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)

Study Overview
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Brief Summary
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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.

Official Title
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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 02C

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Vibostolimab
* Biological: Gebasaxturev
* Biological: MK-4830
* Biological: Favezelimab + Pembrolizumab
* Drug: ATRA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Vibostolimab<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Vibostolimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-7684;|
| Experimental: Pembrolizumab + Gebasaxturev<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Gebasaxturev<br>* Administered via IT injection at a specified dose on specified days<br>* Other names: V937;|
| Experimental: Pembrolizumab<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;|
| Experimental: Pembrolizumab + MK-4830<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* Administered via IV infusion at a specified dose on specified days<br>|
| Experimental: Favezelimab + Pembrolizumab<br>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. | Biological: Favezelimab + Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-4280A;|
| Experimental: Pembrolizumab + all-trans retinoic acid (ATRA)<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Drug: ATRA<br>* Administered via oral capsules at a specified dose on specified days<br>* Other names: Vesanoid®;|

What is the study measuring?
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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  16 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  12 months | 
| Pathological complete response (pCR) rate | pCR rate is defined as the proportion of participants with complete absence of viable tumor in the treated tumor bed. Assessments are according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by central review of the pathology results. 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  1.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Near pathological complete response (near pCR) rate | Near pCR is defined as the proportion of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed. Assessments are according to RECIST 1.1 by central review of the pathology results. 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  1.5 months | 
| Pathological partial response (pPR) rate | pPR rate is defined as the proportion of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells. Assessments are according to RECIST 1.1 by central review of the pathology results. 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  1.5 months | 
| Recurrence-free survival (RFS) | RFS is defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Assessments are according to RECIST 1.1 which 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  60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), Coxsackievirus A21, Intracellular Adhesion Molecule-1 (ICAM-1), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT)