Substudy 02A: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents in Participants With Programmed Cell-death 1 (PD-1) Refractory Melanoma (MK-3475-02A/KEYMAKER-U02)

NCT04305041 | Completed Phase 1 FDA Drug

• 6 other identifiers: 3475-02AMK-3475-02AKEYMAKER-U022023-506312-41-00U1111-1293-56302019-003956-35
• Study Type: interventional
• Target: 100
• Locations: 7 countries
• Sites: 36

Brief Summary

Substudy 02A 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 02A is to evaluate the safety and efficacy of investigational treatment arms in participants with PD-1 refractory melanoma to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available. As of Amendment 4 (effective date: 05JAN2022), a third arm has been opened to participant enrollment, treatment with pembrolizumab and all-trans retinoic acid (ATRA). Enrollment into the first two arms, treatment with pembrolizumab + quavonlimab+ vibostolimab and treatment with pembrolizumab + quavonlimab + lenvatinib has been completed per protocol as of September 2021.

Conditions

Melanoma

Keywords

receptor tyrosine kinase inhibitor; programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); 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 ~28 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 ~24 months

• Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)

  ORR is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters). Responses are according to RECIST 1.1 as assessed by blinded independent central review (BICR). 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 ~30 months

Secondary Outcomes (1)

• Duration of Response (DOR) per RECIST 1.1

  Up to ~30 months

Study Arms (3)

Pembrolizumab + Quavonlimab + Vibostolimab

EXPERIMENTAL

Participants will receive pembrolizumab intravenously (IV) plus quavonlimab IV plus vibostolimab IV at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Biological: Pembrolizumab; Biological: Quavonlimab; Biological: Vibostolimab

Pembrolizumab + Quavonlimab + Lenvatinib

EXPERIMENTAL

Participants will receive pembrolizumab IV plus quavonlimab IV plus lenvatinib orally at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Biological: Pembrolizumab; Biological: Quavonlimab; Drug: Lenvatinib

Pembrolizumab + all-trans retinoic acid (ATRA)

EXPERIMENTAL

Participants will receive pembrolizumab IV plus ATRA orally at specified doses on specified days for a total treatment duration of up to approximately 2 years

Drug: ATRA

Interventions

Pembrolizumab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab + Quavonlimab + Lenvatinib; Pembrolizumab + Quavonlimab + Vibostolimab

Quavonlimab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-1308

Pembrolizumab + Quavonlimab + Lenvatinib; Pembrolizumab + Quavonlimab + Vibostolimab

Vibostolimab BIOLOGICAL

Administered via IV infusion at a specified dose on specified days

Also known as: MK-7684

Pembrolizumab + Quavonlimab + Vibostolimab

Lenvatinib DRUG

Administered via oral capsules at a specified dose on specified days

Also known as: MK-7902, LENVIMA®

Pembrolizumab + Quavonlimab + Lenvatinib

ATRA DRUG

Administered via oral capsules at a specified dose on specified days

Also known as: 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 unresectable Stage III or Stage IV melanoma, not amenable to local therapy
• Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other therapies
• Has imaging documenting progression per RECIST 1.1 and iRECIST after initiation of an anti-PD-1/L1 agent, or by RECIST 1.1 if progression occurred on adjuvant therapy or in the setting of rapid progression.
• Has not received more than 3 lines of therapy for their advanced melanoma
• Has provided a tumor biopsy
• Male participants who receive lenvatinib or 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 lenvatinib or ATRA; for male participants who only receive pembrolizumab, quavonlimab, vibostolimab, or a combination, no contraception measures are needed
• Female participant 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, quavonlimab, vibostolimab or 30 days after the last dose of lenvatinib or 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 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 vaccine within 30 days before the first dose of study intervention

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (36)

The Angeles Clinic and Research Institute ( Site 1009)

Los Angeles, California, 90025, United States

Location

UCLA Hematology & Oncology ( Site 1004)

Los Angeles, California, 90095, United States

Location

Providence Saint John's Health Center ( Site 1010)

Santa Monica, California, 90404, United States

Location

University of Colorado, Anschutz Cancer Pavilion ( Site 1012)

Aurora, Colorado, 80045, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 1022)

Baltimore, Maryland, 21287, United States

Location

NYU Clinical Cancer Center ( Site 1002)

New York, New York, 10016, United States

Location

Duke Cancer Institute ( Site 1005)

Durham, North Carolina, 27710, United States

Location

Martha Morehouse Tower ( Site 1020)

Columbus, Ohio, 43221, United States

Location

Oregon Health & Science University ( Site 1013)

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Abramson Cancer Center ( Site 1008)

Philadelphia, Pennsylvania, 19104, United States

Location

West Cancer Center - East Campus ( Site 1014)

Germantown, Tennessee, 38138, United States

Location

University of Texas MD Anderson Cancer Center ( Site 1006)

Houston, Texas, 77030, United States

Location

Inova Schar Cancer Institute ( Site 1011)

Fairfax, Virginia, 22031, United States

Location

Calvary Mater Newcastle-Medical Oncology ( Site 1404)

Waratah, New South Wales, 2298, Australia

Location

Melanoma Institute Australia ( Site 1402)

Wollstonecraft, New South Wales, 2065, Australia

Location

Tasman Oncology Research Pty Ltd ( Site 1403)

Southport, Queensland, 4215, Australia

Location

Fiona Stanley Hospital ( Site 1401)

Murdoch, Western Australia, 6150, Australia

Location

Hopital La Timone ( Site 1103)

Marseille, Bouches-du-Rhone, 13005, France

Location

Hopital Saint Andre ( Site 1108)

Bordeaux, Gironde, 33075, France

Location

Institut Claudius Regaud ( Site 1105)

Toulouse, Haute-Garonne, 31059, France

Location

Centre Hospitalier Lyon Sud ( Site 1102)

Pierre-Bénite, Rhone, 69495, France

Location

A.P.H. Paris, Hopital Saint Louis ( Site 1107)

Paris, 75010, France

Location

Gustave Roussy ( Site 1101)

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

Location

HaEmek Medical Center ( Site 1703)

Afula, 1834111, Israel

Location

Rambam Health Care Campus-Oncology ( Site 1704)

Haifa, 3109601, Israel

Location

Hadassah Ein Karem Jerusalem ( Site 1702)

Jerusalem, 9112001, Israel

Location

Chaim Sheba Medical Center ( Site 1701)

Ramat Gan, 5265601, Israel

Location

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 1399)

Milan, 20133, Italy

Location

Istituto Europeo di Oncologia ( Site 1301)

Milan, 20141, Italy

Location

Istituto Nazionale Tumori Fondazione Pascale ( Site 1302)

Napoli, 80131, Italy

Location

Istituto Oncologico Veneto IRCCS ( Site 1355)

Padua, 35128, Italy

Location

Policlinico Le Scotte - A.O. Senese ( Site 1377)

Siena, 53100, Italy

Location

CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE-Clinical Trials Unit ( Site 1865)

Port Elizabeth, Eastern Cape, 6055, South Africa

Location

Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 1603)

Geneva, Canton of Geneva, 1211, Switzerland

Location

CHUV Centre Hospitalier Universitaire Vaudois ( Site 1602)

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Universitaetsspital Zuerich ( Site 1601)

Zuerich Flughafen, Canton of Zurich, 8058, Switzerland

Location

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Melanoma; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; lenvatinib; 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 12, 2020
• Study Start: June 26, 2020
• Primary Completion: August 25, 2025
• Study Completion: August 25, 2025
• Last Updated: August 29, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share

Locations

US (13); AU (4); IL (4); IT (5); ZA (1); CH (3); FR (6)