A Phase 1b/2, Multi-center, Uncontrolled, Open-label, Dose Escalation Study of Refametinib (BAY86-9766) in Combination With Regorafenib (BAY73-4506) in Patients With Advanced or Metastatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Bayer
- 入组人数
- 20
- 主要终点
- Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib
研究概览
简要总结
Phase I: Determine the maximum tolerated dose of combination of Regorafenib with Refametinib through a dose escalation study, all tumor types that meet certain inclusion/exclusion criteria can be entered.
After the recommended dose is determined, the Phase II portion of the study will evaluate tolerability and efficacy of the combination treatment in patients with breast cancer, lung cancer, or colorectal cancer, respectively.
详细描述
Number of treatment-emergent Adverse Events (AEs) will be reported in Adverse Events section.
Study was originally designed with both Phase I and Phase II part, but sponsor decided not to conduct Phase 2 part due to strategic portfolio re-prioritization.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Criteria for the Phase 1b:
- •Patients with locally advanced or metastatic solid tumors who have either relapsed following, or progressed through, standard therapy; have a current disease state for which there is no standard effective therapy; is not a candidate for, or is unwilling to undergo, standard therapy in cases where no curative option exists.
- •Cohort-specific criteria for Phase 2:
- •CRC (Colorectal cancer): Patients with metastatic CRC and known KRAS (Kirsten rat sarcoma viral oncogene homolog) status who are eligible for treatment with regorafenib in accordance with the approved labeling.
- •NSCLC (Non-small-cell lung cancer): Patients with NSCLC and known KRAS status after platinum based chemotherapy.
- •Breast cancer: Patients with Her-2 negative breast cancer after anthracycline and taxane based chemotherapy.
- •Baseline tumor tissue to conduct molecular and / or genetic studies should be available from all study patients enrolled in this study. (optional in Phase 1b)
- •Patients must have at least one uni-dimensional measurable lesion by CT or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST)version 1.
- •(applicable only in Phase 2)
- •Male or female patients ≥ 18 years of age (only female patients in breast cancer cohort of Phase 2).
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Life expectancy of at least 3 months
- •Adequate bone marrow, liver and renal function
- •Cardiac function within normal range
排除标准
- •Prior treatment with refametinib or regorafenib.
- •Metastatic brain or meningeal tumors
- •Uncontrolled hypertension despite optimal medical management
- •History of cardiac disease
- •Arterial or venous thrombotic or embolic events
- •Any hemorrhage or bleeding event
- •History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
- •Any condition that was unstable or which could jeopardize the safety of the patient and his/her compliance in the study.
- •Excluded previous therapies and medications:
- •Radiotherapy within 3 weeks prior to start of treatment
- •Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 28 days or 5 drug half-lives (if drug half-life in patients is known), whichever is shorter (or within 6 weeks for mitomycin C) before start of the study treatment
研究组 & 干预措施
Ph1b-Refametinib/Regorafenib Cohort 0
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.
干预措施: Refametinib (BAY86-9766) (Drug)
Ph1b-Refametinib/Regorafenib Cohort 0
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort 0: Refametinib 30mg twice daily (b.i.d) + Regorafenib 80mg once daily (q.d), 3 weeks on/1 week off.
干预措施: Regorafenib (Stivarga, BAY73-4506) (Drug)
Ph1b-Refametinib/Regorafenib Cohort -1
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.
干预措施: Refametinib (BAY86-9766) (Drug)
Ph1b-Refametinib/Regorafenib Cohort -1
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1: Refametinib 20mg b.i.d + Regorafenib 80mg q.d, 3 weeks on/1 week off.
干预措施: Regorafenib (Stivarga, BAY73-4506) (Drug)
Ph1b-Refametinib/Regorafenib Cohort -1a
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
干预措施: Refametinib (BAY86-9766) (Drug)
Ph1b-Refametinib/Regorafenib Cohort -1a
Phase 1b part of study: Participants received different doses of Refametinib and Regorafenib combination therapy to determine recommended Phase 2 dose (RP2D) via dose-escalation. Cohort -1a: Refametinib 20mg b.i.d + Regorafenib 120mg q.d, 3 weeks on/1 week off.
干预措施: Regorafenib (Stivarga, BAY73-4506) (Drug)
结局指标
主要结局
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Maximum drug concentration in plasma after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Refametinib Metabolite M-11
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Maximum drug concentration in plasma after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Plasma Concentration-time Curve From 0 to 12 h After Multiple Dose (AUC(0-12)md) for Refametinib Metabolite M-11
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose
Area under the plasma concentration-time curve from 0 to 12 h after multiple dose for Refametinib metabolite M-11. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Maximum drug concentration in plasma after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-2
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Drug Concentration in Plasma After Multiple Dose (Cmax,md) for Regorafenib Metabolite M-5
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Maximum drug concentration in plasma after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: At Cycle 1
Dose-limiting toxicities (DLTs) were analyzed in the maximum tolerated dose (MTD) analysis set, in which only the six first patients of each dose escalation Cohort could be included according to the modified Rolling-6 method that was applied in this study.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-2
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-2. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Plasma Concentration-time Curve From 0 to 24 h After Multiple Dose (AUC(0-24)md) for Regorafenib Metabolite M-5
时间窗: Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
Area under the plasma concentration-time curve from 0 to 24 h after multiple dose for Regorafenib metabolite M-5. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Tumor Response During Phase 2 as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
时间窗: Up to 12 months
Tumor Response was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
次要结局
- Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Refametinib and Its Metabolite M-11(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose)
- Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Refametinib and Its Metabolite M-11(Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 12 hours post-dose)
- Maximum Drug Concentration in Plasma After Single (First) Dose (Cmax) for Regorafenib and Its Metabolites M-2 and M-5(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose)
- Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Regorafenib and Its Metabolites M-2 and M-5(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose)
- Area Under the Plasma Concentration-time Curve From 0 to 24 h (AUC(0-24)) After Single (First) Dose for Regorafenib and Its Metabolites M-2 and M-5(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4, 8 and 24 hours post-dose)
- Tumor Response During Phase 1b as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(From start of treatment until progression is documented)
- Area Under the Plasma Concentration-time Curve From 0 to 8 h (AUC(0-8)) After Single (First) Dose for Refametinib and Its Metabolite M-11(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose)
- Overall Survival During Phase 2(Up to 12 months after last patient first visit)
- Time to Progression During Phase 2(From start of treatment until progression is documented)
- Progression-free Survival During Phase 2(From start of treatment until progression is documented)
- Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose (Tmax) for Refametinib and Its Metabolite M-11(Cycle 1 Day 1 at 0 (pre-dose), 0.5, 1, 2, 4 and 8 hours post-dose)
- Time to Reach Maximum Drug Concentration in Plasma After Multiple Dose (Tmax,md) for Regorafenib and Its Metabolites M-2 and M-5(Cycle 1 Day 21 at 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose)