A PHASE 1B, OPEN LABEL, DOSE FINDING STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH PEMBROLIZUMAB (MK-3475) IN PATIENTS WITH ADVANCED RENAL CELL CANCER
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 52
- 试验地点
- 19
- 主要终点
- Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase
研究概览
简要总结
Despite substantial improvements of patients outcome in advanced RCC, durable and complete response is uncommon. The majority of patients eventually develop resistance and exhibit disease progression. Combining a PD-1 inhibitor, which has shown single-agent efficacy with axitinib may provide additional clinical benefit compared to axitinib alone.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Histologically or cytologically confirmed advanced RCC with predominantly clear-cell subtype with primary tumor resected
- •At least one measureable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.
- •Eastern Cooperative Oncology Group performance status 0 or 1
- •Controlled hypertension
排除标准
- •Prior treatment with systemic therapy for advanced RCC
- •Prior adjuvant or neoadjuvant therapy if disease progression or relapse has occurred during or within 12 months after the last dose of treatment
- •Prior treatment with any agent specifically targeting T-cell co-stimulation or checkpoint pathways
- •Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis
- •Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of randomization except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low grade prostate cancer with no plans for treatment intervention
- •In past 12 months: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
- •In past 6 months: deep vein thrombosis or pulmonary embolism
研究组 & 干预措施
Dose finding phase and dose expansion phase
To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose
干预措施: Axitinib (Drug)
Dose finding phase and dose expansion phase
To test the maximum tolerated dose of MK-3475 at 2 mg/kg every three weeks intravenous infusion in combination with approved axitinib dose
干预措施: MK-3475 (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicities (DLT): Dose Finding Phase
时间窗: Cycle 1 Day 1 to Cycle 2 Day 21 (up to 42 days)
DLT was defined as any of the following adverse events (AEs) occurring in the first two cycles of treatment which were attributable to one or both the study drugs: 1) Grade 4 neutropenia, 2) Febrile neutropenia lasting greater than (\>) 1 hour, 3) Grade greater than or equal to (\>=) 3 neutropenia with infection, 4) Grade \>=3 thrombocytopenia with bleeding, 4) Grade 4 thrombocytopenia, 5) Any grade \>=3 non-hematologic: non-laboratory toxicities despite maximum supportive therapy or hypertension despite maximal medical therapy, 6) Grade \>=3 non-hematologic toxicities resulted in hospitalisation or medical intervention 7) Inability to complete at least 75 percent (%) of axitinib dosing or 2 infusions of pembrolizumab within the DLT observation period (up to 42 days) due to treatment related toxicity. Severity of AEs was graded according to NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
次要结局
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC 0-12) of Axitinib(Dose Finding Phase:Pre-dose, 1, 2, 3, 4,6,8, 12 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1,2,3,4,6,8,12 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1)
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline up to 28 days after last dose of study drug (approximately up to 1552 days))
- Number of Participants With Laboratory Test Abnormalities: Urinalysis(Baseline up to a maximum of 1083 days)
- Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline up to 28 days after last dose of study drug (approximately up to 1552 days))
- Number of Participants With Adverse Events (AEs) According to Severity of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03(Baseline up to 28 days after last dose of study drug (approximately up to 1552 days))
- Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Hematology(Baseline up to a maximum of 1083 days)
- Number of Participants With Clinically Significant Change From Baseline in Vital Signs(Baseline up to a maximum of 1083 days)
- Number of Participants With Eastern Cooperative Oncology Group [ECOG] Performance Status Score(Baseline up to Cycle 43 (up to 1083 days))
- Objective Response Rate(Baseline until disease progression or death due to any cause, up to a maximum of 1083 days)
- Number of Participants With Programmed Death-Ligand 1 (PD-L1) Tumor Proportion Score(Baseline up to Cycle 43 (up to 1083 days))
- Number of Participants With Vascular Endothelial Growth Factor A (VEGF-A) Tumor Proportion Score(Baseline up to Cycle 64 (up to 1344 days))
- Concentration of Vascular Endothelial Growth Factor A (VEGF-A) in Serum(Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days))
- Concentration of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in Serum(Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days))
- Duration of Response (DR)(Baseline until disease progression or death due to any cause, up to a maximum of 1083 days)
- Time to Response (TTR)(Baseline until disease progression or death due to any cause, up to a maximum of 1083 days)
- Progression-Free Survival (PFS)(Baseline until disease progression or death due to any cause, up to a maximum of 1083 days)
- Overall Survival (OS)(Baseline until disease progression or death due to any cause, up to a maximum of 1552 days)
- Maximum Observed Plasma Concentration (Cmax) of Axitinib(Dose Finding Phase:Pre-dose,1,2,3,4,6,8 hours (hrs) post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1;Dose Expansion Phase:Pre dose,1,2,3,4,6,8 hrs post dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib(Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1)
- Apparent Oral Clearance (CL/F) of Axitinib(Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1)
- Apparent Volume of Distribution (Vz/F) of Axitinib(Dose Finding Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1; Dose Expansion Phase:Pre-dose, 1, 2, 3, 4, 6, 8 hrs post-dose on Day 7 of Lead-in (7 days prior Cycle 1 Day 1), Cycle 7 Day 1)
- Number of Participants With Positive Anti-Drug Antibodies (ADA) of Pembrolizumab (MK-3475)(Day 1 of Cycle 1 up to Day 21 of Cycle 56 (up to 1176 days))
- Concentration of Interleukin 8 (IL-8) in Serum(Baseline, Day 1 of Cycle 2 Pre-dose, Post end of treatment or Withdrawal whichever came first (maximum of 1344 days))