A Phase I/II, Open-Label, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Oral Rucaparib in Patients With gBRCA Mutation Ovarian Cancer or Other Solid Tumor
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 136
- 试验地点
- 15
- 主要终点
- Overall Response Rate Per RECIST Version 1.1 (Part 2)
研究概览
简要总结
Part 1 (Completed Enrollment) - The purpose of the first part of the study was to evaluate the safety of different doses and dosing regimens of oral rucaparib administered daily to patients with solid tumors.
Part 2A (Completed Enrollment) and Part 2B (Completed Enrollment) - The purpose of the second part of the study is to determine the safety and clinical activity of the RP2D of oral rucaparib administered daily to patients with a known deleterious BRCA mutation (germline or somatic).
Part 3 (Completed Enrollment) - The purpose of the third part of the study is to further evaluate PK of higher dose strength tablets at the RP2D in patients with any advanced solid tumor, inclusive of lymphoma, with evidence of a BRCA mutation (germline or somatic).
详细描述
Rucaparib (CO-338; formerly known as PF 01367338 and AG 14699) is an orally available, small molecule inhibitor of poly-adenosine diphosphate [ADP] ribose polymerase (PARP) being developed for treatment of ovarian cancer associated with homologous recombination [HR] DNA repair deficiency (HRD). The safety and efficacy of rucaparib has been evaluated in several Phase 1 and Phase 2 studies.
An oral formulation is the focus of current development efforts. Rucaparib is currently being investigated as monotherapy in patients with cancer associated with BRCA1 or BRCA2 mutations. For this study, it is anticipated that rucaparib will promote cell death in the BRCA-deficient tumor cells of ovarian cancer patients with evidence of a germline mutation, thereby limiting tumor progression and providing therapeutic benefit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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
- •Have a known deleterious BRCA mutation (gBRCA or sBRCA) (as determined by a local laboratory that has received an international or country-specific, quality standards certification)
- •Have evidence of measurable disease as defined by RECIST Version 1.1
- •Have sufficient archival FFPE tumor tissue available for planned analyses. Archival tissue from the most recently collected biopsy or debulking surgery should be provided, if available.
- •Have a histologically confirmed diagnosis of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer
- •Have received at least three prior chemotherapy regimens and have relapsed disease confirmed by radiologic assessment
排除标准
- •Active second malignancy, i.e., patient known to have potentially fatal cancer present for which she may be (but not necessarily) currently receiving treatment
- •a. Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed >6 months prior and/or bone marrow transplant (BMT) >2 years prior to first dose of rucaparib
- •Prior treatment with any PARP inhibitor.
- •Untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases are eligible provided they have been clinically stable for at least 4 weeks.
- •Received treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs 14 days prior to first dose of rucaparib and/or ongoing adverse effects from such treatment > NCI CTCAE Grade 1 (Grade 2 non-hematologic toxicity to most recent treatment may be permitted with prior advanced approval from Sponsor).
- •Hospitalization for bowel obstruction within 3 months prior to enrollment.
研究组 & 干预措施
Part 1 (Phase 1)
Rucaparib 40, 80, 160, 300, 500 mg QD and 240, 360, 480, 600, 840 mg BID, for continuous 21-day cycles. Patients in Part 1 were initially treated in a Dose-escalation Evaluation Period (Cycle 1) and could then continue to receive treatment in an optional Treatment-extension Period (Cycle 2 and beyond).
干预措施: Rucaparib (Drug)
Part 2A (Phase 2)
Rucaparib 600 mg BID for 21-day cycles.
干预措施: Rucaparib (Drug)
Part 2B (Phase 2)
Rucaparib 600 mg BID for 21-day cycles.
干预措施: Rucaparib (Drug)
Part 3 (Phase 2)
Rucaparib 600 mg BID for 21-day cycles. Patients also received a single administration of 600 mg rucaparib on both Day -7 and Day 1 for assessing the effect of food on PK.
干预措施: Rucaparib (Drug)
结局指标
主要结局
Overall Response Rate Per RECIST Version 1.1 (Part 2)
时间窗: Time from first dose to date of progression, up to approximately 8 months
The confirmed response rate by RECIST v1.1 is defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR) on subsequent tumor assessment at least 28 days after first response documentation.
Number of Participants With a Dose Limiting Toxicity (DLT)
时间窗: Cycle 1 Day 1 to Cycle 1 Day 21
The number of Part 1 (Phase 1) patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
PK Profile of Rucaparib - Tmax (Part 1)
时间窗: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
Tmax = time to maximum concentration following administration of rucaparib
PK Profile of Rucaparib - Cmax (Part 1)
时间窗: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
Cmax = maximum concentration following administration of rucaparib
PK Profile of Rucaparib - AUC Last (Part 1)
时间窗: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days
AUC last = Area under the plasma concentration-time curve from time 0 to the last recorded observation
次要结局
- Progression-free Survival (PFS) According to RECIST v1.1, as Assessed by the Investigator (Part 2)(Cycle 1 Day 1 to End of Treatment, up to approximately 51 months)
- Duration of Response Per RECIST Version 1.1 (Part 2)(Cycle 1 Day 1 to End of Treatment, up to approximately 48 months)
- Food Effect on PK of Rucaparib - Cmax (Part 1 and Part 3)(Day -7 to Cycle 1 Day 1, or approximately 7 days)
- Food Effect on PK of Rucaparib - Tmax (Part 1 and Part 3)(Day -7 to Cycle 1 Day 1, or approximately 7 days)
- Food Effect on PK of Rucaparib - AUC Last (Part 1 and Part 3)(Day -7 to Cycle 1 Day 1, or approximately 7 days)
- QTcF Value Change From Baseline (Part 1)(Screening to End of Treatment, up to approximately 15 months)
- Overall Survival (Part 2B)(Cycle 1 Day 1 to date of death, assessed up to 38 months)