Clinical trial NCT02089685: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Renal Cell Carcinoma
Melanoma
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-03-18
Enrollment: 295
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* 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

Primary outcomes:
measure: Percentage of Participants With Dose-limiting Toxicities (DLTs) (Part 1A)
timeFrame: Up to ~6 Weeks
measure: Percentage of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to ~84 months
measure: Percentage of Participants Discontinuing Study Drug Due to AEs
timeFrame: Up to ~24 months
measure: Percentage of Participants Experiencing Adverse Events of Special Interest (AEOSIs) (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Percentage of Participants Experiencing Grade 3-5 Drug-related AEs (Part 1C)
timeFrame: Up to ~84 months
measure: Objective Response Rate (ORR) (Part 1C)
timeFrame: Up to ~84 months
measure: Progression-free Survival (PFS) (Part 2)
timeFrame: Up to ~84 months
Secondary outcomes:
measure: Objective Response Rate (ORR) (Part 1B)
timeFrame: Up to ~84 months
measure: ORR by Programmed-death Receptor-ligand 1 (PD-L1) Status Using RECIST 1.1 (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Percentage of Participants With an Ordinal Response, Estimated by a Best Overall Response of VGPR or MPR (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Duration of Response (DOR) (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Progression-free Survival (PFS) (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Overall Survival (OS) (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: PFS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: OS by PD-L1 Status Using RECIST 1.1 (Parts 1B and 1C)
timeFrame: Up to ~84 months
measure: Percentage of Participants Experiencing Grade 3-5 DRAEs (Parts 1A and 1B)
timeFrame: Up to ~84 months
measure: ORR (Part 2)
timeFrame: Up to ~84 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.