Olaparib in People With Malignant Mesothelioma

Background:

- Malignant mesothelioma is an invasive and often fatal neoplasm that arises from
mesothelium that lines several organs.

- Recent studies have identified germline mutations in the gene encoding BRCA1 associated
protein-1 (BAP1) which can predispose to mesothelioma

- In addition to mesothelioma, germline BAP1 mutations confer increased susceptibility for
the development of several other tumors including uveal melanoma, cutaneous melanoma,
renal cell cancers and possibly other cancers

- In addition to BAP1, we found several novel germline variants that have previously not
been associated with risk of developing mesothelioma.

- As evidenced by recent data derived from ovarian and prostate cancer patients, mutations
in DNA repair genes can define subgroups of cancer patients with distinct
vulnerabilities to DNA damage response inhibitors.

- Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or
suspected deleterious germline BRCA mutated

- Both established and patient derived mesothelioma cell lines with mutated DNA repair
genes are sensitive to olaparib.

Objective:

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

Eligibility:

- Patients must have progressive, histologically or cytologically confirmed malignant
mesothelioma.

- Age >18 years

- Patients must have received prior platinum and pemetrexed based therapies

- Adequate organ and bone marrow function

Design:

- This is a phase II, single center study of olaparib in subjects with malignant
mesothelioma

- All subjects will take olaparib by mouth twice daily until disease progression or
intolerable side effects

- Subjects will be assessed for safety (continuously) and efficacy (every 6 weeks)

- Subjects will be analyzed in 3 separate comparison groups according to their mutation
status

- Comparison Group 1: Patients with a germline mutation in DNA repair genes

- Comparison Group 2: Patients with BAP1 somatic mutations

- Comparison Group 3: Patients with neither germline mutations nor BAP 1 somatic
mutations

- Up to 30 evaluable subjects will be enrolled

- INCLUSION CRITERIA:

- 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.

- 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.

- Patients must have measurable disease.

- Patients must have progressive disease at study entry

- Patients must have received prior platinum and pemetrexed based therapies. Response to
platinum is not an eligibility criterion for enrollment.

- Age greater than or equal to 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.

- ECOG performance status less than or equal to 1.

- Patients must have a life expectancy of greater than or equal to 16 weeks

- Patients must have adequate organ and marrow function less than or equal to 5days
prior to C1D1 as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to greater than or equal to
1,500/mcL without growth factor support

- platelets greater than or equal to 100,000/mcL

- hemoglobin greater than or equal to 10 g/dL with no blood transfusion in the past
28 days

- total bilirubin less than or equal to 1.5 x ULN (unless Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of
normal (less than or equal to 5X ULN in the presence of liver metastases)

- creatinine clearance greater than or equal to 51 mL/min (calculated using the
-Cockcroft-Gault formula.

- 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:

- 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 other method 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.

- 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 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.

- Acceptable birth control methods:

- 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.

- Vasectomised sexual partner PLUS male condom. With participant assurance that
partner received post-vasectomy confirmation of azoospermia.

- Tubal occlusion PLUS male condom

- Intrauterine Device PLUS male condom. Provided coils are copper-banded.

- Etonogestrel implants (e.g., Implanon , Norplant ) PLUS male condom

- Normal and low dose combined oral pills PLUS male condom

- Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom

- Intrauterine system device (e.g., levonorgestrel-releasing intrauterine system
-Mirena ) PLUS male condom

- Norelgestromin/ethinyl estradiol transdermal system PLUS male condom

- Intravaginal device (e.g., ethinyl estradiol and etonogestrel) PLUS male condom

- Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly
efficacious progesterone based pill.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Patients who have received any previous treatment with a PARP inhibitor, including
olaparib.

- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
reasons) within 3 weeks prior to study treatment

- Patients with other malignancy documented as occurring within the last 1 year except:
adequately treated nonmelanoma 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 includinglymphomas (without bone marrow involvement) documented as
curatively treated or under control for greater than or equal to 1 year.

- Patients with features suggestive of MDS/AML on peripheral blood smear.

- 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.

- History of allergic reactions or hypersensitivity attributed to compounds of similar
chemical or biologic composition to olaparib or its excipients.

- Patients who have had a whole blood transfusion within 120 days prior to enrollment.
(Packed red blood cells and platelet transfusions are acceptable)

- Patients with persistent toxicities (greater than or equal to CTCAE grade 2) with the
exception of alopecia,caused by previous cancer therapy

- 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.

- 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.

- Resting ECG with QTcF > 470 msec on 2 or more time points within a 24-hour period or
family history of long QT syndrome

- 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.

- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.

- 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.

- 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 a negative pregnancy test (urine or serum) less than or equal to 28 days prior to
enrollment and confirmed on day 1 of cycle 1 of study therapy. Postmenopausal is
defined as:

Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

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)

- 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.

- Immunocompromised patients are excluded.

- 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.

- Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids

- Previous allogeneic hematopoietic stem cell transplant, allogeneic bone marrow
transplant or double umbilical cord blood transplant (duCBT)