A Phase I/II Evaluation of Olaparib in Combination With Durvalumab (Medi4736) and Tremelimumab in the Treatment of Recurrent Platinum Sensitive or Resistant or Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients Who Carry a BRCA1 or BRCA2 Mutation
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- BRCA1 Gene Mutation
- Sponsor
- Roswell Park Cancer Institute
- Enrollment
- 40
- Locations
- 2
- Primary Endpoint
- 3 Month Progression Free Survival (PFS) in the All Eligible Patients by Group/Arm
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of olaparib when give together with durvalumab and tremelimumab and to see how well they work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer with BRCA1 or BRCA2 genetic mutation that has come back or has not responded to treatment. Drugs, such as olaparib, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and kill tumors cells with BRCA1 or BRCA2 mutation. Monoclonal antibodies, such as durvalumab and tremelimumab, may help stimulate the immune system in different ways to attack and stop tumor cells from growing. Giving olaparib with durvalumab and tremelimumab may work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To assess the safety and toxicity of the combination of PARP inhibitor olaparib with anti-PD-L1 antibody durvalumab and anti-CTLA4 antibody tremelimumab. (Phase I) II. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on progression free survival (PFS) rates. (Phase II) SECONDARY OBJECTIVES: I. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on anti-tumor immune responses in patients with recurrent platinum sensitive or resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or somatic BRCA1 or BRCA2 mutation and/or a homologous recombination deficiency (HRD). II. To assess the impact of the combination of olaparib with durvalumab and tremelimumab on PFS and overall survival (OS) in patients with recurrent platinum sensitive or resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer who carry a germline and/or somatic BRCA1 or BRCA2 mutation and/or a HRD. OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study. Patients receive olaparib orally (PO) twice daily (BID), and tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 90 days, and every 2 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have platinum-sensitive or platinum-resistant recurrent or persistent or refractory ovarian, fallopian tube, or primary peritoneal carcinoma AND have one or more of the following characteristics documented on a validated platform (documented genetic test report is required). Historic report is permitted.
- •A germline BRCA1 or BRCA2 deleterious alteration.
- •A somatic mutation in BRCA1 or BRCA2 detected in a tumor sample or on circulating tumor DNA
- •Carry a known or likely loss of function alteration in one or more of the homologous recombination or mismatch repair pathways genes
- •Demonstrate a genomic phenotype of HR deficiency as measured by a LOH-high score.
- •Recurrent ovarian cancer is defined as recurrence of disease in a patient who achieved initial complete response to primary therapy
- •Persistent ovarian cancer is defined as having residual disease in the form of elevated tumor markers or microscopic or clinically evident disease in a patient who has completed and apparently responded to initial chemotherapy
- •Refractory ovarian cancer is defined as patients who have failed to achieve at least a partial response to therapy including patients with either stable disease or disease progression during primary therapy
- •Platinum-sensitive is defined as achievement of documented response to initial platinum-based treatment and has been off treatment for an extended period of time (more than 6 months)
- •Platinum-resistant is defined as relapse within 6 months of last platinum-based chemotherapy or progression while on platinum-based therapy
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrollment in the present study
- •Participation in another clinical study with an investigational product during the last 4 weeks (prior use of bevacizumab in the upfront setting is allowed)
- •History of discontinuation of any previous treatment with PARP inhibitors, including olaparib, or a PD-1 or PD-L1 inhibitor, including durvalumab or anti-CTLA4 antibody, including tremelimumab due to toxicity.
- •Patients with myelodysplastic syndrome/acute myeloid leukemia
- •History and/or confirmed interstitial lung disease (ILD)/pneumonitis, extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan
- •Concomitant use of a strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole. Fosamprenavir, imatinib, verapamil)
- •Concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's wort) and moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin)
- •History of another primary malignancy except for:
- •Malignancy treated with curative intent and with no known active disease \>= 5 years before the first dose of study drug and of low potential risk for recurrence
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease (e.g. basal cell or squamous cell carcinoma of the skin)
Arms & Interventions
Treatment (olaparib, tremelimumab, durvalumab)
Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Durvalumab
Treatment (olaparib, tremelimumab, durvalumab)
Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (olaparib, tremelimumab, durvalumab)
Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Olaparib
Treatment (olaparib, tremelimumab, durvalumab)
Patients receive olaparib PO BID, and tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with olaparib continues for up to 12 months in the absence of disease progression or unacceptable toxicity. Treatment with tremelimumab repeats every 4 weeks for up to 4 courses and treatment with durvalumab repeats every 4 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
3 Month Progression Free Survival (PFS) in the All Eligible Patients by Group/Arm
Time Frame: At 3 months
Progression free survival (PFS) rate will be assessed at 3 months in the platinum resistant group using Kaplan-Meier methods. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Incidence of Dose-limiting Toxicities (DLTs) Defined as the Rate of Drug-related Grade 3-5 Adverse Events Assessed Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (Phase I)
Time Frame: Up to 8 weeks
The maximum tolerated dose is defined as the highest dose studied, for which the observed incidence of DLT is less than 33%. Number of Participants with Dose-limiting Toxicities (DLTs) in Phase I and Phase II will be reported.
6 Month Progression Free Survival (PFS) in the Platinum Sensitive Group (Phase II)
Time Frame: At 6 months
6-month progression-free survival rate is the probability of patients remaining alive and progression-free at 6 months from study entry estimated using Kaplan-Meier methods. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesion
Secondary Outcomes
- Anti-tumor Immune Response of the Treatment Combination Assessed in Tumor Biopsy(At 12 weeks)
- Overall Survival (OS)(35 months)