A Phase 3 Placebo-Controlled Study of Carboplatin/Paclitaxel With or Without Concurrent and Continuation Maintenance Veliparib (PARP Inhibitor) in Subjects With Previously Untreated Stages III or IV High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 1,140
- 试验地点
- 210
- 主要终点
- Progression-Free Survival (PFS) in the BRCA-deficient Population (Arm 3 vs Arm 1)
研究概览
简要总结
The primary objective of the study was to evaluate whether progression-free survival (PFS) was prolonged with the addition of veliparib to standard platinum-based chemotherapy (carboplatin/paclitaxel [C/P]) and continued as maintenance therapy compared with chemotherapy alone.
详细描述
Participants were randomized in a 1:1:1 ratio to one of three arms. Randomization in the entire population was stratified according to the timing of surgery and residual disease status (any residual disease after primary surgery vs. no residual disease after primary surgery vs. interval surgery) and the paclitaxel schedule (weekly vs. every 3 -weeks), stage of disease (III vs. IV), geographic region (Japan vs. North America and rest of world [ROW]), and germline breast cancer susceptibility gene (BRCA) mutation status (positive versus negative or Unknown).
Cytoreductive surgery could be performed before randomization and the initiation of study treatment (primary) or after 3 cycles of study treatment (interval). The weekly or every-3-week paclitaxel schedule and the choice of primary or interval cytoreductive surgery were determined at the discretion of the investigator.
The primary objective was evaluated in the BRCA-deficient cohort, participants with homologous recombination deficiency (HRD), and the intention-to-treat (ITT) population. These populations were sequentially inclusive, with the HRD population including the BRCA-deficient population, and the ITT population including the HRD and BRCA-deficient populations. The BRCA-deficient population was defined as participants with either a germline (gBRCA) and/or tissue-based (tBRCA) deleterious or suspected deleterious mutation in BRCA1 or BRCA2 confirmed by centralized testing. The HRD population was defined as participants with HRD tumors based on HRD score or presence of a deleterious or suspected deleterious mutation in BRCA1 or BRCA2 as determined by centralized testing.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologic diagnosis of International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, with the appropriate tissue available for histologic evaluation.
- •High-grade serous adenocarcinoma
- •Willing to undergo testing for gBRCA.
- •Adequate hematologic, renal, and hepatic function.
- •Neuropathy (sensory and motor) less than or equal to Grade
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •Participants who undergo primary cytoreductive surgery must be entered between 1 and 12 weeks after surgery. Participants undergoing interval surgery must have a tumor sample confirming the histological diagnosis prior to enrollment.
- •Participants with measurable disease or non-measurable disease are eligible. Participants may or may not have cancer-related symptoms.
- •Participant has one of the following available for pharmacodynamic analyses including somatic BRCA testing: Archived diagnostic formalin-fixed paraffin embedded (FFPE) tumor tissue; or tumor tissue biopsy collected prior to Cycle 1 Day 1.
排除标准
- •Endometrioid adenocarcinoma, carcinosarcoma, undifferentiated carcinoma, mixed epithelial adenocarcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, clear cell adenocarcinoma, low-grade serous adenocarcinoma, or malignant Brenner's tumor.
- •Participants with synchronous primary endometrial cancer, or a past history of endometrial cancer unless all of the following conditions are met: endometrial cancer stage not greater than IA, no vascular or lymphatic invasion, no poorly differentiated subtypes including serous, clear cell, or other FIGO grade 3 lesions.
- •Participants with any evidence of other invasive malignancy being present within the last 3 years (with the exception of non-melanoma skin cancer). Participants are also excluded if their previous cancer treatment contraindicates this protocol's therapy.
- •Received prior radiotherapy to any portion of the abdominal cavity or pelvis.
- •Received prior chemotherapy for any abdominal or pelvic tumor.
- •Clinically significant uncontrolled condition(s).
- •Known history of allergic reaction to Cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine (also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C Yellow 6 or E110) or known contraindications to any study supplied drug.
- •History or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months of Cycle 1 Day 1.
研究组 & 干预措施
Placebo + Carboplatin + Paclitaxel -> Placebo
Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Carboplatin (Drug)
Placebo + Carboplatin + Paclitaxel -> Placebo
Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Paclitaxel (Drug)
Placebo + Carboplatin + Paclitaxel -> Placebo
Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Placebo to Veliparib (Other)
Veliparib + Carboplatin + Paclitaxel -> Placebo
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Veliparib (Drug)
Veliparib + Carboplatin + Paclitaxel -> Placebo
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Paclitaxel (Drug)
Veliparib + Carboplatin + Paclitaxel -> Placebo
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Carboplatin (Drug)
Veliparib + Carboplatin + Paclitaxel -> Placebo
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles.
干预措施: Placebo to Veliparib (Other)
Veliparib + Carboplatin + Paclitaxel -> Veliparib
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
干预措施: Veliparib (Drug)
Veliparib + Carboplatin + Paclitaxel -> Veliparib
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
干预措施: Paclitaxel (Drug)
Veliparib + Carboplatin + Paclitaxel -> Veliparib
Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
干预措施: Carboplatin (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) in the BRCA-deficient Population (Arm 3 vs Arm 1)
时间窗: From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.
PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death prior to the analysis cut-off date, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The analysis of PFS occurred when the protocol-specified number of PFS events was reached. Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
Progression-Free Survival (PFS) in the Homologous Recombination Deficiency Cohort (Arm 3 vs Arm 1)
时间窗: From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.
PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death if disease progression was not reached. If the participant did not have an event of disease progression or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached and was performed in 3 sequentially inclusive populations. Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions. .
Progression-Free Survival (PFS) in the Intention-to-treat Population (Arm 3 vs Arm 1)
时间窗: From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.
PFS was defined as the time from the date that the participant was randomized to the date the participant experienced an event of disease progression, according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 (as determined by the investigator) or to the date of death (all causes of mortality) if disease progression was not reached. If the participant did not have an event of disease progression according to RECIST criteria (as or death, the participant's data were censored at the date of their last evaluable disease assessment. PFS was estimated using the Kaplan-Meier method. Progressive Disease (PD): At least a 20% increase in the size of target lesions, compared with the smallest size recorded since the treatment started, and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions. The primary analysis of PFS occurred when the protocol-specified number of PFS events was reached.
次要结局
- Progression-Free Survival (PFS) in the BRCA-deficient Population (Arm 2 vs Arm 1)(From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.)
- Progression-Free Survival (PFS) in the Homologous Recombination Deficiency Cohort (Arm 2 vs Arm 1)(From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.)
- Progression-Free Survival (PFS) in the Intention-to-treat Population (Arm 2 vs Arm 1)(From randomization until the primary analysis data cut-off date of 03 May 2019, the median duration of follow-up was 28 months.)
- Overall Survival (OS) in the BRCA-deficient Population(From the time of randomization to the end of the study, up to 98 months)
- Overall Survival (OS) in the Homologous Recombination Deficiency Population(From the time of randomization to the end of the study, up to 98 months)
- Overall Survival (OS) in the Whole Population(From the time of randomization to the end of the study, up to 98 months)
- Change From Baseline in Disease Related Symptom (DRS) Score in the BRCA-mutation Population(Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35)
- Change From Baseline in Disease Related Symptom (DRS) Score in the HRD Population(Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35)
- Change From Baseline in Disease Related Symptom (DRS) Score in the Whole Population(Baseline and Day 1 of Cycles 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35)