Randomized Phase II Clinical Trial of Olaparib + Pembrolizumab vs. Olaparib Alone as Maintenance Therapy in Metastatic Pancreatic Cancer Patients With Germline BRCA1 or BRCA2 Mutations
Overview
- Phase
- Phase 2
- Intervention
- Magnetic Resonance Imaging
- Conditions
- Metastatic Pancreatic Adenocarcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 88
- Locations
- 1069
- Primary Endpoint
- Progression-free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- yesterday
Overview
Brief Summary
This phase II trial studies whether adding pembrolizumab to olaparib (standard of care) works better than olaparib alone in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged deoxyribonucleic acid (DNA) and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to some types of cancer, including pancreatic cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Olaparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink tumors in patients with metastatic pancreatic cancer with BRCA1 or BRCA2 mutations.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the progression free survival (PFS) of advanced pancreatic cancer patients with germline BRCA1 or BRCA2 mutations treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability associated with the combination of olaparib + pembrolizumab versus (vs.) olaparib alone as maintenance therapy. II. To evaluate the overall survival (OS) of patients treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. III. To evaluate the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, including confirmed and unconfirmed, complete and partial response, of patients treated with olaparib + pembrolizumab compared to olaparib alone, in the subset of patients with measurable disease. IV. To evaluate the duration of response (DoR) by RECIST 1.1 in patients treated with olaparib + pembrolizumab compared to olaparib alone. BANKING OBJECTIVE: I. To bank tissue and blood specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), tumor biopsy and blood sample collection throughout the study. After completion of study treatment, patients are followed for 30 days and every 6 months for 3 years from the date of randomization.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histologic or cytologic diagnosis of pancreatic adenocarcinoma. Patients with neuroendocrine tumors, acinar cell and adenosquamous carcinomas are excluded. All disease must be assessed and documented on the Baseline Tumor Assessment Form
- •Patients must have one of the following mutations: germline mutation in BRCA 1 or 2 that was tested in a Clinical Laboratory Improvement Act (CLIA) certified lab defined as positive and/or deleterious (that is, pathogenic or likely pathogenic variant). (NOTE: Patients with tumor somatic mutations are not eligible)
- •Patients must have metastatic disease and received first line platinum-based chemotherapy (i.e. fluorouracil, irinotecan, leucovorin and oxaliplatin \[FOLFIRINOX\], leucovorin calcium, 5-fluorouracil, and oxaliplatin \[FOLFOX\], gemcitabine + nab-paclitaxel + cisplatin or gemcitabine + cisplatin)
- •Patients must have had a CT or MRI showing stable or responding disease on first line platinum-based chemotherapy within 30 days prior to registration
- •Patients with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration
- •Patients with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 30 days prior to registration
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 30 days prior to registration
- •Patients must have received at least 16 weeks of first line platinum-based chemotherapy for metastatic disease. Patients may have also received one cycle of treatment (no more than 4 weeks) with gemcitabine + nab-paclitaxel while waiting for germline test results, prior to platinum-based therapy
- •Patients' last chemotherapy treatment must be within 30 days prior to registration
- •Patients must have resolved or stable =\< grade 1 toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment, excluding neuropathy and alopecia
Exclusion Criteria
- Not provided
Arms & Interventions
Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Arm B (olaparib)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Olaparib
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Olaparib
Arm A (olaparib, pembrolizumab)
Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI, tumor biopsy and blood sample collection throughout the study.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Progression-free survival (PFS)
Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), or death due to any cause, assessed up to 3 years
Primary analysis of PFS will be conducted in all eligible patients according to the intent-to-treat principle using a log rank test stratified by first line chemotherapy, performance status and disease status after first line platinum-based treatment. Distributions of PFS by treatment arm will be estimated using the method of Kaplan-Meier.
Progression-free survival (PFS)
Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), or death due to any cause, assessed up to 3 years
Primary analysis of PFS will be conducted in all eligible patients according to the intent-to-treat principle using a log rank test stratified by first line chemotherapy, performance status and disease status after first line platinum-based treatment. Distributions of PFS by treatment arm will be estimated using the method of Kaplan-Meier.
Secondary Outcomes
- Incidence of adverse events(Up to 3 years)
- Overall survival(From date of registration to date of death due to any cause, assessed up to 3 years)
- Overall response rate (ORR) per RECIST 1.1(Up to 3 years)
- Duration of response (DoR)(Up to 3 years)
- Incidence of adverse events(Up to 3 years)
- Overall survival(From date of registration to date of death due to any cause, assessed up to 3 years)
- Overall response rate (ORR) per RECIST 1.1(Up to 3 years)
- Duration of response (DoR)(Up to 3 years)