A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 260
- 试验地点
- 36
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
The study will evaluate the clinical activity of PD-(L)1 Checkpoint Inhibitor regimens in combination with the investigational agent sitravatinib in patients with advanced or metastatic urothelial carcinoma.
详细描述
Sitravatinib is an orally-available, small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Nivolumab is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including anti-tumor immune response. Combining an immunotherapeutic PD-L1 checkpoint inhibitor with an agent that has both immune modulatory and antitumor properties could enhance the antitumor efficacy observed with either agent alone. Sitravatinib selectively inhibits key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance and therefore represents a rational strategy to enhance or restore anti-tumor immunity when combined with nivolumab, a checkpoint inhibitor therapy.
Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor and selectively blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. Enfortumab vedotin (enfortumab) is an investigational ADC that is comprised of a fully human anti-Nectin-4 IgG1 monoclonal antibody conjugated to MMAE via a protease-cleavable linker. Enfortumab binds to cells that express Nectin-4 with high affinity, triggering the internalization and release of MMAE in target cells, inducing cell cycle arrest and apoptotic cell death. Early efficacy results from enfortumab in combination with pembrolizumab in frontline cisplatin-ineligible urothelial carcinoma in the ongoing EV-103 study have demonstrated encouraging activity with a safety profile that appears manageable and tolerable. Addition of sitravatinib to this combination might further augment clinical activity by selectively inhibiting key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance.
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
- •Diagnosis of urothelial carcinoma
- •Adequate bone marrow and organ function
排除标准
- •Uncontrolled tumor in the brain
- •Unacceptable toxicity with prior checkpoint inhibitor
- •Impaired heart function
研究组 & 干预措施
Cohort 1
Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 1
Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 2
Patients previously treated with checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 2
Patients previously treated with checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 3
Patients previously treated with selected immunotherapies and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 3
Patients previously treated with selected immunotherapies and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 4
Patients previously treated with with selected immunotherapies, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 4
Patients previously treated with with selected immunotherapies, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 5
Patients previously treated with platinum-based chemotherapy, but never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 5
Patients previously treated with platinum-based chemotherapy, but never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 6
Patients ineligible for treatment with platinum-based chemotherapy and never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 6
Patients ineligible for treatment with platinum-based chemotherapy and never treated with checkpoint inhibitor. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 7
Patients previously treated with antibody-drug conjugate, checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 7
Patients previously treated with antibody-drug conjugate, checkpoint inhibitor and platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 8
Patients previously treated with antibody-drug conjugate and checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Sitravatinib (Drug)
Cohort 8
Patients previously treated with antibody-drug conjugate and checkpoint inhibitor, but ineligible for platinum-based chemotherapy. Nivolumab over 30 min IV infusion (240 mg IV every 2 weeks or 480 mg every 4 weeks) and sitravatinib 120 mg orally once per day continuously in 28-day cycles.
干预措施: Nivolumab (Drug)
Cohort 9
Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. There are 2 parts to this Cohort - a lead-in dose escalation portion and a dose expansion portion. In the dose escalation portion, treatment with up to 3 dose levels of sitravatinib in combination with up to 2 dose levels of pembrolizumab and enfortumab combination regimen to determine the recommended doses to be used in the combination treatment regimen and those doses will be further studied in the dose expansion portion. Pembrolizumab 200 mg over 30 min IV infusion every 3 weeks, sitravatinib orally once per day continuously in 21-day cycles (at 35 mg, 50 mg, 70 mg, or 100 mg) and enfortumab vedotin over 30 min IV infusion on Day 1 and Day 8 in 21-day cycles (at 1 mg/kg or 1.25 mg/kg).
干预措施: Sitravatinib (Drug)
Cohort 9
Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. There are 2 parts to this Cohort - a lead-in dose escalation portion and a dose expansion portion. In the dose escalation portion, treatment with up to 3 dose levels of sitravatinib in combination with up to 2 dose levels of pembrolizumab and enfortumab combination regimen to determine the recommended doses to be used in the combination treatment regimen and those doses will be further studied in the dose expansion portion. Pembrolizumab 200 mg over 30 min IV infusion every 3 weeks, sitravatinib orally once per day continuously in 21-day cycles (at 35 mg, 50 mg, 70 mg, or 100 mg) and enfortumab vedotin over 30 min IV infusion on Day 1 and Day 8 in 21-day cycles (at 1 mg/kg or 1.25 mg/kg).
干预措施: Pembrolizumab (Drug)
Cohort 9
Patients previously treated with checkpoint inhibitor and platinum-based chemotherapy. There are 2 parts to this Cohort - a lead-in dose escalation portion and a dose expansion portion. In the dose escalation portion, treatment with up to 3 dose levels of sitravatinib in combination with up to 2 dose levels of pembrolizumab and enfortumab combination regimen to determine the recommended doses to be used in the combination treatment regimen and those doses will be further studied in the dose expansion portion. Pembrolizumab 200 mg over 30 min IV infusion every 3 weeks, sitravatinib orally once per day continuously in 21-day cycles (at 35 mg, 50 mg, 70 mg, or 100 mg) and enfortumab vedotin over 30 min IV infusion on Day 1 and Day 8 in 21-day cycles (at 1 mg/kg or 1.25 mg/kg).
干预措施: Enfortumab vedotin (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to approximately 3 years
ORR was defined as the number of participants documented to have a confirmed investigator-assessed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions.
次要结局
- Number of Participants Who Experienced an Adverse Event (AE)(Day 1 up to approximately 3 years)
- Geometric Mean Blood Plasma Concentration of Sitravatinib(Cycle(C)1 Day(D)1 pre-dose, 30min, 2,4,6,7,8,24hr post-dose, C1D15 pre-dose, 30min,2,4,6,7,8,24hr post-dose, C2D1 pre-dose,7hr post-dose, C2D8,C3D1,C3D8,C5D1,C6D8 pre-dose (28 day cycles Cohorts 1-8, 21 day cycles Cohort 9))
- Duration of Response (DOR)(Up to approximately 3 years)
- Number of Participants Who Experienced a Serious Adverse Event (SAE)(Day 1 up to approximately 3 years)
- 1-Year Survival Rate(1 year)
- Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)(Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days))
- Number of Participants Who Experienced a Treatment-related Adverse Event(Day 1 up to approximately 3 years)
- Overall Survival (OS)(Up to approximately 3 years)
- Clinical Benefit Rate (CBR)(Up to approximately 3 years)
- Progression-Free Survival (PFS)(Up to approximately 3 years)