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)
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Renal Cell Carcinoma
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 295
- Primary Endpoint
- Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- Not provided
Outcomes
Primary Outcomes
Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A)
Time Frame: 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)
Time Frame: 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
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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.
Secondary Outcomes
- 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)