Phase I Study of Single Agent Pembrolizumab (MK-3475) in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (KEYNOTE 001)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 1,260
- 主要终点
- Number of Participants Who Experienced an Adverse Event (AE)
研究概览
简要总结
The present study has 5 parts. In Parts A and A1, the dose of intravenous (IV) pembrolizumab (MK-3475) will be escalated from 1 to 10 mg/kg to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for participants with a histologically- or cytologically-confirmed diagnosis of any type of carcinoma or melanoma (MEL) by evaluating the Dose Limiting Toxicities (DLTs). Following completion of the dose escalation, additional patients will be enrolled in Part A2 to further define pharmacokinetic characteristics. Part B of the study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL and compare every 2 week dosing (Q2W) to every 3 week dosing (Q3W). Part C of the study will investigate the safety, tolerability, and efficacy of pembrolizumab administered at 10 mg/kg Q3W in participants with non-small cell lung carcinoma (NSCLC) that is locally advanced or metastatic. Part D of the study will investigate the low and high doses of study drug identified in Parts A and B (2 mg/kg and 10 mg/kg) administered Q3W in participants with advanced or metastatic MEL. Part E (closed with Amendment 7) was planned to investigate low, medium, and high doses of pembrolizumab in combination with standard chemotherapy in participants with locally advanced or metastatic NSCLC. Part F will investigate low and high doses of pembrolizumab (2 mg/kg and 10 mg/kg) administered Q2W or Q3W in treatment-naive and previously-treated participants with NSCLC with programmed cell death 1 ligand (PD-L1) gene expression. The primary hypotheses are the following: that pembrolizumab will have acceptable safety and tolerability; that pembrolizumab will show a clinically meaningful response rate (RR) or disease-control rate (DCR) in participants with melanoma (ipilimumab-refractory or not) and NSCLC, and that pembrolizumab will show a more clinically meaningful RR in participants with either cancer whose tumors express PD-L1.
详细描述
Per protocol, all participants who were receiving study intervention or in survival follow-up could enroll in the extension study, KEYNOTE-587 (NCT03486873), which would allow further study participation after the Primary Completion Date cut-off. Thus, all efficacy outcome measures except for survival (Overall Survival [OS]) were to be followed up to the Interim Database cut-off of 18-Sept-2018, and the primary safety analyses (except for the DLT analysis) and Overall Survival were to be followed up to the study Primary Completion Date (Final Database cut-off of 05-Nov-2018).
Five participants did not have end of study assessments completed by the Primary Completion Date cut-off and were subsequently followed up to the Study Completion Date (11-Dec-2018). End of treatment and end of study assessments are missing for these 5 and the status was noted as unknown as of the Primary Completion Date cut-off. Per protocol, any safety information after the Primary Completion Date cut-off (Final Database cut-off of 05-Nov-2018) would not be included in the safety analysis but reported by the Investigator to the Sponsor via the Sponsor Communication Form and filed in the electronic Trial Master File.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- 未提供
结局指标
主要结局
Number of Participants Who Experienced an Adverse Event (AE)
时间窗: Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for each arm.
Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D)
时间窗: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRO was reported as the ORR for each melanoma dose arm (Parts B plus D).
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1)
时间窗: Up to 28 days in Cycle 1
DLTs were assessed according to NCI-CTCAE v.4.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥14 days; Gr 3 nonhematologic toxicity lasting \>3 days despite optimal supportive care; any Grade 3 non-hematologic laboratory value if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for \>1 week; Gr 3 or 4 febrile neutropenia; thrombocytopenia \<25,000 cells/mm\^3 (if associated with a bleeding event requiring an elective platelet transfusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to an Intensive Care Unit); or Gr 5 toxicity. The number of participants in Part A and Part A1 with a DLT were reported by pembrolizumab dose received.
ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F)
时间窗: Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
ORR was defined as the percentage of participants in the analysis population who had a confirmed CR (disappearance of all lesions) or PR (at least a 30% decrease in the sum of diameters \[SOD\] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRC was reported as the ORR for each NSCLC dose arm (Parts C plus F).
次要结局
- Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)(From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months))
- Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)(From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months))
- PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)(From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months))
- ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)(Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1)(Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2)(Cycle 1: Day 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours; Day 5, Day 8: pre- and post-dose; Day 15 (Cycle = 21 days))
- Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2)(Cycle 1: Day 21; Cycle 2: Day 1: Pre-dose, post-dose at 0.5 and 24 hours, Day 3, Day 8, Day 15 (Cycle = 21 days))
- Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F)(Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015))
- Overall Survival (OS) in Melanoma Participants (Parts B Plus D)(Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018))
- Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2)(Parts A and A1: pre-dose at Cycles 2, 4, 6, 8, 10, 12, 14 (cycle=14 days); A2 Cohorts: pre-dose at Cycles 2, 3, 5, 7, 9, 11 (cycle=21 days))
- Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F)(Part C: pre-dose at Cycles 2,5,9,13,17,21 (cycle=21 days); Part F treated every 3 weeks: pre-dose at Cycles 2,3,6,8,12,14,16,24,32 (cycle=21 days); Part F treated every 2 weeks: pre-dose at Cycles 2,3,6,7,8,9,12,16,18,24,32,36,40,48 (cycle=14 days))
- DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1)(Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days))
- Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)(Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days))
- Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D)(Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015))
- DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)(From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months))
- PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)(Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015))
- OS in NSCLC Participants (Parts C Plus F)(Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018))
- Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)(Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days))
- Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D)(Part B arms treated every 3 weeks: pre-dose at Cycles 2,5,9,13,17,25,33 (cycle=21 days); Part B treated every 2 weeks: pre-dose at Cycles 2,3,7,13,19,25,31,37 (cycle=14 days); Part D: pre-dose at Cycles 2,3,6,8,12,16,24,32 (cycle=21 days))