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)

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: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Biological: Pembrolizumab; Biological: Vibostolimab; Biological: Quavonlimab; Drug: Lenvatinib; Drug: ATRA

• Study Type: Interventional
• Enrollment (Estimated): 200
• 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
    • 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 cedex 9, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 1105)
  • Ile-de-France
    • Villejuif, Ile-de-France, France, 94800
      • Gustave Roussy ( Site 1101)
  • Rhone
    • Pierre Benite, Rhone, France, 69495
      • Centre Hospitalier Lyon Sud ( Site 1102)
• 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
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 1399)
  • Milano, Italy, 20141
    • Istituto Europeo di Oncologia ( Site 1301)
  • Napoli, 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)
• Switzerland
  • Geneve
    • Genève, Geneve, Switzerland, 1211
      • Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 1603)
  • Vaud
    • Lausanne, Vaud, Switzerland, 1011
      • CHUV Centre Hospitalier Universitaire Vaudois ( Site 1602)
  • Zurich
    • Zuerich Flughafen, 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

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 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

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: ATRA; Administered via oral capsules at a specified dose on specified days; Other Names: 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 ~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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR) per RECIST 1.1	For participants in the analysis population who show 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 is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by 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

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 12, 2020

Study Record Updates

• Last Update Posted (Actual): December 27, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• 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)
• 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; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: 3475-02A; KEYMAKER-U02 (Other Identifier: Merck); MK-3475-02A (Other Identifier: Merck); 2019-003956-35 (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