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)

Merck Sharp & Dohme (MSD)

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Melanoma

Treatments: Drug: Lenvatinib; Biological: Pembrolizumab; Drug: ATRA; Biological: Quavonlimab; Biological: Vibostolimab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04305041

MK-3475-02A (Other Identifier)

3475-02A

2019-003956-35 (EudraCT Number)

KEYMAKER-U02 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 200 estimated patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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200 participants in 3 patient groups

Pembrolizumab + Quavonlimab + Vibostolimab

Experimental group

Description:

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.

Treatment:

Biological: Vibostolimab

Biological: Quavonlimab

Biological: Pembrolizumab

Pembrolizumab + Quavonlimab + Lenvatinib

Experimental group

Description:

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.

Treatment:

Biological: Quavonlimab

Drug: Lenvatinib

Biological: Pembrolizumab

Pembrolizumab + all-trans retinoic acid (ATRA)

Experimental group

Description:

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

Treatment:

Drug: ATRA