Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/KEYMAKER-U02)

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants With Melanoma (KEYMAKER-U02): Substudy 02C

Substudy 02C is part of a larger research study that is testing experimental treatments for melanoma, a type of skin cancer. The larger study is the umbrella study.

The goal of substudy 02C is to evaluate the safety and efficacy of investigational treatment arms in participants with Stage III melanoma who are candidates for neoadjuvant therapy to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.

Arm 1: Pembrolizumab + Vibostolimab, Arm 2: Pembrolizumab + Gebasaxturev, and Arm 3: Pembrolizumab were added in the base protocol on 13-Nov-2019, and enrollment into those arms has been completed. Arm 4: Pembrolizumab + MK-4830 was added in Amendment 04 on 20-Dec-2021, and enrollment into that arm has been completed. Arm 5: Favezelimab + Pembrolizumab and Arm 6: Pembrolizumab + all-trans retinoic acid (ATRA) were added in Amendment 06 on 25-Jun-2022, and enrollment is ongoing.

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Vibostolimab; Drug: ATRA; Biological: Gebasaxturev; Biological: MK-4830; Biological: Favezelimab + Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@merck.com

Study Locations

• Australia
  • New South Wales
    • Wollstonecraft, New South Wales, Australia, 2065
      • Melanoma Institute Australia ( Site 3402)
  • Queensland
    • Southport, Queensland, Australia, 4215
      • Tasman Oncology Research Pty Ltd ( Site 3403)
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital ( Site 3401)
• France
  • Paris, France, 75010
    • A.P.H. Paris, Hopital Saint Louis ( Site 3107)
  • Bouches-du-Rhone
    • Marseille, Bouches-du-Rhone, France, 13005
      • Hopital La Timone ( Site 3103)
  • Haute-Garonne
    • Toulouse cedex 9, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 3105)
  • Ile-de-France
    • Villejuif, Ile-de-France, France, 94805
      • Gustave Roussy ( Site 3101)
  • Rhone
    • Pierre Benite, Rhone, France, 69495
      • Centre Hospitalier Lyon Sud ( Site 3102)
• Israel
  • Afula, Israel, 1834111
    • HaEmek Medical Center ( Site 3703)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus-Oncology ( Site 3704)
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Jerusalem ( Site 3702)
  • Petah-Tikva, Israel, 4941492
    • Rabin Medical Center-Oncology ( Site 3705)
  • Ramat Gan, Israel, 5265601
    • Chaim Sheba Medical Center ( Site 3701)
• Italy
  • Milano, Italy, 20141
    • Istituto Europeo di Oncologia ( Site 3301)
  • Siena, Italy, 53100
    • Policlinico Le Scotte - A.O. Senese ( Site 3377)
• Switzerland
  • Geneve
    • Genève, Geneve, Switzerland, 1211
      • Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 3603)
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • CHUV Centre Hospitalier Universitaire Vaudois ( Site 3602)
  • Zurich
    • Zuerich Flughafen, Zurich, Switzerland, 8058
      • Universitaetsspital Zuerich ( Site 3601)
• United States
  • California
    • Los Angeles, California, United States, 90025
      • The Angeles Clinic and Research Institute ( Site 3009)
    • Santa Monica, California, United States, 90404
      • Providence Saint John's Health Center ( Site 3010)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Anschutz Cancer Pavilion ( Site 3012)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 3022)
  • New York
    • New York, New York, United States, 10016
      • NYU Clinical Cancer Center ( Site 3002)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute ( Site 3005)
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Martha Morehouse Tower ( Site 3020)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University ( Site 3013)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Abramson Cancer Center ( Site 3008)
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • West Cancer Center - East Campus ( Site 3014)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute ( Site 3011)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has histologically or cytologically confirmed melanoma
• Has clinically detectable and resectable Stage IIIB or IIIC or IIID melanoma amenable to surgery

• Has been untreated for Stage IIIB, IIIC or IIID melanoma

  • surgical resection of primary melanoma is allowed
  • prior radiotherapy to the primary melanoma is allowed
• Has provided a baseline tumor biopsy
• Male participants who receive gebasaxturev are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 120 days after the last dose of gebasaxturev
• Male participants who receive ATRA are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after the last dose of ATRA
• Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) OR use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after the last dose of pembrolizumab, vibostolimab, gebasaxturev, or MK-4830, favezelimab + pembrolizumab, or 30 days after the last dose of ATRA, whichever occurs last
• Has adequate organ function
• Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia)

Exclusion Criteria:

• Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days before the first dose of study intervention
• Has a known additional malignancy that is progressing or requires active treatment within the past 2 years
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has ocular or mucosal melanoma
• Has known hypersensitivity including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• Has an active autoimmune disease that has required systemic treatment in the past 2 years
• Has an active infection requiring systemic therapy
• Has known history of human immunodeficiency virus (HIV)
• Has known history of hepatitis B
• Has a history of (noninfectious) pneumonitis
• Has a history of active tuberculosis (TB)
• Has received prior systemic anticancer therapy within 4 weeks prior to randomization
• Has received prior radiotherapy within 2 weeks of first dose of study intervention
• Has had major surgery <3 weeks prior to first dose of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
• Has participated in a study of an investigational agent within 4 weeks prior to the first dose of study intervention
• Has had an allogeneic tissue/solid organ transplant
• Has only mucosal lesions
• Is not naïve to Talimogene laherparepvec (TVEC) and other oncolytic viruses

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Vibostolimab; Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab intravenously (IV) plus vibostolimab IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: Vibostolimab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-7684
Experimental: Pembrolizumab + Gebasaxturev; Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus gebasaxturev (V937) intratumorally (IT) at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: Gebasaxturev; Administered via IT injection at a specified dose on specified days; Other Names: Coxsackievirus A21 (CVA21); Formerly known as CAVATAK®; CAV21; V937
Experimental: Pembrolizumab; Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®
Experimental: Pembrolizumab + MK-4830; Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus MK-4830 IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Biological: MK-4830; Administered via IV infusion at a specified dose on specified days
Experimental: Favezelimab + Pembrolizumab; Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive MK-4280A (favezelimab and pembrolizumab administered as a co-formulation) IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Favezelimab + Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-4280A
Experimental: Pembrolizumab + all-trans retinoic acid (ATRA); Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus ATRA orally at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®; Drug: ATRA; Administered via oral capsules at a specified dose on specified days; Other Names: Tretinoin; Vesanoid®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants who experience an adverse event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience an AE will be reported.	Up to ~16 months
Percentage of participants who discontinue study treatment due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study treatment due to an AE will be reported.	Up to ~12 months
Pathological complete response (pCR) rate	pCR rate is defined as the proportion of participants with complete absence of viable tumor in the treated tumor bed. Assessments are according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~1.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Near pathological complete response (near pCR) rate	Near pCR is defined as the proportion of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed. Assessments are according to RECIST 1.1 by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~1.5 months
Pathological partial response (pPR) rate	pPR rate is defined as the proportion of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells. Assessments are according to RECIST 1.1 by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~1.5 months
Recurrence-free survival (RFS)	RFS is defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Assessments are according to RECIST 1.1 which has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.	Up to ~60 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2020
• Primary Completion (Estimated): April 3, 2030
• Study Completion (Estimated): April 3, 2030

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (Actual): March 10, 2020

Study Record Updates

• Last Update Posted (Estimated): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Coxsackievirus A21; programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); Intracellular Adhesion Molecule-1 (ICAM-1); T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Dermatologic Agents; Immune Checkpoint Inhibitors; Keratolytic Agents; Pembrolizumab; Tretinoin
• Other Study ID Numbers: 3475-02C; KEYMAKER-U02 (Other Identifier: Merck); MK-3475-02C (Other Identifier: Merck); 2019-003978-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No