Substudy 02B: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With First Line (1L) Advanced Melanoma (MK-3475-02B/KEYMAKER-U02)

Merck Sharp & Dohme (MSD)

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

Conditions: Melanoma

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT04305054

U1111-1293-5644 (Registry Identifier)

2019-003977-24 (EudraCT Number)

2023-506313-21-00 (Registry Identifier)

3475-02B

KEYMAKER-U02 (Other Identifier)

MK-3475-02B (Other Identifier)

Details and patient eligibility

About

Substudy 02B is part of a larger research study where researchers are looking for new ways to treat advanced melanoma that has not been treated before. The larger study is the umbrella study. Researchers want to know if adding other treatments to pembrolizumab can treat advanced melanoma. The goals of this study are to learn:

• About the safety and how well people tolerate pembrolizumab given with other treatments
• How many people have melanoma that responds (gets smaller or goes away) to treatment

Full description

With Amendment 6, all arms are closed to enrollment. Participants in arms 2 (pembrolizumab), 3 (coformulation pembrolizumab/quavonlimab), and 4 (coformulation pembrolizumab/quavonlimab + lenvatinib) who complete study treatment or otherwise meet end of treatment (EOT) criteria will be discontinued from the study after completing the EOT visit and any required safety follow-up visits. Participants in arm 6 (coformulation favezelimab/pembrolizumab + All-trans Retinoic Acid [ATRA]) will discontinue ATRA and participants in arms 5 and 6 can continue on coformulation favezelimab/pembrolizumab or pembrolizumab.

Enrollment: 315 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 been untreated for advanced disease.

• Has provided a tumor biopsy

• If capable of producing sperm, male participants agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention (7 days):

  • Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR
  • Uses contraception unless confirmed to be azoospermic

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

  • Is not a WOCBP OR
  • Is a WOCBP and Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
  • MK-4280A: 120 days
  • MK-1308A: 120 days
  • MK-7684: 50 days
  • MK-3475: 120 days
  • Lenvatinib: 30 days
  • ATRA: 30 days

• Has adequate organ function

• Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia and Grade 2 neuropathy)

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 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 history of Hepatitis B or known Hepatitis C virus infection

• 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 known psychiatric or substance abuse disorder that would interfere with requirements of the study

• Participants who receive lenvatinib have the following additional exclusion criteria:

  • Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
  • Has radiographic evidence of encasement of invasion of a 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
  • Has urine protein ≥1 g/24-hour.
  • Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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315 participants in 7 patient groups

Pembrolizumab + Vibostolimab

Experimental group

Description:

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

Treatment:

Biological: Pembrolizumab

Biological: Vibostolimab

Pembrolizumab

Active Comparator group

Description:

Participants will receive pembrolizumab IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years.

Treatment:

Biological: Pembrolizumab

Coformulation Pembrolizumab/Quavonlimab

Experimental group

Description:

Participants will receive coformulation of pembrolizumab and quavonlimab (MK-1308A) IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years.

Treatment:

Biological: Pembrolizumab

Biological: Pembrolizumab/Quavonlimab

Coformulation Pembrolizumab/Quavonlimab + Lenvatinib

Experimental group

Description:

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

Treatment:

Biological: Pembrolizumab

Biological: Pembrolizumab/Quavonlimab

Drug: Lenvatinib

Coformulation Favezelimab/Pembrolizumab

Experimental group

Description:

Participants will receive cofomulation of favezelimab + pembrolizumab (MK-4280A) IV at specified dose on specified days every 3 weeks (Q3W) for up to approximately 2 years

Treatment:

Biological: Favezelimab/Pembrolizumab

Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA)

Experimental group

Description:

Participants will receive coformulation of favezelimab and pembrolizumab IV Q3W for up to 35 cycles, plus ATRA orally (for 3 days surrounding each infusion of MK-4280A, including Days 1, 2, and 3 of Cycle 1 and on Days -1, 1, and 2 of all subsequent cycles).

Treatment:

Drug: ATRA

Coformulation Favezelimab/Pembrolizumab + Vibostolimab

Experimental group

Description:

Participants will receive coformulation of favezelimab and pembrolizumab (MK-4280A) IV and vibostolimab IV at specified doses on specified days for a total treatment duration of up to approximately 2 years.

Treatment:

Biological: Favezelimab/Pembrolizumab

Biological: Vibostolimab