Safety and Tolerability of Pembrolizumab (MK-3475) + Pegylated Interferon Alfa-2b and Pembrolizumab+ Ipilimumab in Participants With Advanced Melanoma or Renal Cell Carcinoma (MK-3475-029/KEYNOTE-29)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Renal Cell Carcinoma, Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: PegIFN-2b
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + PegIFN-2b<br>Participants in Part 1A receive pembrolizumab intravenously (IV) 200 mg every three weeks (Q3W) + PEG-IFN at assigned dose subcutaneously (SC) once a week for up to  2 years. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Biological: PegIFN-2b<br>* Subcutaneous infusion<br>* Other names: Sylatron®;|
| Experimental: Pembrolizumab + IPI Q3W<br>Participants in Parts 1A and 1B receive pembrolizumab IV 200 mg Q3W for up to  2 years + IPI IV 1 mg/kg Q3W for up to  12 weeks. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Biological: Ipilimumab<br>* IV infusion<br>* Other names: Yervoy®;|
| Experimental: Pembrolizumab + IPI Q6W<br>Participants in Part 1C receive pembrolizumab IV 200 mg Q3W for up to  2 years + IPI IV 50 mg every 6 weeks (Q6W) for up to  24 weeks. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Biological: Ipilimumab<br>* IV infusion<br>* Other names: Yervoy®;|
| Experimental: Pembrolizumab + IPI Q12W<br>Participants in Part 1C receive pembrolizumab IV 200 mg Q3W for up to  2 years + IPI IV 100 mg every 12 weeks (Q12W) for up to  48 weeks. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Biological: Ipilimumab<br>* IV infusion<br>* Other names: Yervoy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A) | 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. | Up to  6 Weeks | 
| Percentage of Participants Experiencing Adverse Events (AEs) | 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. | Up to  84 months | 
| Percentage of Participants Discontinuing Study Drug Due to AEs | 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. | Up to  24 months | 
| Percentage of Participants Experiencing Adverse Events of Special Interest (AEOSIs) (Parts 1B and 1C) | 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. | Up to  84 months | 
| Percentage of Participants Experiencing Grade 3-5 Drug-related AEs (Part 1C) | 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. | Up to  84 months | 
| Objective Response Rate (ORR) (Part 1C) | 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. | Up to  84 months | 
| Progression-free Survival (PFS) (Part 2) | 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. | Up to  84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) (Part 1B) | ORR was defined as the percentage of participants who had a CR: Disappearance of all target lesions or a PR: At least a 30% decrease in the sum of diameters of target lesions as assessed using RECIST 1.1. The percentage of participants who experienced a CR or PR is presented. Per protocol, ORR in Part 1B was planned and conducted as a pre-specified secondary outcome analysis. ORR in Part 1C was planned and conducted as a protocol-specified primary outcome analysis and has been reported earlier in the record. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| ORR by Programmed-death Receptor-ligand 1 (PD-L1) Status Using RECIST 1.1 (Parts 1B and 1C) | ORR was defined as the percentage of participants who had a CR: Disappearance of all target lesions or a PR: At least a 30% decrease in the sum of diameters of target lesions as assessed using RECIST 1.1. The percentage of participants that experienced a CR or PR by PD-L1 status is presented. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. ORR for participants in Parts 1B and 1C with measurable disease at baseline based on central independent review, who had ORR data available for PD-L1+ and PD-L1- participants are presented. Outcome analysis of ORR in Part 1A was not planned or conducted in this study, per protocol. | 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) | Ordinal response, per RECIST 1.1 included the best overall responses of Very Good Partial Response ([VGPR]>60% tumor reduction) as well as Moderate Partial Response ([MPR]>30%- ≤60% tumor reduction). The percentage of participants in Part 1B and 1C who experienced a MPR or VGPR (based on the degree of tumor shrinkage) in participants with advanced melanoma is presented. Outcome analysis of ordinal response in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| Duration of Response (DOR) (Parts 1B and 1C) | DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on central imaging review with confirmation. The DOR as assessed using RECIST 1.1 for participants with measurable disease at baseline based on central independent review in Parts 1B and 1C who experienced a confirmed CR or PR with DOR data available is presented. Outcome analysis of DOR in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| Progression-free Survival (PFS) (Parts 1B and 1C) | PFS was defined as the time from randomization to the first documented 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 as assessed by independent central review per RECIST 1.1 for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had PFS data available is presented. Outcome analysis of PFS in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| Overall Survival (OS) (Parts 1B and 1C) | OS was defined as the time from randomization to death due to any cause. OS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had OS data available is presented. Outcome analysis of OS in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| PFS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C) | PFS was defined as the time from randomization to the first documented 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. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. PFS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had PFS data available for PD-L1+ and PD-L1- participants is presented. Outcome analysis of PFS in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| OS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C) | OS was defined as the time from randomization to death due to any cause. PD-L1 positivity was defined as ≥1% staining in tumor and inflammatory cells, while PD-L1 negativity is defined as <1% staining. OS for all participants who received at least one dose of study treatment in Part 1B and all randomized participants in Part 1C, who had OS data available for PD-L1+ and PD-L1- participants is presented. Outcome analysis of OS in Part 1A was not planned or conducted in this study, per protocol. | Up to  84 months | 
| Percentage of Participants Experiencing Grade 3-5 DRAEs (Parts 1A and 1B) | Participants in Parts 1A and 1B who experienced DRAEs using CTCAE Version 4.0 are presented. Grade 3-5 DRAEs for Part 1C was a primary outcome analysis, per protocol and reported earlier in the record. | Up to  84 months | 
| ORR (Part 2) | 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 RECIST 1.1. Part 2 of the study was not conducted, based on protocol specified criteria and this Part 2 specific outcome measure was not reported. | Up to  84 months |