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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 152
- 试验地点
- 457
- 主要终点
- Improvement in relapse-free survival (RFS)
研究概览
简要总结
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.
详细描述
PRIMARY OBJECTIVE:
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.
SECONDARY OBJECTIVES:
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 have no evidence of recurrent or metastatic pancreatic cancer at the time of randomization as documented by baseline scans obtained =< 4 weeks prior to Step 1 randomization
- •Patient must not have previously had evidence of progressive pancreatic cancer while receiving platinum-based therapy
- •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)
- •Patient must not be receiving any other investigational agents at the time of Step 1 randomization and while on protocol treatment
- •Patient must not have any history of allergic reactions attributed to compounds of similar chemical or biological composition to olaparib
- •Patient must not have any personal history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
- •Patient must not have any uncontrolled gastrointestinal disorder that would, in the opinion of the investigator, interfere with the ingestion or absorption of olaparib
- •Patient must not be pregnant or breast-feeding due the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- •Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after the last dose of protocol treatment for female patients and for 3 months after the last dose of protocol treatment for male patients. Patients must also not donate sperm while on protocol treatment and for 3 months after the last dose of protocol treatment. Patients must also not breast-feed while on protocol treatment and for 1 month after the last dose of protocol treatment
- •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 x 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 not have resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTc] prolongation > 500 ms, electrolyte disturbances, etc.) or have congenital long QT syndrome
- •Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir is prohibited
- •Patients who are being actively treated for an ongoing concurrent malignancy are ineligible, with the exception of those receiving adjuvant hormone therapies and those receiving topical therapies for skin cancers
- •Patient must not have, in the opinion of the investigator, any other concurrent medical condition that would prevent the patient from complying with the study procedures
- •Patient must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
- •Patient must have the ability to understand and the willingness to sign a written informed consent document, or have legally authorized representative provide authorization to participate
- •Patient must not have had major surgery within 2 weeks prior to Step 1 randomization and patients must have recovered from any effects of any major surgery
排除标准
- 未提供
研究组 & 干预措施
Arm I (olaparib)
Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm I (olaparib)
Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Computed Tomography (Procedure)
Arm I (olaparib)
Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Olaparib (Drug)
Arm II (placebo)
Patients receive placebo PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm II (placebo)
Patients receive placebo PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Computed Tomography (Procedure)
Arm II (placebo)
Patients receive placebo PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (olaparib)
Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (placebo)
Patients receive placebo PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scans or CT/MRI and collection of blood throughout the study.
干预措施: Placebo Administration (Drug)
结局指标
主要结局
Improvement in relapse-free survival (RFS)
时间窗: From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed from 22 months to 44 months
Will demonstrate an improvement in the RFS from 22 months to 44 months (hazard ratio 0.5) in patients treated with olaparib after perioperative (neoadjuvant, adjuvant or a combination) chemotherapy compared to those treated with perioperative therapy alone.
次要结局
- RFS(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- Overall survival (OS)(From randomization until 10 years after registration or until death, whichever comes first)
- Differences in survival(Up to 10 years)
- RFS in those who received =< 3 months of perioperative platinum chemotherapy compared to > 3 months of perioperative platinum chemotherapy(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- OS in those who received =< 3 months of perioperative platinum chemotherapy versus > 3 months of perioperative platinum chemotherapy(From randomization until 10 years after registration or until death, whichever comes first)
- RFS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- OS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy(From randomization until 10 years after registration or until death, whichever comes first)
- RFS(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- Overall survival (OS)(From randomization until 10 years after registration or until death, whichever comes first)
- Efficacy of olaparib after chemotherapy in patients with a pathogenic germline BRCA or PALB2 mutation(Up to 10 years)
- Differences in survival(Up to 10 years)
- RFS in those who received =< 3 months of perioperative platinum chemotherapy compared to > 3 months of perioperative platinum chemotherapy(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- OS in those who received =< 3 months of perioperative platinum chemotherapy versus > 3 months of perioperative platinum chemotherapy(From randomization until 10 years after registration or until death, whichever comes first)
- RFS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy(From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years)
- OS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy(From randomization until 10 years after registration or until death, whichever comes first)