A Phase III Trial of One vs. Two Years of Maintenance Olaparib, With or Without Bevacizumab, in Patients With BRCA1/2 Mutated or Homologous Recombination Deficient (HRD+) Ovarian Cancer Following Response to First Line Platinum-Based Chemotherapy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- NRG Oncology
- 入组人数
- 880
- 试验地点
- 1,311
- 主要终点
- Progression free survival (PFS) at least 360 days after randomization (PFS360)
研究概览
简要总结
This phase III trial compares the effect of olaparib for one year versus two years, with or without bevacizumab, for the treatment of BRCA 1/2 mutated or homologous recombination deficient stage III or IV ovarian cancer. Olaparib is a polyadenosine 5'-diphosphoribose polymerase (PARP) enzyme inhibitor and may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving olaparib for one year with or without bevacizumab may be effective in treating patients with BRCA 1/2 mutated or homologous recombination deficient stage III or IV ovarian cancer, when compared to two years of olaparib.
详细描述
PRIMARY OBJECTIVE:
I. To determine investigator assessed progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (non-inferiority) for one versus (vs.) two years of maintenance olaparib.
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS360) in the modified intent to treat (ITT) population, with time at risk for progression/death starting 360 days after randomization.
II. To evaluate progression-free survival (PFS), PFS2 and overall survival (OS) in the ITT population.
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
- None
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
- •Patients with newly diagnosed, pathologically confirmed, Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer of the following types:
- •High grade serous
- •High grade endometrioid (excluding tumors that are known mismatch repair deficient/microsatellite instability high (MMR-D/MSI-H) or POLE ultramutated)
- •Carcinosarcoma (excluding tumors that are known mismatch repair deficient/microsatellite instability high (MMR-D/MSI-H) or POLE ultramutated), and/or
- •Other epithelial ovarian cancer with BRCA1/2 deleterious alteration (germline or somatic), (excluding tumors that are known mismatch repair deficient/microsatellite instability high (MMR-D/MSI-H) or POLE ultramutated)
- •Submission of pathology report is required
- •Ovarian cancer = ovarian, fallopian, or primary peritoneal cancer
- •Patients must have:
- •Documented variant (tumor or germline) in BRCA1 or BRCA2 that is predicted to be pathogenic or suspected pathogenic (deleterious alteration)
- •Submission of testing report is required. OR
- •BRCA 1/2 wildtype AND known HRD deficient tumor determined by any commercial or academic, Clinical Laboratory Improvement Act (CLIA)-certified laboratory (e.g., Myriad MyChoice©)
- •Submission of testing report is required
- •Patient must have undergone cytoreductive surgery (primary or interval)
- •Patients must have completed first line platinum-based therapy prior to registration:
- •Platinum based chemotherapy course must have consisted of a minimum of 4 treatment cycles and a maximum of 9, although it is strongly recommended that patients receive at least 6 cycles unless medically contraindicated
- •For those receiving less than 6 cycles of platinum-based therapy, the reason for this must be documented and could include hematologic toxicity or non-hematologic toxicities directly related to therapy
- •Intravenous, intraperitoneal, or neoadjuvant platinum-based chemotherapy is allowed; for weekly therapy, three weeks are considered one cycle
- •Patients must not have received an investigational agent during their first line course of chemotherapy
- •Patients must have, in the opinion of the investigator, no clinical evidence of disease progression following completion of this chemotherapy course (partial or complete response to platinum-based chemotherapy)
- •Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression and patients are neurologically stable off steroid therapy
- •Patients must be randomized at least 3 weeks and no more than 12 weeks after their last dose of chemotherapy (last dose is the day of the last infusion of platinum agent)
- •No previous treatment with a PARP inhibitor, including olaparib, niraparib, and rucaparib
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Not pregnant and not nursing
- •Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
- •Platelets ≥ 100,000 cells/mm^3
- •Hemoglobin ≥ 9 g/dl
- •Creatinine clearance (CrCL) of > 30 mL/min by the Cockcroft-Gault formula
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN
- •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- •No active infection requiring parental antibiotic(s)
- •No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or need for drainage nasogastric or gastrostomy tube
- •No current inability to swallow orally administered medication
- •No history of myelodysplastic syndrome and/or acute myeloid leukemia
- •No history of allogeneic bone marrow transplant
- •No concomitant use of strong or moderate CYP3A inducers
- •No known hypersensitivity to olaparib or any of the excipients of the product
排除标准
- 未提供
研究组 & 干预措施
Arm I (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Bevacizumab (Biological)
Arm I (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm I (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Computed Tomography (Procedure)
Arm I (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Olaparib (Drug)
Arm II (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm II (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Computed Tomography (Procedure)
Arm II (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Olaparib (Drug)
Arm II (olaparib, bevacizumab)
Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients may also receive bevacizumab IV on day 1 of each cycle. Cycles of bevacizumab repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT and/or MRI throughout the study.
干预措施: Bevacizumab (Biological)
结局指标
主要结局
Progression free survival (PFS) at least 360 days after randomization (PFS360)
时间窗: From completing 360 days of maintenance therapy to disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) or death, whichever occurs first, assessed up to 5 years
PFS will be tested using a one-sided, alpha = 0.05 level logrank test. Treatment hazard ratios and their 90% confidence intervals will be estimated using a Cox proportional hazards model specified with a main effect for the randomized treatment assignment and stratified using the stratification factors applied at randomization.
次要结局
- Overall survival (OS) 360(From 360 days after randomization to death from any cause, assessed up to 5 years)
- PFS(From randomization to progression or death, whichever occurs first, or date of the last computed tomography scan if neither progression nor death has occurred, assessed up to 5 years)
- PFS2(From randomization to objective tumor progression on next-line treatment or death, assessed up to 5 years)
- OS(From randomization to death, assessed up to 5 years)
- Incidence of adverse events (AEs)(Up to 30 days after last dose of study treatment)