A Phase 1/2 Clinical Trial to Study the Safety and Tolerability of MK-3475 + Pegylated Interferon Alfa-2b (PEG-IFN) and MK-3475 + Ipilimumab (IPI) in Subjects With Advanced Melanoma (MEL) and Renal Cell Carcinoma (RCC) (KEYNOTE 029)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 295
- 主要终点
- Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A)
研究概览
简要总结
This study is being done to analyze the safety, tolerability, and efficacy of treatment for advanced melanoma (MEL) and renal cell carcinoma (RCC) using combination regimens of pembrolizumab + pegylated interferon alfa-2b (PegIFN-2b) and pembrolizumab + ipilimumab (IPI). The primary hypothesis is that these combinations will be sufficiently well-tolerated to permit continued clinical investigation.
详细描述
The trial is being done in three parts: Part 1A (MEL and RCC) will define the maximum tolerated dose (MTD)/maximum administered dose (MAD) for the drug combinations; a recommended Phase 2 dose (RP2D) for each combination will be identified. Part 1B (MEL-single arm expansion) will better characterize safety and efficacy and provide preliminary efficacy data for the pembrolizumab + IPI combination in participants with MEL. Part 1C (MEL) is added as the third part of the study with Amendment 3. Part 1C will evaluate safety and efficacy for different doses and dosing intervals for IPI in combination with pembrolizumab in participants with advanced MEL.
In the pembrolizumab + IPI study arms, qualified participants who receive the first course but experience disease progression after discontinuing pembrolizumab with stable disease or better, may, at the investigator's discretion, initiate a second course of pembrolizumab at the same dose and schedule for up to 17 doses (up to ~1 additional year) + IPI at the same dose and schedule for up to 4 doses (up to ~12 additional weeks). In the pembrolizumab + PEG-IFN study arms, qualified participants who receive the first course but experience disease progression after discontinuing pembrolizumab with stable disease or better may, at the investigator's discretion, initiate a second course of pembrolizumab at the same dose and schedule for up to 17 doses (up to ~1 additional year). Per protocol, response or progression during the second course will not count towards efficacy outcome measure and adverse events during the second course will not count towards safety outcome measures.
Part 2 (MEL and RCC) is a randomized portion of the trial and will evaluate preliminary efficacy of the drug combinations for advanced MEL participants. Part 2 was removed from the study with Amendment 3 of the protocol.
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
- •Histologically- or cytologically-confirmed diagnosis of advanced/unresectable or metastatic MEL or RCC (Part 1A only) with predominantly clear cell elements
- •Previously untreated stage III/IV advanced or metastatic MEL (Part 1C only)
- •MEL subjects may be treatment naïve or may have received prior lines of therapy for metastatic disease (Parts 1A and 1B)
- •RCC subjects must have received ≥1 prior line of therapy for metastatic disease (Part 1A)
- •Measurable disease as defined by RECIST 1.1
- •Must provide a tumor sample (archival or newly obtained biopsy) that is adequate for determination of PD (programmed cell death)-Ligand 1 status by immunohistochemistry at a central pathology laboratory prior to enrollment. Note: Adequacy of the tumor sample for PD-Ligand 1 testing is not required prior to enrollment in Part 1C
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Adequate organ function
- •Resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (Parts 1A and 1B) and/or recovered from major surgery or radiation therapy
- •Female participants of childbearing potential must be willing to use adequate contraception during the course of the study through 120 days after the last dose of study drug
- •Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study drug
- •Exclusion Criteria
- •Uveal or ocular MEL
- •Prior therapy with an anti-programmed cell death (anti-PD)-1, anti-PD-Ligand 1, anti-PD-Ligand 2 or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in a pembrolizumab clinical trial. Note: In Part 1C, participants may have received anti-PD-1 and/or anti-Cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) as part of their neo/adjuvant treatment.
- •Has received prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before first dose of trial drug or not recovered (≤ Grade 1 or at baseline) from AEs due to previously administered agents (Parts 1A and 1B)
- •Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- •Known additional malignancy that is progressing or requires active treatment with the exception of early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer or in situ breast cancer that has undergone potentially curative therapy
- •Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Severe hypersensitivity to any pembrolizumab excipients
- •Active autoimmune disease requiring systemic treatment in the past 2 years
- •History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- •Active infection requiring systemic therapy
- •Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial from screening through 120 days after the last dose of study drug
- •Prior therapy with interferon alfa (in neoadjuvant, adjuvant, or metastatic settings) (Part 1A only)
- •Uncontrolled thyroid dysfunction
- •Uncontrolled diabetes mellitus.
- •Known history of human immunodeficiency virus (HIV)
- •Known history of or is positive for Hepatitis B or Hepatitis C
- •Received a live vaccine within 30 days prior to first dose of study drug
排除标准
- 未提供
结局指标
主要结局
Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A)
时间窗: Up to ~6 Weeks
Participants in Part 1A were analyzed for DLTs. DLTs included all adverse experiences that were clearly not related to disease progression or intercurrent illness if judged by the investigator to be possibly, probably, or definitely related to study intervention. Reported adverse experiences used the Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.0. DLTs were analyzed and reported separately for protocol specified clinical indications of metastatic melanoma (MEL) and renal cell carcinoma (RCC) in Part 1A: Part 1A Pembrolizumab + IPI 1mg/kg (MEL), Part 1A Pembrolizumab + IPI 1 mg/kg (RCC), Part 1A Pembrolizumab + PEG-IFN 1 µg/kg (MEL), Part 1A Pembrolizumab + PEG-IFN 1 µg/kg (RCC), Part 1A Pembrolizumab + PEG-IFN 2 µg/kg (RCC). Per protocol, DLT outcome analysis did not include Parts 1B and 1C.
Percentage of Participants Experiencing Adverse Events (AEs)
时间窗: Up to ~84 months
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Reported adverse experiences used the Common Terminology for Adverse Events (CTCAE) Version 4.0.The number of participants who experienced at least one AE was reported.
Percentage of Participants Discontinuing Study Drug Due to AEs
时间窗: Up to ~24 months
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Reported adverse experiences used the CTCAE Version 4.0. The percentage of participants who discontinued study treatment due to an AE was reported.
Percentage of Participants Experiencing Adverse Events of Special Interest (AEOSIs) (Parts 1B and 1C)
时间窗: Up to ~84 months
AEOSIs consist of immune-mediated events, infusion reactions and depression. Events include Pneumonitis, Colitis, Hepatitis, Nephritis, Adrenal Insufficiency, Hypophysitis, Hyperthyroidism, Hypothyroidism, Thyroiditis, Type 1 Diabetes Mellitus, Skin Disorders, Uveitis, Pancreatitis, Myositis, Guillain-Barre Syndrome, Myocarditis, Encephalitis, Sarcoidosis, Infusion Reactions, Myasthenic Syndrome, Myelitis, Vasculitis, and Cholangitis Sclerosing. Per protocol Part 1B and Part 1C are reported. Part 1A was not included in the AEOIs outcome analysis, per protocol.
Progression-free Survival (PFS) (Part 2)
时间窗: Up to ~84 months
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was to be assessed by independent central review per RECIST 1.1. Part 2 of the study was not conducted, based on protocol specified criteria and this Part 2 specific outcome measure could not be reported.
Percentage of Participants Experiencing Grade 3-5 Drug-related AEs (Part 1C)
时间窗: Up to ~84 months
Participants in Part 1C who experienced grade 3-5 drug-related AEs (DRAEs) using CTCAE Version 4.0 are presented. Grade 3-5 DRAEs for Parts 1A and 1B was a secondary outcome analysis, per protocol and reported later in the record.
Objective Response Rate (ORR) (Part 1C)
时间窗: Up to ~84 months
ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percentage of participants who experienced a CR or PR is presented. Per protocol, ORR in Part 1C was planned and conducted as a pre-specified primary outcome analysis. ORR in Part 1B was planned and conducted as a protocol-specified secondary outcome analysis and has been reported later in the record. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol.
次要结局
- Objective Response Rate (ORR) (Part 1B)(Up to ~84 months)
- ORR by Programmed-death Receptor-ligand 1 (PD-L1) Status Using RECIST 1.1 (Parts 1B and 1C)(Up to ~84 months)
- Percentage of Participants With an Ordinal Response, Estimated by a Best Overall Response of VGPR or MPR (Parts 1B and 1C)(Up to ~84 months)
- Duration of Response (DOR) (Parts 1B and 1C)(Up to ~84 months)
- Progression-free Survival (PFS) (Parts 1B and 1C)(Up to ~84 months)
- Overall Survival (OS) (Parts 1B and 1C)(Up to ~84 months)
- PFS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C)(Up to ~84 months)
- OS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C)(Up to ~84 months)
- Percentage of Participants Experiencing Grade 3-5 DRAEs (Parts 1A and 1B)(Up to ~84 months)
- ORR (Part 2)(Up to ~84 months)