Olaparib for the Treatment of Homologous Recombination Deficient Malignant Mesothelioma

Inclusion Criteria

• Histologically confirmed diagnosis of malignant pleural, peritoneal, or tunica vaginalis mesothelioma (epithelial, biphasic, or sarcomatoid subtypes allowed)
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions, listed in the informed consent form (ICF) and in this protocol
• Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses
• Willingness to undergo genetic testing of both tumor and normal body cells to determine study eligibility
• For inclusion in the exploratory genetic and biomarker research, patients must provide informed consent for genetic and biomarker research on the treatment phase consent form prior to collection of research samples
• Subject must be > 18 years of age, inclusive, at the time of signing the informed consent form
• Evidence of an HR pathway genetic abnormality defined as follows: * BAP1 loss by immunohistochemistry on stained tumor slides verified by centralized pathology at The University of Chicago AND/OR * A heterozygous germline and/or a heterozygous, compound heterozygous, or homozygous somatic loss of function mutation(s) (each defined as a variant that results in premature protein truncation (splice site, nonsense, frameshift) OR a missense mutation or non-frameshift small insertion/deletion with experimental evidence that it disrupts protein function OR a large genomic gain or loss) in at least one of the following genes: ** ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PRKDC, RAD50, RAD51, RAD51C, RAD51D, WRN, WT1, XRCC2, XRCC3 ** NOTE #1: Patients with a known germline mutation and/or somatic mutation in their mesothelioma tumor fitting the above description and determined prior to study enrollment in a Clinical Laboratory Improvement Act (CLIA)-certified germline or tumor sequencing laboratory will fit this eligibility criteria once the official mutation report is received, and the principal investigator confirms that the identified mutation fits the definition outlined above. All other patients must consent to undergo sequencing of both tumor and normal samples as described in study procedures below during the prescreening phase to determine eligibility ** NOTE #2: Rare variants with conflicting evidence regarding their effect on protein function will be interpreted on an individual basis by the principal investigator
• Prior treatment with cisplatin or carboplatin is required
• Patients must have platinum-sensitive disease, defined as no disease progression while on or for at least 3 months after completing treatment with a platinum agent
• Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (measured within 28 days prior to administration)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior to administration of study treatment)
• Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of study treatment)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be =< 5x ULN (measured within 28 days prior to administration of study treatment)
• Patients must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft-Gault equation (measured within 28 days prior to administration of study treatment)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have a life expectancy >= 16 weeks
• Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) for mesothelioma for pleural mesothelioma (Byrne 2004) and RECIST 1.1 for peritoneal and tunica vaginalis mesothelioma (Eisenhauer, 2009). There must be at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) and which is suitable for accurate repeated measurements
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as: * 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 * Radiation-induced oophorectomy with last menses > 1 year ago * Chemotherapy-induced menopause with > 1 year interval since last menses * Surgical sterilization (bilateral oophorectomy or hysterectomy)
• 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

Exclusion Criteria

• As judged by the investigator, any evidence of inter-current illness which in the investigator’s opinion makes it undesirable for the patient to participate in the trial
• Other malignancy unless curatively treated with no evidence of disease for >= 3 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma
• Patients with BAP1 tumor predisposition syndrome (an autosomal dominant hereditary cancer syndrome due to carrying a heterozygous pathogenic or likely pathogenic germline mutation in the gene BAP1, characterized predominantly by mesothelioma, uveal melanoma, cutaneous melanoma, meningioma, and renal cell carcinoma) will be included in the trial. These patients may be eligible if they have a history of syndrome-related cancers, provided they completed their surgery and adjuvant chemotherapy more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
• Patients with platinum-resistant disease, defined as disease progression during or within 3 months of receiving platinum chemotherapy
• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's correction formula (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
• Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with findings suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• 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
• 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
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
• Patients with known active hepatitis (i.e. hepatitis B or C) * Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• Any previous treatment with a PARP inhibitor, including olaparib
• Receipt of any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Major surgery within 2 weeks of starting study treatment; patients must have recovered from any effects of any major surgery
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Participation in another clinical study with an investigational product administered in the last 1 month
• Patients with a known hypersensitivity to olaparib or any of the excipients of the product
• Involvement in the planning and/or conduct of the study
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• Pregnant or breast-feeding women