Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/KEYMAKER-U02)

Merck Sharp & Dohme (MSD)

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

Conditions: Melanoma

Treatments: Biological: Gebasaxturev; Drug: ATRA; Biological: Favezelimab + Pembrolizumab; Biological: Vibostolimab; Biological: MK-4830; Biological: Pembrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT04303169

2019-003978-22 (EudraCT Number)

3475-02C

KEYMAKER-U02 (Other Identifier)

MK-3475-02C (Other Identifier)

Details and patient eligibility

About

Substudy 02C 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 02C is to evaluate the safety and efficacy of investigational treatment arms in participants with Stage III melanoma who are candidates for neoadjuvant therapy to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.

Arm 1: Pembrolizumab + Vibostolimab, Arm 2: Pembrolizumab + Gebasaxturev, and Arm 3: Pembrolizumab were added in the base protocol on 13-Nov-2019, and enrollment into those arms has been completed. Arm 4: Pembrolizumab + MK-4830 was added in Amendment 04 on 20-Dec-2021, and enrollment into that arm has been completed. Arm 5: Favezelimab + Pembrolizumab and Arm 6: Pembrolizumab + all-trans retinoic acid (ATRA) were added in Amendment 06 on 25-Jun-2022, and enrollment is ongoing.

Enrollment: 90 estimated patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Has histologically or cytologically confirmed melanoma

• Has clinically detectable and resectable Stage IIIB or IIIC or IIID melanoma amenable to surgery

• Has been untreated for Stage IIIB, IIIC or IIID melanoma

  • surgical resection of primary melanoma is allowed
  • prior radiotherapy to the primary melanoma is allowed

• Has provided a baseline tumor biopsy

• Male participants who receive gebasaxturev are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 120 days after the last dose of gebasaxturev

• Male participants who receive 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 ATRA

• Female participants 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, vibostolimab, gebasaxturev, or MK-4830, favezelimab + pembrolizumab, or 30 days after the last dose of 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 monoclonal antibody (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 or live-attenuated 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 only mucosal lesions
• Is not naïve to Talimogene laherparepvec (TVEC) and other oncolytic viruses

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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90 participants in 6 patient groups

Pembrolizumab + Vibostolimab

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab intravenously (IV) plus vibostolimab IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Pembrolizumab

Biological: Vibostolimab

Pembrolizumab + Gebasaxturev

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus gebasaxturev (V937) intratumorally (IT) at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Pembrolizumab

Biological: Gebasaxturev

Pembrolizumab

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Pembrolizumab

Pembrolizumab + MK-4830

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus MK-4830 IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Pembrolizumab

Biological: MK-4830

Favezelimab + Pembrolizumab

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive MK-4280A (favezelimab and pembrolizumab administered as a co-formulation) IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Favezelimab + Pembrolizumab

Pembrolizumab + all-trans retinoic acid (ATRA)

Experimental group

Description:

Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus ATRA orally at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.

Treatment:

Biological: Pembrolizumab

Drug: ATRA