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)

NCT04303169 | Completed Phase 1 FDA Drug

• 6 other identifiers: 3475-02CMK-3475-02CKEYMAKER-U022023-506314-51-00U1111-1293-56652019-003978-22
• Study Type: interventional
• Target: 146
• Locations: 6 countries
• Sites: 29

Brief Summary

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.

Conditions

Melanoma

Keywords

programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); Coxsackievirus A21; Intracellular Adhesion Molecule-1 (ICAM-1); T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT)

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Near pathological complete response (near pCR) rate

  Up to ~1.5 months

• Pathological partial response (pPR) rate

  Up to ~1.5 months

• Recurrence-free survival (RFS)

  Up to ~60 months

Study Arms (6)

Pembrolizumab + Vibostolimab

EXPERIMENTAL

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; Biological: Vibostolimab

Pembrolizumab + Gebasaxturev

EXPERIMENTAL

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; Biological: Gebasaxturev

Pembrolizumab

EXPERIMENTAL

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

Pembrolizumab + MK-4830

EXPERIMENTAL

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; Biological: MK-4830

Favezelimab + Pembrolizumab

EXPERIMENTAL

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

Pembrolizumab + all-trans retinoic acid (ATRA)

EXPERIMENTAL

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; Drug: ATRA

Interventions

Pembrolizumab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab; Pembrolizumab + Gebasaxturev; Pembrolizumab + MK-4830; Pembrolizumab + Vibostolimab; Pembrolizumab + all-trans retinoic acid (ATRA)

Vibostolimab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-7684

Pembrolizumab + Vibostolimab

Gebasaxturev BIOLOGICAL

Administered via IT injection at a specified dose on specified days

Also known as: Coxsackievirus A21 (CVA21), Formerly known as CAVATAK®, CAV21, V937

Pembrolizumab + Gebasaxturev

MK-4830 BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Pembrolizumab + MK-4830

Favezelimab + Pembrolizumab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-4280A

Favezelimab + Pembrolizumab

ATRA DRUG

Administered via oral capsules at a specified dose on specified days

Also known as: Tretinoin, Vesanoid®

Pembrolizumab + all-trans retinoic acid (ATRA)

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (29)

The Angeles Clinic and Research Institute ( Site 3009)

Los Angeles, California, 90025, United States

Location

Providence Saint John's Health Center ( Site 3010)

Santa Monica, California, 90404, United States

Location

University of Colorado, Anschutz Cancer Pavilion ( Site 3012)

Aurora, Colorado, 80045, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 3022)

Baltimore, Maryland, 21287, United States

Location

NYU Clinical Cancer Center ( Site 3002)

New York, New York, 10016, United States

Location

Duke Cancer Institute ( Site 3005)

Durham, North Carolina, 27710, United States

Location

Martha Morehouse Tower ( Site 3020)

Columbus, Ohio, 43221, United States

Location

Oregon Health & Science University ( Site 3013)

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Abramson Cancer Center ( Site 3008)

Philadelphia, Pennsylvania, 19104, United States

Location

West Cancer Center - East Campus ( Site 3014)

Germantown, Tennessee, 38138, United States

Location

Inova Schar Cancer Institute ( Site 3011)

Fairfax, Virginia, 22031, United States

Location

Melanoma Institute Australia ( Site 3402)

Wollstonecraft, New South Wales, 2065, Australia

Location

Tasman Oncology Research Pty Ltd ( Site 3403)

Southport, Queensland, 4215, Australia

Location

Fiona Stanley Hospital ( Site 3401)

Murdoch, Western Australia, 6150, Australia

Location

Hopital La Timone ( Site 3103)

Marseille, Bouches-du-Rhone, 13005, France

Location

Institut Claudius Regaud ( Site 3105)

Toulouse, Haute-Garonne, 31059, France

Location

Centre Hospitalier Lyon Sud ( Site 3102)

Pierre-Bénite, Rhone, 69495, France

Location

A.P.H. Paris, Hopital Saint Louis ( Site 3107)

Paris, 75010, France

Location

Gustave Roussy ( Site 3101)

Villejuif, Île-de-France Region, 94805, France

Location

HaEmek Medical Center ( Site 3703)

Afula, 1834111, Israel

Location

Rambam Health Care Campus-Oncology ( Site 3704)

Haifa, 3109601, Israel

Location

Hadassah Ein Karem Jerusalem ( Site 3702)

Jerusalem, 9112001, Israel

Location

Rabin Medical Center-Oncology ( Site 3705)

Petah Tikva, 4941492, Israel

Location

Chaim Sheba Medical Center ( Site 3701)

Ramat Gan, 5265601, Israel

Location

Istituto Europeo di Oncologia ( Site 3301)

Milan, 20141, Italy

Location

Policlinico Le Scotte - A.O. Senese ( Site 3377)

Siena, 53100, Italy

Location

Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 3603)

Geneva, Canton of Geneva, 1211, Switzerland

Location

CHUV Centre Hospitalier Universitaire Vaudois ( Site 3602)

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Universitaetsspital Zuerich ( Site 3601)

Zuerich Flughafen, Canton of Zurich, 8058, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 39775043 RESULT

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Melanoma; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; Tretinoin

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

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 9, 2020
• First Posted: March 10, 2020
• Study Start: June 26, 2020
• Primary Completion: September 24, 2025
• Study Completion: September 24, 2025
• Last Updated: October 27, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share

Locations

AU (3); FR (5); IL (5); US (11); IT (2); CH (3)