A PHASE 1B/2, OPEN-LABEL, DOSE-FINDING STUDY TO EVALUATE SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AVELUMAB (MSB0010718C) IN COMBINATION WITH EITHER CRIZOTINIB OR PF-06463922 IN PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 43
- 试验地点
- 20
- 主要终点
- Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b
研究概览
简要总结
The purpose of this study is to evaluate the safety and efficacy of avelumab when combined with either crizotinib or PF-06463922.
详细描述
This is a Phase 1b/2, open label, multi center, multiple dose, safety, pharmacokinetic and pharmacodynamic study of Group A and Group B in cohorts of adult patients with locally advanced or metastatic NSCLC.
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
- 未提供
排除标准
- •No prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody.
- •No Severe or Chronic medical conditions including gastrointestinal abnormalities or significant cardiac history
- •No active infection requiring systemic therapy
- •Prior organ transplantation including allogenic stem cell transplantation.
研究组 & 干预措施
Group A
ALK negative Non-Small Cell Lung Cancer
干预措施: Avelumab (Drug)
Group A
ALK negative Non-Small Cell Lung Cancer
干预措施: Crizotinib (Drug)
Group B
ALK positive Non-Small Cell Lung Cancer
干预措施: Avelumab (Drug)
Group B
ALK positive Non-Small Cell Lung Cancer
干预措施: PF-06463922 (Drug)
结局指标
主要结局
Number of Participants With Dose-limiting Toxicities (DLTs): Phase 1b
时间窗: First 2 cycles (1 cycle = 14 days)
Any of the following adverse events (AEs) occurring during the primary DLT observation period that are attributable to one, the other, or both study drugs were classified as DLTs: Grade 4 (life-threatening) neutropenia if \>7 days in duration; febrile neutropenia; Grade \>=3 (severe or life threatening) neutropenic infection; Grade \>=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia \>7 days; Grade 4 anemia; any Grade \>=3 toxicity, except for any of the following: transient (\<=6 hours) Grade 3 (severe) flu like symptoms or fever; transient (\<=24 hours) Grade 3 fatigue, local reactions, or headache that resolved to Grade \<=1 (no AE or mild AE); Grade 3 nausea and/or vomiting, diarrhea or skin toxicity that resolved to Grade \<=1 within 7 days; any Grade \>=3 amylase or lipase abnormality; tumor flare phenomenon; single laboratory values out of normal range that were not related to treatment, did not have any clinical correlate, and resolve to Grade \<=1 within 7 days.
Percentage of Participants With Objective Response (OR): Phase 2
时间窗: Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years)
OR is defined as complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 from start date (the date of first dose of study treatment) until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to \<10 mm and all lymph nodes must be non-pathological in size (\<10 mm short axis). PR is defined as a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Percentage of Participants With CR for Group B: Phase 2
时间窗: Baseline up to 60 months
Per RECIST v1.1: CR is defined as the disappearance of all target or non-target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to \<10 mm and all lymph nodes must be non-pathological in size (\<10 mm short axis).
次要结局
- Number of Participants With Baseline Laboratory Abnormalities Grade <=2 and Post-Baseline Laboratory Abnormalities of Grades 3 or 4 Per NCI CTCAE v4.03(Screening up to end of treatment/withdrawal (maximum of 5 years))
- Disease Control Rate (DCR)(Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years))
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(Baseline up to 30 days after last dose of study treatment or the day before start day of new anti-cancer therapy (maximum of 5 years))
- Number of Participants With Vital Signs Meeting Pre-defined Criteria(Screening up to end of treatment/withdrawal (maximum of 5 years))
- Progression-free Survival (PFS)(Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years))
- Apparent Plasma Clearance (CL/F) of Crizotinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Tmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Duration of Response (DR)(Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years))
- Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Multiple Doses of Avelumab(Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 2 Day 1)
- Time to Tumor Response (TTR)(Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years))
- Kaplan-Meier Estimates of Overall Survival (OS)(Screening, Day 1 of each cycle starting Cycle 3, up to end of treatment/withdrawal (maximum of 5 years))
- Maximum Plasma Concentration (Cmax) of Crizotinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Time to Cmax (Tmax) of Crizotinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Area Under The Plasma Concentration-Time Curve During The Dosing Interval Time Course (AUCtau) of Crizotinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Cmax of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- AUCtau of Crizotinib Metabolite PF-06260182 in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Metabolite to Parent Ratio for AUCtau (MRAUCtau) of PF-06260182 in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Metabolite to Parent Ratio for Cmax (MRCmax) of PF-06260182 in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6 and 8 hours post dose on Day 1 of Cycle 2)
- Cmax of Lorlatinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2)
- Tmax of Lorlatinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2)
- AUCtau of Lorlatinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2)
- Area Under The Plasma Concentration Time Curve From Time of Dosing to The Last Collection Time Point (AUClast) of Lorlatinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2)
- CL/F of Lorlatinib in The Presence of Avelumab(Pre-dose, 1, 2, 4, 6, 8, and 24 hours (prior to Day 2 lorlatinib dose) post dose on Day 1 of Cycle 2)
- Cmax of Avelumab in The Presence of Crizotinib (Group A) or Lorlatinib (Group B) After Single Dose of Avelumab(Pre-dose, 1, and 168 hours post dose of avelumab on Cycle 1 Day 1.)
- Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Crizotinib (Group A) Following Multiple Doses of Avelumab(Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, and 47.)
- Trough Serum Concentration (Ctrough) of Avelumab in The Presence of Lorlatinib (Group B) Following Multiple Doses of Avelumab(Pre-dose on Day 1 of Cycles 2-5, 11, 17, 23, 29, 35, 41, and 47.)
- Number of Participants With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status(Day 1 of Cycles 1-5, then every 12 weeks thereafter, end of treatment/withdrawal, and 30 days after last avelumab dose (up to a maximum of 5 years))
- Number of Participants With Positive Programmed Death Ligand-1 (PD-L1) Biomarker Expression(Baseline)
- Number of Participants With Positive Tumor Infiltrating CD8+ Lymphocytes(Baseline)