A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab, in BRCA1 and BRCA2 Mutation Carriers With Recurrent Ovarian Cancer

INST 1419

Of the approximately 21,000 cases of ovarian cancer diagnosed annually in the U.S, ten percent are attributed to hereditary syndromes, most commonly the result of mutations in the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Mutation in these genes results in the inability to repair double-stranded breaks in DNA. Treating these tumors with poly(adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitors results in the specific killing of BRCA negative cells by blocking a second DNA-repair mechanism. Treatment of ovarian cancer patients with PARP inhibitors has resulted in improved progression free survival (PFS), but not overall survival (OS). It's not completely understood why this is the case, but some preclinical studies using ovarian cancer models in mice have suggested that combining PARP inhibitors with immune system modulators like T cell checkpoint inhibitors improves long-term survival. Therefore, the purpose of this study is to evaluate the safety and efficacy of a combination of a PARP inhibitor (Olaparib) with a T cell checkpoint inhibitor (the anti-CTLA-4 antibody Tremelimumab) in women with recurrent BRCA mutation-associated ovarian cancer.

2016-02-23

2020-12-02

2027-07-15

Active (not recruiting)

Early phase I

50

Inclusion Criteria: * Patients must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma for which standard curative measures do not exist. * Patients must have a confirmed germline mutation in the BRCA1 or BRCA2 gene * Patients must have measurable disease as defined by World Health Organization (WHO) criteria: at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be \>1.0cm when measured by CT, MRI, or caliper measurement by clinical exam; or \>2.0cm when measured by chest x-ray. Lymph nodes must be \>1.5cm in short axis when measured by CT or MRI * Patients with platinum-sensitive or platinum-resistant disease are eligible * Patients must have received at least 1 prior course of platinum-based chemotherapy for the management of primary disease including carboplatin, cisplatin, or another platinum compound * There are no restrictions on the total number of prior regimens patients may have received * Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 * Adequate organ and marrow function as defined below: * Absolute neutrophil count (ANC) \>1,500/mcl * Platelets \> 100,000/mcl * Creatinine \< 1.5x the institutional upper limit of normal (ULN) * Bilirubin \< 1.5x ULN * Aspartate aminotransferase and Alanine aminotransferase \< 3x ULN * Alkaline phosphatase \< 2.5x ULN * Women of child-bearing potential must have a negative pregnancy test prior to study entry and agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 180 days following completion of therapy * Ability to understand and the willingness to sign a written informed consent document * Patients must meet pre-entry requirements as specified Exclusion Criteria: * Recovery from effects of recent surgery, radiotherapy, or chemotherapy must be demonstrated * Patients should be free of active infection requiring antibiotic therapy (except for uncomplicated urinary tract infections) * Hormonal therapy directed at treatment for the cancer must be discontinued at least 1 week prior to enrollment. Hormone replacement therapy for symptom management is permitted. * Any other therapy directed at treating the cancer including chemotherapy, biologic/targeted agents, and immunologic agents, must be discontinued at least 3 weeks prior to enrollment. * Any prior radiation therapy must be discontinued at least 4 weeks prior to enrollment. * A history of autoimmune disorders other than vitiligo (e.g., psoriasis, extensive atopic dermatitis, asthma, inflammatory bowel disease, multiple sclerosis, uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study. Any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve. Mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded. * Chronic use of immune-suppressive drugs (i.e., systemic corticosteroids used in the management of cancer or non-cancer related illnesses, e.g., COPD). * Known HIV-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to tremelimumab, and the higher risk of active opportunistic infections. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or tremelimumab, or other agents used in study. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Concomitant use of known potent cytochrome P450 isoform 3A4 (CYP3A4) inhibitors * Persistent toxicities (\> Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by prior cancer therapy, excluding alopecia * Must not be pregnant or nursing as the potential of this regimen to harm nursing infants has not been evaluated. * Patients who are receiving any other investigational agent For Phase 2, the inclusion/exclusion criteria above apply. In addition, the following exclusion criteria apply: * Resting electrocardiogram with corrected QT interval (QTc) \>470msec on two or more time points within a 24hr period, or a family history of long QT syndrome * Patients who have previously received anti-CTLA-4 antibody therapy

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1', 'PHASE2'], 'designInfo': {'allocation': 'NA', 'interventionModel': 'SINGLE_GROUP', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 50, 'type': 'ESTIMATED'}}

2024-01-11