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)

NCT02089685 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: 3475-029MK-3475-029KEYNOTE-292013-004072-36
• Study Type: interventional
• Target: 295
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Renal Cell Carcinoma; Melanoma

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (10)

• 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

Study Arms (4)

Pembrolizumab + PegIFN-2b

EXPERIMENTAL

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; Biological: PegIFN-2b

Pembrolizumab + IPI Q3W

EXPERIMENTAL

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; Biological: Ipilimumab

Pembrolizumab + IPI Q6W

EXPERIMENTAL

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; Biological: Ipilimumab

Pembrolizumab + IPI Q12W

EXPERIMENTAL

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; Biological: Ipilimumab

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: KEYTRUDA®, MK-3475

Pembrolizumab + IPI Q12W; Pembrolizumab + IPI Q3W; Pembrolizumab + IPI Q6W; Pembrolizumab + PegIFN-2b

PegIFN-2b BIOLOGICAL

Subcutaneous infusion

Also known as: PegIntron®, Sylatron®

Pembrolizumab + PegIFN-2b

Ipilimumab BIOLOGICAL

IV infusion

Also known as: Yervoy®

Pembrolizumab + IPI Q12W; Pembrolizumab + IPI Q3W; Pembrolizumab + IPI Q6W

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (3)

• Long GV, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, Hill AG, Ribas A, Atkins MB, Thompson JA, Hwu WJ, Hodi FS, Menzies AM, Guminski AD, Kefford R, Kong BY, Tamjid B, Srivastava A, Lomax AJ, Islam M, Shu X, Ebbinghaus S, Ibrahim N, Carlino MS. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017 Sep;18(9):1202-1210. doi: 10.1016/S1470-2045(17)30428-X. Epub 2017 Jul 17.

  PMID: 28729151 RESULT

• Carlino MS, Menzies AM, Atkinson V, Cebon JS, Jameson MB, Fitzharris BM, McNeil CM, Hill AG, Ribas A, Atkins MB, Thompson JA, Hwu WJ, Hodi FS, Guminski AD, Kefford R, Wu H, Ibrahim N, Homet Moreno B, Long GV. Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B. Clin Cancer Res. 2020 Oct 1;26(19):5086-5091. doi: 10.1158/1078-0432.CCR-20-0177. Epub 2020 Jun 30.

  PMID: 32605909 RESULT

• Atkins MB, Hodi FS, Thompson JA, McDermott DF, Hwu WJ, Lawrence DP, Dawson NA, Wong DJ, Bhatia S, James M, Jain L, Robey S, Shu X, Homet Moreno B, Perini RF, Choueiri TK, Ribas A. Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study. Clin Cancer Res. 2018 Apr 15;24(8):1805-1815. doi: 10.1158/1078-0432.CCR-17-3436. Epub 2018 Jan 22.

  PMID: 29358500 DERIVED

Related Links

• Merck Oncology Clinical Trials Information

MeSH Terms

Conditions

Carcinoma, Renal Cell; Melanoma

Interventions

pembrolizumab; peginterferon alfa-2b; Ipilimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2014
• First Posted: March 18, 2014
• Study Start: March 17, 2014
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: September 13, 2022
• Results First Posted: May 18, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share