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)

August 28, 2026 updated by: Merck Sharp & Dohme LLC

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 02A

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Australia
    • New South Wales
      • Waratah, New South Wales, Australia, 2298
        • Calvary Mater Newcastle-Medical Oncology ( Site 1404)
      • Wollstonecraft, New South Wales, Australia, 2065
        • Melanoma Institute Australia ( Site 1402)
    • Queensland
      • Southport, Queensland, Australia, 4215
        • Tasman Oncology Research Pty Ltd ( Site 1403)
    • Western Australia
      • Murdoch, Western Australia, Australia, 6150
        • Fiona Stanley Hospital ( Site 1401)
  • France
      • Paris, France, 75010
        • A.P.H. Paris, Hopital Saint Louis ( Site 1107)
    • Bouches-du-Rhone
      • Marseille, Bouches-du-Rhone, France, 13005
        • Hopital La Timone ( Site 1103)
    • Gironde
      • Bordeaux, Gironde, France, 33075
        • Hopital Saint Andre ( Site 1108)
    • Haute-Garonne
      • Toulouse, Haute-Garonne, France, 31059
        • Institut Claudius Regaud ( Site 1105)
    • Rhone
      • Pierre-Bénite, Rhone, France, 69495
        • Centre Hospitalier Lyon Sud ( Site 1102)
    • Île-de-France Region
      • Villejuif, Île-de-France Region, France, 94805
        • Gustave Roussy ( Site 1101)
  • Israel
      • Afula, Israel, 1834111
        • HaEmek Medical Center ( Site 1703)
      • Haifa, Israel, 3109601
        • Rambam Health Care Campus-Oncology ( Site 1704)
      • Jerusalem, Israel, 9112001
        • Hadassah Ein Karem Jerusalem ( Site 1702)
      • Ramat Gan, Israel, 5265601
        • Chaim Sheba Medical Center ( Site 1701)
  • Italy
      • Milan, Italy, 20133
        • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 1399)
      • Milan, Italy, 20141
        • Istituto Europeo di Oncologia ( Site 1301)
      • Naples, Italy, 80131
        • Istituto Nazionale Tumori Fondazione Pascale ( Site 1302)
      • Padova, Italy, 35128
        • Istituto Oncologico Veneto IRCCS ( Site 1355)
      • Siena, Italy, 53100
        • Policlinico Le Scotte - A.O. Senese ( Site 1377)
  • South Africa
    • Eastern Cape
      • Port Elizabeth, Eastern Cape, South Africa, 6055
        • CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE-Clinical Trials Unit ( Site 1865)
  • Switzerland
    • Canton of Geneva
      • Geneva, Canton of Geneva, Switzerland, 1211
        • Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 1603)
    • Canton of Vaud
      • Lausanne, Canton of Vaud, Switzerland, 1011
        • CHUV Centre Hospitalier Universitaire Vaudois ( Site 1602)
    • Canton of Zurich
      • Zuerich Flughafen, Canton of Zurich, Switzerland, 8058
        • Universitaetsspital Zuerich ( Site 1601)
  • United States
    • California
      • Los Angeles, California, United States, 90025
        • The Angeles Clinic and Research Institute ( Site 1009)
      • Los Angeles, California, United States, 90095
        • UCLA Hematology & Oncology ( Site 1004)
      • Santa Monica, California, United States, 90404
        • Providence Saint John's Health Center ( Site 1010)
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado, Anschutz Cancer Pavilion ( Site 1012)
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 1022)
    • New York
      • New York, New York, United States, 10016
        • NYU Clinical Cancer Center ( Site 1002)
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke Cancer Institute ( Site 1005)
    • Ohio
      • Columbus, Ohio, United States, 43221
        • Martha Morehouse Tower ( Site 1020)
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University ( Site 1013)
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania Abramson Cancer Center ( Site 1008)
    • Tennessee
      • Germantown, Tennessee, United States, 38138
        • West Cancer Center - East Campus ( Site 1014)
    • Texas
      • Houston, Texas, United States, 77030
        • University of Texas MD Anderson Cancer Center ( Site 1006)
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • Inova Schar Cancer Institute ( Site 1011)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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 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)

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 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
  • 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 a pre-existing Grade ≥3 gastrointestinal fistula or nongastrointestinal fistula
  • Has radiographic evidence of encasement of invasion of major blood vessel or of intratumoral cavitation
  • Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study intervention
  • Has clinically significant cardiovascular disease within 12 months from first dose of study intervention

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Pembrolizumab + Quavonlimab + Vibostolimab
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
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
Biological: Quavonlimab
Administered via IV infusion at a specified dose on specified days
Other Names:
  • MK-1308
Experimental: Pembrolizumab + Quavonlimab + Lenvatinib
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
Administered via IV infusion at a specified dose on specified days
Other Names:
  • MK-3475
  • KEYTRUDA®
Biological: Quavonlimab
Administered via IV infusion at a specified dose on specified days
Other Names:
  • MK-1308
Drug: Lenvatinib
Administered via oral capsules at a specified dose on specified days
Other Names:
  • MK-7902
  • LENVIMA®
Experimental: Pembrolizumab + all-trans retinoic acid (ATRA)
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
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:
  • VESANOID

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Percentage of Participants Who Experienced an Adverse Event (AE)
Time Frame: Up to approximately 39 months
An AE was 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 is reported.
Up to approximately 39 months
Percentage of Participants Who Discontinued Study Treatment Due to an AE
Time Frame: Up to 35 months
An AE was 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 treatment due to an AE is reported.
Up to 35 months
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) With 95% Confidence Interval (CI)
Time Frame: Up to approximately 59 months
ORR was 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 was modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Per protocol, ORR with 95% CI was reported.
Up to approximately 59 months
ORR Per RECIST 1.1 With 90% CI
Time Frame: Up to approximately 59 months
ORR was 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 BICR. RECIST 1.1 was modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Per protocol, ORR with 90% CI was reported.
Up to approximately 59 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Duration of Response (DOR) Per RECIST 1.1
Time Frame: Up to approximately 59 months
For participants in the analysis population who showed a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to RECIST 1.1 as assessed by BICR. RECIST 1.1 was modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Up to approximately 59 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Merck Sharp & Dohme LLC

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 26, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 25, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 25, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 9, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 9, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 12, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 1, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 28, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 3475-02A
  • 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-3475-02A (Other Identifier: MSD)
  • 2019-003956-35 (EudraCT Number)
  • 2023-506312-41-00 (Registry Identifier: EU CT)
  • U1111-1293-5630 (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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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