                                                    | Intramural Material Transfer Agreement (iMTA)      |                                                          |
| 11.3                                                                    | Quality Agreement                                  |                                                          |
| 12                                                                      | HUMAN SUBJECTS PROTECTIONS .                       |                                                          |
| 12.1                                                                    | Rationale for Subject Selection .                  |                                                          |
| 12.2                                                                    | Participation of Children                          |                                                          |
| 12.3                                                                    | Participation of Subjects Unable to Give Consent . |                                                          |
| 12.4                                                                    | Evaluation of Benefits and Risks/Discomforts .     |                                                          |
| 12.4.1                                                                  | Risks                                              |                                                          |
| Image Guided Biopsy Collection                                          |                                                    |                                                          |
| 12.4.2                                                                  |                                                    |                                                          |
| 12.4.3                                                                  | Non-Physical Risks of Genetic Research .           |                                                          |
| 12.4.4 Benefits                                                         |                                                    |                                                          |
| 12.5                                                                    | Risk Benefit Assessment                            |                                                          |  
7 Abbreviated Title: Ph 2 Olaparib in Mesothelioma  
| Version Date: 02/24/20                                                         |                                                                                                                                                                      |
|--------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 12.6                                                                           | Consent Process and Documentation                                                                                                                                    |
| 12.6.1 Telephone Re-consent.                                                   |                                                                                                                                                                      |
| 13                                                                             | PHARMACEUTICAL INFORMATION                                                                                                                                           |
| 13.1                                                                           | Olaparib)                                                                                                                                                            |
| S SOURCE                                                                       |                                                                                                                                                                      |
| 13.1.1                                                                         | Mode of Action:                                                                                                                                                      |
| 13.1.2                                                                         |                                                                                                                                                                      |
| 13.1.3                                                                         | T Toxicity .                                                                                                                                                         |
| Formulation and preparation                                                    |                                                                                                                                                                      |
| 13.1.4                                                                         | Stability and Storage                                                                                                                                                |
| 13.1.5                                                                         |                                                                                                                                                                      |
| 13.1.6 Administration Procedures                                               |                                                                                                                                                                      |
| 13.1.7 Incompatibilities .                                                     |                                                                                                                                                                      |
| 13.2                                                                           | ClinOmics Platform (NSR Device)                                                                                                                                      |
| 13.2.1 Source                                                                  |                                                                                                                                                                      |
| 13.2.2 Toxicity                                                                |                                                                                                                                                                      |
| 14                                                                             | REFERENCES .                                                                                                                                                         |
| 15                                                                             | APPENDICES .......................................................................................................................................................62 |
| A Appendix A - Performance Status Criteria .                                   |                                                                                                                                                                      |
| 15.1                                                                           | Appendix B -Cockcroft-Gault formula                                                                                                                                  |
| 15.2                                                                           |                                                                                                                                                                      |
| 15.3                                                                           | Appendix C - Participant Olaparib Pill Diary .................................................................................. 64                                   |
| Appendix D - Actions Required in Cases of Liver Biochemistry and Evaluation of |                                                                                                                                                                      |
| 15.4                                                                           | HY'S Law .                                                                                                                                                           |
| 15.4.1                                                                         | Introduction                                                                                                                                                         |
| 15.4.2 Definitions                                                             |                                                                                                                                                                      |
| 15.4.3                                                                         | Identification of Potential Hy's Law Cases .                                                                                                                         |
| Follow-up                                                                      |                                                                                                                                                                      |
| 15.4.4                                                                         |                                                                                                                                                                      |
| 15.4.5 Actions Required for Repeat Episodes of Potential Hy's Law              |                                                                                                                                                                      |  
8
untitled h1
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
untitled h1
1.2 background and rationale 1.2.1

Figure 1: Frequencies of germline mutations in DNA
repair genes among 241 consecutive patients with mesothelioma (confidential; unpublished)
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 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.
untitled h1
figure 2. expression of bap1

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 *BAP1*were 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.  
| Table 1. BAP1 expression and sensitivity to olaparib in mesothelioma cell lines.  Olaparib IC50 Cell Line BAP1 Expression  (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.**  
  
  
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]
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 GHSHQGHQFHDWȝJmL).
untitled h1
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.
untitled h1
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 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.
untitled h1
2 eligibility assessment and enrollment

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 3DWLHQWVPXVWKDYHDOLIHH[SHFWDQF\RIZHHNV 2.1.1.9 Patients must have adequate organ and marrow function GD\VSULRUWR&'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 [8/1XQOHVV*LOEHUW¶V'LVHDVH AST(SGOT)/ALT(SGPT) <;LQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO ;  
ULN in the presence of liver metastases)  
creatinine clearance  51 mL/min (calculated using the -CockcroftGault 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  
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 solid tumors including lymphomas (without bone marrow involvement) documented as curatively treated or under control IRU1 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 3DWLHQWVZLWK SHUVLVWHQWWR[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 DQHJDWLYHSUHJQDQF\WHVWXULQHRUVHUXP28 days prior to enrollment and confirmed on day 1 of cycle 1 of study therapy.  
Postmenopausal is defined as:
Ph 2 Version Date: *02/24/20* 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.
untitled h1
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 Ph 2 Version Date: *02/24/20* 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)
untitled h1
2.3 registration procedures

| Arms   |
|--------|  
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
untitled h1
stratifications

| Number   | Name         | Description                          |
|----------|--------------|--------------------------------------|
| 1        | Mesothelioma | Subjects with malignant mesothelioma |
| Number   | Name         | Description                          |
| 1        | Olaparib     | Twice daily oral olaparib            |  
None.
untitled h1
randomization and arm assignment

This is not a randomized study. Subjects in Cohort 1 will be directly assigned to Arm 1.
untitled h1
3 study implementation 3.1 study

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.
untitled h1
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 selfadministered 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.  
Ph 2 Version Date: *02/24/20*
untitled h1
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.  
| 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  
| Hemoglobin                                                                            | Action to be taken   |             |            |           |       |              |     |
|---------------------------------------------------------------------------------------|----------------------|-------------|------------|-----------|-------|--------------|-----|
| Hb < 9 but •JdL                                                                                       | 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 •JGL, 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.                      |             |            |           |       |              |     |
| +EJdL                                                                                       | Give                 | appropriate | supportive | treatment | (e.g. | transfusion) | and |
| investigate causality.                                                                |                      |             |            |           |       |              |     |
| (CTCAE Grade 3)                                                                       | Interrupt olaparib for a maximum of 4 weeksXQWLOLPSURYHGWR+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 |                      |             |            |           |       |              |     |  
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 KHPDWRORJLFDOWR[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. 3.3.1.2 Neutropenia, Leukopenia and Thrombocytopenia  
| 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. )RUFDVHVZKHUHSDWLHQWVGHYHORSSURORQJHGKHPDWRORJLFDOWR[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. 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 NCICTCAE 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.
untitled h1
3.3.2.3 renal impairment

If subsequent to study entry and while still on study therapy, a patient's estimated CrCl falls below WKHWKUHVKROGIRUVWXG\LQFOXVLRQmL/min), retesting should be performed promptly. 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.  
| Abbreviated Title: Ph 2 Olaparib in Mesothelioma Version Date: 02/24/20   | 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   |    |    |    |                 |
|---------------------------------------------------------------------------|-----------------------------------------------|--------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|-------------|----|----|----|-----------------|
| Therapy  Follow-up                                                        |                                               |                    |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Post                                                                      | discontinuation visit2                        |                    |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Treatment                                                                 | X                                             | X                  | X                                                                                                                                                                                                                                                                  | X                                                                                                                        |                                                                                                                                                   |             |    |    |    |                 |
| Subsequent  Cycles Day 1                                                  | X                                             | X                  | X                                                                                                                                                                                                                                                                  |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Day 1 Day                                                                            | X                                             | X                  |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Cycle 1                                                                   | X                                             | X  X               | X                                                                                                                                                                                                                                                                  | X                                                                                                                        | X                                                                                                                                                 |             |    |    |    |                 |
| Screening1 Baseline  X                                                    | X                                             | X                  | X                                                                                                                                                                                                                                                                  | X                                                                                                                        | X                                                                                                                                                 | X           | X  | X  | X  | Biochemistry6 X |
| hematology                                                                |                                               |                    |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Prior cancer therapies  including radiotherapy                            | Archival or fresh tissue  for dx confirmation |                    |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Demographics  Medical and surgical  history                               | Inclusion exclusion                           | criteria           | Performance Score                                                                                                                                                                                                                                                  |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Informed consent                                                          | History of blood  transfusions3               | Physical exam      | assessment5                                                                                                                                                                                                                                                        |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |
| Vital signs                                                               | Labs4 Full                                    |                    |                                                                                                                                                                                                                                                                    |                                                                                                                          |                                                                                                                                                   |             |    |    |    |                 |  
24  
| 25                                                                      | 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.   |    |                                |    |                         |
|-------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|--------------------------------|----|-------------------------|
| Therapy  Follow-up                                                      |                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Post                                                                    | X14 X15                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| discontinuation visit2                                                  |                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Treatment                                                               | X                                                                                                                                                                                                         | X                                                                                                                                                                                                                                                                                                                                  | X                                                                                                                                                   |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Subsequent  Cycles Day 1                                                | X                                                                                                                                                                                                         | X                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Day 1 Day                                                                          |                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Cycle 1                                                                 | Every 6  weeks ±  7 days                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| X                                                                       | X                                                                                                                                                                                                         | X                                                                                                                                                                                                                                                                                                                                  | X                                                                                                                                                   | X                                                                                                                                                                                                                                                                             | X  | X                              |    |                         |
| Screening1 Baseline                                                     | X                                                                                                                                                                                                         | X12                                                                                                                                                                                                                                                                                                                                | X                                                                                                                                                   |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Abbreviated Title: Ph 2 Olaparib in Mesothelioma Version Date: 02/24/20 | Procedure                                                                                                                                                                                                 | Urinalysis7 X Coagulation8 X                                                                                                                                                                                                                                                                                                       | X                                                                                                                                                   | Electrocardiogram10 X                                                                                                                                                                                                                                                         |    | NIH Advance Directives  Form13 | X  | Concomitant Medications |
| CT CAP (MRI if  appropriate); FDG-PET                                   |                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Serum or Urine hCG in                                                   | women of childbearing  potential9                                                                                                                                                                         | NIH 527 release form                                                                                                                                                                                                                                                                                                               |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |
| Sample collection for  mutational analysis  (mandatory)11               | Correlative Research  Studies (See 5.1.2)                                                                                                                                                                 | Adverse Events                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                     |                                                                                                                                                                                                                                                                               |    |                                |    |                         |  
Ph 2 **Version Date:** *02/24/20* 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, gammaglutamyltransferase (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[8/1RUWRWDO ELOLUXELQ [8/1 SOHDVH UHIHUWR 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.  
Ph 2 **Version Date:** 02/24/20 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 12.3DOOVXEMHFWVDJHZLOOEHRIIHUHGWKHRSSRUWXQLW\WRFRPSOHWHDQ1,+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.
untitled h1
3.5 criteria for removal from

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
untitled h1
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)
x Death  
x Participant lost to follow-up x The study is discontinued
untitled h1
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 ncicentralregistrationl@mail.nih.gov.
untitled h1
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).
untitled h1
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.
untitled h1
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 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.
untitled h1
4.3 permitted with olaparib dosing

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.
untitled h1
4.4 permitted with caution 4.4.1

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.
untitled h1
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. 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
untitled h1
4.5 permitted medications 4.5.1 anticoagulant

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.
untitled h1
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.
untitled h1
5 biospecimen collection 5.1 correlative

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.
untitled h1
5.1.1.1 sample collection

Samples will be prior to the first olaparib dose of each cycle and at the end of treatment. 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   |
|-----------------------------------------------------------|---------------------------|-------------------------------------------|----------------------------------------|---------------------|
| Day 1 of each  cycle (pre-dose)  and at end of  treatment | (Deliver to  Dr. Figg's   |                                           |                                        |                     |
| 3.5 mL serum                                              |                           |                                           |                                        |                     |
| MPF and                                                   | 2 mL                      | separator                                 |                                        |                     |
| mesothelin                                                | (tiger top)               | Baseline if                               |                                        |                     |
| NA                                                        | NA                        | tissue (fresh or  archival)  collected at | Entire  collected  specimen  stored in |                     |
| Mandatory  Mutational  Analysis                           |                           |                                           |                                        |                     |  
Specimen Storage  
Location of specimen analysis  
(Deliver to Dr. Figg's  
lab) Hassan Lab  
| Location of  specimen  analysis  Retrospectively  analyzed using  platform in a   |
|-----------------------------------------------------------------------------------|  
| Version Date: 02/24/20  Test/assay Volume  blood  (approx)   | Type of tube                                                                                          | Collection  point (+/-  KUV                 | Specimen                                        | Location of   |
|--------------------------------------------------------------|-------------------------------------------------------------------------------------------------------|-----------------|-------------------------------------------------|---------------|
| Storage                                                      | specimen  analysis                                                                                    |                 |                                                 |               |
| (Tumor  Biopsy)                                              | screening is                                                                                          | the             |                                                 |               |
| insufficient                                                 | Laboratory  of  Pathology  (Ordered  in CRIS)                                                         | ClinOmics  Core |                                                 |               |
| OR                                                           | Baseline if  tissue (fresh or  archival)  collected at  screening is  insufficient                    | Laboratory  of  | Retrospectively                                 |               |
| Pathology                                                    | analyzed in  the ClinOmics  Core                                                                      |                 |                                                 |               |
| (Archival                                                    | NA                                                                                                    |                 |                                                 |               |
| Tumor  Sample)                                               | Molecular  Pathology  - Deliver  blood  STAT to  building  10/Room  3S245  (open 7:30  AM - 4:30  PM) |                 |                                                 |               |
| Mandatory  Mutational  Analysis  (Blood)                     | Retrospectively  analyzed in the  ClinOmics  Core                                                     |                 |                                                 |               |
| 8.5 mL                                                       | Sodium  citrate                                                                                       | Baseline        | Ordered in  CRIS  (indicate  for storage  only) |               |
untitled h1
5.2 sample storage tracking and

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. 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.
untitled h1
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.
untitled h1
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. 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.
untitled h1
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 Ph 2 Version Date: *02/24/20* 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.
untitled h1
6 data collection and evaluation

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.
untitled h1
6.2 recording 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
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.
untitled h1
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.
untitled h1
how and where will the

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.
untitled h1
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 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 GLDPHWHUPPRUSDWKRORJLFDOO\PSKQRGHVZLWKWRPPVKRUWD[LVDUHFRQVLGHUHG non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.  
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 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 FDGPET 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 FDGPET 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.  
Ph 2 Version Date: *02/24/20* 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.  
| Target   | Non-Target   | New     | Overall   | Best Overall Response when   |
|----------|--------------|---------|-----------|------------------------------|
| Lesions  | Lesions      | Lesions | Response  | Confirmation is Required*    |
| CR       | CR           | No      | CR        | >4 wks. Confirmation**       |
untitled h1
for patients with measurable disease

Ph 2  
Version Date: *02/24/20*  
| Version Date: 02/24/20  Target  Non-Target   | New                                                                                                                                                                                                                                                                                                                          | Overall   | Best Overall Response when   |                                                   |
|----------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|------------------------------|---------------------------------------------------|
| Lesions                                      | Lesions                                                                                                                                                                                                                                                                                                                      | Lesions   | Response                     | Confirmation is Required*                         |
| CR                                           | NonCR/Non-PD                                                                                                                                                                                                                                                                                                                              | No        | PR                           |                                                   |
| CR                                           | Not                                                                                                                                                                                                                                                                                                                          | No        | PR                           |                                                   |
| evaluated                                    | >4 wks. Confirmation**                                                                                                                                                                                                                                                                                                       |           |                              |                                                   |
| PR                                           | NonCR/NonPD/not  evaluated                                                                                                                                                                                                                                                                                                                              | No        | PR                           |                                                   |
| SD                                           | NonCR/NonPD/not  evaluated                                                                                                                                                                                                                                                                                                                              | No        | SD                           | Documented at least once >4  wks. from baseline** |
| PD                                           | Any                                                                                                                                                                                                                                                                                                                          | Yes       | or                           | PD                                                |
| No                                           |                                                                                                                                                                                                                                                                                                                              |           |                              |                                                   |
| Any                                          | PD***                                                                                                                                                                                                                                                                                                                        | Yes       | or                           | no prior SD, PR or CR                             |
| PD                                           |                                                                                                                                                                                                                                                                                                                              |           |                              |                                                   |
| No                                           |                                                                                                                                                                                                                                                                                                                              |           |                              |                                                   |
| 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. |           |                              |                                                   |  
| 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                 |
untitled h1
for patients with non-measurable disease

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
untitled h1
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.
untitled h1
6.4.2.1 modified recist criteria for

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.  
  
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/NonPD 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  
Any PD* Yes or No PD no prior SD, PR or CR  
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.
untitled h1
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.  
Ph 2 Version Date: *02/24/20* 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
untitled h1
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).
untitled h1
7 nih reporting requirements /

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
untitled h1
7.2 ohsrp office of compliance

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.
untitled h1
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.
untitled h1
7.4 nih required data and

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.
untitled h1
safety reporting criteria to the

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
untitled h1
8.1.2 adverse events of special

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 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.
untitled h1
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   | Investigational Medical Product (IMP) dose, start & stop date                        |
| o   | Event term as reported by the investigator and/or the CTCAE V5 term                  |
| o   | Investigator's assessment of seriousness, according to ICH definitions               |
| o   | Investigator's assessment of causality                                               |  
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)
untitled h1
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 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).
untitled h1
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 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).
untitled h1
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. 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.
untitled h1
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  [8/1WRJHWKHUZLWKWRWDO ELOLUXELQ  [8/1PD\ QHHGWR 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.
untitled h1
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.
untitled h1
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
untitled h1
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 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.
untitled h1
10 statistical considerations 10.1 statistical

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.