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: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Vibostolimab; Drug: ATRA; Biological: Gebasaxturev; Biological: MK-4830; Biological: Favezelimab + Pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 2; Phase 1

Contacts and Locations

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, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 3105)
  • Rhone
    • Pierre-Bénite, Rhone, France, 69495
      • Centre Hospitalier Lyon Sud ( Site 3102)
  • Île-de-France Region
    • Villejuif, Île-de-France Region, France, 94805
      • Gustave Roussy ( Site 3101)
• 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
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia ( Site 3301)
  • Siena, Italy, 53100
    • Policlinico Le Scotte - A.O. Senese ( Site 3377)
• Switzerland
  • Canton of Geneva
    • Geneva, Canton of Geneva, Switzerland, 1211
      • Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 3603)
  • Canton of Vaud
    • Lausanne, Canton of Vaud, Switzerland, 1011
      • CHUV Centre Hospitalier Universitaire Vaudois ( Site 3602)
  • Canton of Zurich
    • Zuerich Flughafen, Canton of 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 and re-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 all-trans retinoic acid (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; Neoadjuvant treatment: Participants received pembrolizumab 200 mg by intravenous (IV) infusion administered on Day 1 of a 21-day cycle for 2 cycles, plus vibostolimab 200 mg by IV infusion administered on Day 1 of a 21-day cycle for 2 cycles, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	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; Neoadjuvant treatment: Participants received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 1 cycle, plus gebasaxturev 3 × 10^8 tissue culture infectious dose 50%/mL (TCID50) administered intratumorally on Days 1, 3, 5, 8, and 22 of a 42-day cycle for 1 cycle, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	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; Neoadjuvant treatment: Participants received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 1 cycle, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	Biological: Pembrolizumab; Administered via IV infusion at a specified dose on specified days; Other Names: MK-3475; KEYTRUDA®
Experimental: Pembrolizumab + MK-4830; Neoadjuvant treatment: Participants received pembrolizumab 200 mg by IV infusion administered on Day 1 of a 21-day cycle for 2 cycles, plus MK-4830 800 mg by IV infusion administered on Day 1 of a 21-day cycle for 2 cycles, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	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; Neoadjuvant treatment: Participants received a coformulation of favezelimab 800 mg (+) pembrolizumab 200 mg by IV infusion administered on Day 1 of a 21-day cycle for 2 cycles, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	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); Neoadjuvant treatment: Participants received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 1 cycle, plus ATRA 75 mg/m^2 orally twice a day (bid) on Days 1, 2, and 3 of a 21-day cycle for 2 cycles, prior to surgery. Adjuvant treatment: Following surgery, participants who were disease free with tumor negative margins, as assessed by the investigator, received pembrolizumab 400 mg by IV infusion administered on Day 1 of a 42-day cycle for 8 cycles. A subset of participants who had confirmed radiographic disease progression with unresectable tumor, unacceptable toxicity, a confirmed positive pregnancy test, withdrawal of consent, or distant metastasis did not receive surgery or adjuvant treatment.	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 Experienced 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 experienced an AE was reported.	Up to approximately 17 months
Percentage of Participants Who Discontinued Study Intervention 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 discontinued study intervention due to an AE was reported.	Up to approximately 13 months
Pathological Complete Response (pCR) Rate With 90% Confidence Interval (CI)	pCR rate was defined as the percentage of participants with complete absence of viable tumor in the treated tumor bed as assessed by central review of the pathology results. Per protocol, pCR rate with 90% CI was reported.	Up to approximately 6 weeks
pCR Rate With 95% CI	pCR rate was defined as the percentage of participants with complete absence of viable tumor in the treated tumor bed as assessed by central review of the pathology results. Per protocol, pCR rate with 95% CI was reported.	Up to approximately 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Near pCR Rate With 90% CI	Near pCR was defined as the percentage of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed as assessed by central review of the pathology results. Per protocol, near pCR rate with 90% CI was reported.	Up to approximately 6 weeks
Near pCR Rate With 95% CI	Near pCR was defined as the percentage of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed as assessed by central review of the pathology results. Per protocol, near pCR rate with 95% CI was reported.	Up to approximately 6 weeks
Pathological Partial Response (pPR) Rate With 90% CI	pPR rate was defined as the percentage of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells as assessed by central review of the pathology results. Per protocol, pPR rate with 90% CI was reported.	Up to approximately 6 weeks
pPR Rate With 95% CI	pPR rate was defined as the percentage of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells as assessed by central review of the pathology results. Per protocol, pPR rate with 95% CI was reported.	Up to approximately 6 weeks
Recurrence-Free Survival (RFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by The Investigator	RFS was defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) per RECIST 1.1 as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Per protocol, RECIST 1.1 was modified to allow up to 10 target lesions total (up to 5 per organ). Per protocol, RFS per RECIST 1.1 as assessed by the investigator was presented.	Up to approximately 62 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Dummer R, Robert C, Scolyer RA, Taube JM, Tetzlaff MT, Menzies AM, Hill A, Grob JJ, Portnoy DC, Lebbe C, Khattak MA, Cohen J, Bar-Sela G, Mehmi I, Shapira-Frommer R, Meyer N, Webber AL, Ren Y, Fukunaga-Kalabis M, Krepler C, Long GV. Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial. Nat Med. 2025 Jan;31(1):144-151. doi: 10.1038/s41591-024-03411-x. Epub 2025 Jan 7.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2020
• Primary Completion (Actual): September 24, 2025
• Study Completion (Actual): September 24, 2025

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 (Actual): August 27, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 1, 2026

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 Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Parkinson Disease 4, Autosomal Dominant Lewy Body; Organic Chemicals; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Diterpenes; Vitamin A; Tretinoin; pembrolizumab
• Other Study ID Numbers: 3475-02C; 2019 (U.S. NIH Grant/Contract: Chief Medical Office (CMO) Alberta Health Services); 2023 (U.S. NIH Grant/Contract: GRAMMY Museum Foundation); KEYMAKER-U02 (Other Identifier: MSD); MK-3475-02C (Other Identifier: MSD); 2019-003978-22 (EudraCT Number); 2023-506314-51-00 (Registry Identifier: EU CT); U1111-1293-5665 (Registry Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/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