A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal and Genitourinary Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 263
- 试验地点
- 65
- 主要终点
- Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, and efficacy of single agent ibrutinib or the combination treatments of ibrutinib with everolimus, paclitaxel, docetaxel, pembrolizumab or cetuximab in selected advance gastrointestinal and genitourinary tumors.
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
- •RCC (clear cell), urothelial carcinoma (UC) (transitional cell), gastric or gastro-esophageal junctional (GEJ) adenocarcinoma, or K-RAS or N-RAS wild-type EGFR expressing CRC For cohort 1 RCC: minimum of 1 and maximum of 4 prior regimens, one or more of which must have included a VEGF-TKI For UC cohort 2: minimum of 1 and maximum of 2 prior regimens, one of which must have included a platinum-based regimen For UC cohort 5: Minimum of 1 and maximum of 2 prior regimens, one of which must have included a checkpoint inhibitor.
- •For UC cohort 6:
- •Locally advanced or mUC who are not eligible for cisplatin chemo with a PDL-1 score (CPS) of ≥ 10 without prior treatment.
- •Locally advanced or mUC who have progressed on platinum chemo or within 12 months of neo- or adjuvant therapy with a platinum chemotherapy. A minimum of 1 and maximum of 2 prior therapies.
- •For cohort 3 gastric or GEJ adenocarcinoma: minimum of 1 and maximum of 3 prior regimens one of which must have included a fluoropyrimidine regimen For cohort 4 CRC: minimum of 2 and maximum of 4 prior regimens, which must have included both an irinotecan and an oxaliplatin based regimen unless unable to tolerate irinotecan chemotherapy
- •Laboratory:
- •Adequate hematologic function:
- •Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L) Platelet count >80,000 cells/mm3 (80 x 109/L) for cohort 1 (RCC) Platelet counts >100,000 cells/mm3 (100 x 109/L) for all UC cohorts Hemoglobin ≥8.0 g/dL. for cohort 1 (RCC),all UC cohorts, and cohort 3 (GC) Hemoglobin ≥9.0 g/dL for cohort 4 (CRC)
- •Adequate hepatic and renal function defined as:
- •Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, such as hemolysis) with the exception of subjects in the GC cohort where docetaxel is administered, these subjects must have bilirubin within normal limits (WNL) Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault)
- •Exclusion Criteria
- •Prior treatment with:
- •Everolimus or temsirolimus (RCC cohort 1) Any taxane (UC cohort of ibrutinib + paclitaxel) (cohort 2) Checkpoint inhibitors (UC cohort 6) Any taxane (GC cohort 3) Cetuximab or panitumumab (CRC cohort 4)
- •For all Cohorts:
- •Concomitant use of warfarin or other Vitamin K antagonists History of stroke or intracranial hemorrhage within 6 months prior to enrollment Major surgery within 4 weeks of first dose of study drug Requires treatment with strong CYP3A inhibitors known bleeding disorders or hemophilia
- •UC cohort 6 only:
- •Subjects who have an active, known or suspected autoimmune disease. Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
- •Non-steroid immunosuppressive medications within 14 days before the first dose of ibrutinib and pembrolizumab.
- •Subjects in whom prior anti PD-1 / anti-PD-L1 therapy was intolerable and required discontinuation of treatment.
排除标准
- 未提供
研究组 & 干预措施
Cohort 4: Colorectal Adenocarcinoma (CRC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of cetuximab to determine RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab.
干预措施: cetuximab (Drug)
Cohort 1: Renal Cell Carcinoma (RCC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of everolimus to determine the recommended phase 2 dose (RP2D) of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in phase 1b in combination with everolimus.
干预措施: ibrutinib (Drug)
Cohort 1: Renal Cell Carcinoma (RCC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of everolimus to determine the recommended phase 2 dose (RP2D) of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in phase 1b in combination with everolimus.
干预措施: everolimus (Drug)
Cohort 2: Urothelial Carcinoma (UC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of paclitaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with paclitaxel.
干预措施: ibrutinib (Drug)
Cohort 2: Urothelial Carcinoma (UC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of paclitaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with paclitaxel.
干预措施: paclitaxel (Drug)
Cohort 3: Gastric Adenocarcinoma (GA or GC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of docetaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel.
干预措施: ibrutinib (Drug)
Cohort 3: Gastric Adenocarcinoma (GA or GC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of docetaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel.
干预措施: docetaxel (Drug)
Cohort 4: Colorectal Adenocarcinoma (CRC)
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of cetuximab to determine RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab.
干预措施: ibrutinib (Drug)
Cohort 5: Urothelial Carcinoma (UC) Ibrutinib
Phase 1b: Participants receive ibrutinib at various dose levels to determine the RP2D of ibrutinib.(The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b.
干预措施: ibrutinib (Drug)
Cohort 6: Urothelial Carcinoma (UC) With Pembrolizumab
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of pembrolizumab to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab.
干预措施: ibrutinib (Drug)
Cohort 6: Urothelial Carcinoma (UC) With Pembrolizumab
Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of pembrolizumab to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)
Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab.
干预措施: pembrolizumab (Drug)
结局指标
主要结局
Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6
时间窗: 21 days after the initiation of therapy at the start of Cycle 1
A DLT was defined as any Grade 3 (severe) or higher non-hematologic or Grade 4 (life-threatening) hematologic adverse event (AE) occurring during the DLT observation period that was considered to be at least possibly related to the study treatment (ibrutinib or drug combination).
Phase 1b/2 RP2D: Progression-Free Survival (PFS) as Assessed by Investigator in Cohorts 1 and 2
时间窗: Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months.
PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease (PD) or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PD was defined in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
Phase 1b/2 RP2D: Overall Response Rate (ORR) as Assessed by Investigator in Cohorts 3 to 6
时间窗: Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.
ORR is defined as the percentage of participants who have a best response of partial response (PR) or complete response (CR) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (\< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
次要结局
- Phase 1b: ORR in Cohorts 1 to 6(Maximum time on study (Phase 1b only) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 34.2 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.)
- Phase 1b: Time to Cmax (Tmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Area Under the Concentration-Time Curve From Time 0 to Hour 24 (AUC0-24h) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Area Under the Concentration-Time Curve to Last Observed Time Point (AUClast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Disease Control Rate (DCR) in Cohorts 1 to 6(Maximum time on study (Phase 1b only) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 34.2 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months.)
- Phase 1b/2 RP2D: PFS in Cohorts 3 to 6(Maximum time on study (Phase 1b/2 RP2D) for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates))
- Phase 1b/2 RP2D: ORR in Cohorts 1 and 2(Maximum time on study for Cohort 1 (Phase 1b/2 RP2D) was 37.4 months; for Cohort 2 (Phase 1b/2 RP2D) was 44.7 months. (Reverse Kaplan-Meier estimates))
- Phase 1b/2 RP2D: Duration of Response (DOR) in Cohorts 1 to 6(Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates))
- Phase 1b/2 RP2D: DCR in Cohorts 1 to 6(Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates))
- Phase 1b/2 RP2D: Overall Survival (OS) in Cohorts 1 to 6(Maximum time on study (Phase 1b/2 RP2D) for Cohort 1 was 37.4 months; for Cohort 2 was 44.7 months; for Cohort 3 was 41.9 months; for Cohort 4 was 23.5 months; for Cohort 5 was 17.3 months; for Cohort 6 was 20.1 months. (Reverse Kaplan-Meier estimates))
- Phase 1b: Observed Maximum Concentration (Cmax) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Time of Last Observed Concentration (Tlast) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Terminal Elimination Rate Constant (λz) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Terminal Elimination Half-Life (t1/2term) for Ibrutinib and Its Metabolite PCI-45227 in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)
- Phase 1b: Apparent Total Clearance at Steady-State (CLss/F) for Ibrutinib in Cohorts 1 to 4(Cycle 2 Day 1: predose, 1 h ± 15 min, 2 h ± 15 min, 4 h ± 15 min, 6 h ± 15 min postdose)