This phase II trial studies how well olaparib with or without tremelimumab works in treating patients with ovarian, fallopian tube, or peritoneal cancer that has come back (recurrent). PARPs are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and tremelimumab together may work better than olaparib alone in treating patients with ovarian, fallopian tube, or peritoneal cancer.
PRIMARY OBJECTIVES: I. To determine whether olaparib plus tremelimumab has adequate safety in the study population. (Safety Lead-in Trial Components) II. To compare the progression-free survival (PFS) duration of olaparib monotherapy versus olaparib plus tremelimumab in women with recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer. (Phase II Trial Component) SECONDARY OBJECTIVES: I. To compare the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in women with recurrent, platinum sensitive ovarian, primary peritoneal or fallopian tube cancer treated with either olaparib monotherapy or olaparib plus tremelimumab. II. To compare the overall survival (OS) of women with recurrent, platinum sensitive ovarian, primary peritoneal or fallopian tube cancer treated with either olaparib monotherapy or olaparib plus tremelimumab. EXPLORATORY OBJECTIVES: I. To explore whether conditions in the tumor microenvironment (as measured by gene expression signature in archived tumor samples) identify patients that benefit from combined olaparib and tremelimumab immunotherapy. II. To explore whether mutations in BRCA1/2 genes or other evidence of homologous repair deficiency (HRD+) is prognostic and/or predictive of response to combined olaparib and tremelimumab immunotherapy. III. To explore associations between PD1 expression in the tumor microenvironment and outcome and changes in circulating leukocyte populations. IV. To explore the correlation between tumor mutational burden and response to olaparib and tremelimumab immunotherapy. V. To explore the impact of olaparib and tremelimumab versus olaparib monotherapy on circulating leukocyte subsets via exploration of the immunomodulatory effects of PARP inhibition and the added impact of CTLA4 blockade in this patient population. VI. To explore cytokine/chemokine levels using a multiplex immunoassay (Olink) and correlate these levels with clinical endpoints. VII. To use cell-free deoxyribonucleic acid (DNA) to assess BRCA mutation status as a mechanism of acquired resistance to prior PARP inhibition and to compare with treatment efficacy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive olaparib orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) as well as blood sample collection throughout the trial. ARM II: Patients receive olaparib as in Arm I. Patients also receive tremelimumab intravenously (IV) over 60 minutes on day 1. Cycles of tremelimumab repeat every 4 weeks for 4 doses and then every 12 weeks for up to 2 years total in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI as well as blood sample collection throughout the trial. After completion of study treatment, patients are followed up monthly for 3 months, then every 3 months for 2 years, followed by every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
61
Undergo blood sample collection
Undergo CT
Undergo MRI
Given PO
Given IV
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
Hartford Hospital
Hartford, Connecticut, United States
Augusta University Medical Center
Augusta, Georgia, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
Washington University School of Medicine
St Louis, Missouri, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
UHHS-Chagrin Highlands Medical Center
Beachwood, Ohio, United States
Case Western Reserve University
Cleveland, Ohio, United States
...and 10 more locations
Progression Free Survival (PFS)
The count of participants who have progressed or died (death due to any cause). Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Summary of RECIST 1.1 criteria for progression for this trial: 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 progression).
Time frame: PFS is monitored for progression or death due to any cause, whichever occurs first. The median follow-up time is 22 months. Since the study was stopped early, the follow-up for progression-free survival was significantly reduced.
Dose-limiting Toxicity (DLT) (Safety Lead-In)
The outcome measure presents the count of participants who experienced a DLT. If more than six of the first 25 patients treated with Tremelimumab and Olaparib are unable to complete at least 3 cycles of treatment due to DLTs then the study will be stopped. If not, then enrollment will continue until 45 patients are enrolled. If more than 11 of the first 45 patients treated with the combination regimen are unable to complete the first 3 cycles of treatment, then enrollment will be stopped, otherwise, the trial till proceed to the third component (i.e. a phase 2 comparison of study treatments).
Time frame: At least 4 weeks after initiating treatment, no longer than 12 weeks (three complete treatment cycles). Maximum follow-up was 12 weeks.
Objective Response (RECIST 1.1)
The objective response (RECIST 1.1) is the count of subjects with a best overall complete response (CR) or partial response (PR) among those with target lesions at the time of enrollment. : Summary of RECIST 1.1 criteria for progression for this trial: 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 progression).
Time frame: The median follow-up is 22 months. Since the study was stopped early, the follow-up time frame for objective response was significantly reduced.
Number of Participants Died
Overall survival (OS) will be presented as survival events (deaths).
Time frame: Overall survival will be monitored from enrollment to randomization to the date of death due to any cause. The median follow-up is 22 months. Since the study was stopped early, the time frame for OS follow-up was significantly reduced.
Number of Participants With Adverse Event of Grade 3 or Higher
Safety data will be summarized for all treated subjects. All adverse events, including severe adverse events (SAEs) and treatment-related adverse events, will be categorized and graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. This will be presented as the count of participants who experienced an adverse event (AE) of grade 3 or higher.
Time frame: During treatment period and up to 30 days after treatment end. The mean follow-up for adverse events was 6.4 months. Note: survival is monitored for a longer period of time (i.e. up to five years) as compared to the period for collecting adverse events.
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