APOLLO: A Randomized Phase II Double-Blind Study of Olaparib versus Placebo Following Curative Intent Therapy in Patients with Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation
18 Years and older, Male and Female
This phase II trial investigates how well the addition of olaparib following completion of surgery and chemotherapy works in treating patients with pancreatic cancer that has been surgically removed (resected) and has a pathogenic mutation in BRCA1, BRCA2, or PALB2. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy.
I. To determine the relapse-free survival (RFS)-benefit from the addition of a maintenance olaparib following completion of chemotherapy in patients with resected pancreatic carcinoma and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2.
I. To evaluate RFS in patients with olaparib after perioperative chemotherapy compared to those treated with perioperative therapy alone among patients who received prior platinum-based perioperative chemotherapy.
II. To evaluate overall survival (OS) in patients treated with olaparib after adjuvant chemotherapy compared to those treated with adjuvant treatment alone.
III. To analyze the efficacy of olaparib after chemotherapy in patients with a pathogenic germline BRCA or PALB2 mutation compared to those with a somatic mutation.
IV. To analyze survival differences between patients who received neoadjuvant or perioperative chemotherapy compared to those who received adjuvant therapy alone.
V. To analyze RFS and OS differences in those who received =< 3 months of perioperative platinum chemotherapy compared to those who received > 3 months of perioperative platinum chemotherapy.
VI. To analyze RFS and OS differences in those who received any platinum-based perioperative chemotherapy compared to no-platinum based perioperative chemotherapy.
I. To analyze RFS and OS differences in patients who had R1 versus (vs) R0 resections, lymph node positivity at resection, and/or elevated or rising CA 19-9 or CEA at time of study enrollment in the post-operative setting.
II. To analyze RFS and OS differences with those who had resectable disease at diagnosis compared to those who did not.
III. To analyze RFS and OS differences in those with gBRCA1 mutations compared to those with gBRCA2 mutations and gPALB2 mutations.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) scans/magnetic resonance imaging (MRI) and collection of blood throughout the study.
ARM II: Patients receive placebo PO BID on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans/MRI and collection of blood throughout the study.
After completion of study treatment, patients are followed up at 30 days, every 4 months for year 1, then every 6 months for years 2-10.
- STEP 0 (PRE-REGISTRATION) INCLUSION CRITERIA
- Patient must be >= 18 years of age on day of consent
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- Patient must have a diagnosis of pancreatic cancer and have successfully undergone a curative intent surgical resection and must have no evidence of recurrent disease as determined by the investigator
* NOTE: This includes patients with adenocarcinoma, acinar carcinoma, squamous cell carcinoma adenosquamous and variants thereof. Patients with neuroendocrine tumors are excluded from enrolling
- Patient must (1) be planning to receive, (2) be receiving or (3) have received at least three combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 month course)
- Patient must be no more than 12 weeks from their most recent treatment (this may be chemotherapy, radiotherapy or surgery)
- Patient must have a known pathogenic or likely pathogenic germline or somatic mutation in BRCA1, BRCA2, or PALB2, as determined by a Clinical Laboratory Improvement Amendments (CLIA) certified or equivalently-accredited laboratory. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org
- STEP 1 (RANDOMIZATION) INCLUSION CRITERIA
- Patient must have met the eligibility criteria outlined above
- Patient must have undergone at least 3 combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 months course)
- Central expert reviewer must have determined the patient eligible for randomization after review of local genetic testing reports
- If mutation in BRCA1, BRCA2 or PALB2 was identified in tumor tissue and the patient has not previously undergone germline testing, the patient must agree to undergo germline testing
- Patient must be >= 21 days (three weeks) from their last treatment (including chemotherapy radiotherapy or surgery) but =< 84 days (twelve weeks) from their last treatment at the time of Step 1 randomization. Patients who have received neoadjuvant and/or adjuvant radiotherapy are eligible
- Patient must have recovered from any adverse events due to prior anti-cancer therapy (i.e., have no residual toxicities > grade 1 with the exception of alopecia and/or neuropathy)
- Leukocytes >= 3,000/mcL (obtained =< 28 days prior to Step 1 randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to Step 1 randomization)
- Platelets >= 100,000/mcL (obtained =< 28 days prior to Step 1 randomization)
- Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days (obtained =< 28 days prior to Step 1 randomization)
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin =< 2.5 x ULN of the direct bilirubin (obtained =< 28 days prior to Step 1 randomization)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional ULN (obtained =< 28 days prior to Step 1 randomization)
- Creatinine =< 1.5 institutional ULN OR calculated Cockcroft Gault creatinine clearance > 50 mL/min/1.73 m^2 (obtained =< 28 days prior to Step 1 randomization)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- 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, they are eligible if they have an undetectable HCV viral load
- Patient must have the ability to understand the willingness to sign a written informed consent document, or have legally authorized representative provide authorization to participate
Treatment Sites in Georgia
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