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)

Study Overview
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Brief Summary
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Substudy 02B 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 02B is to evaluate the safety and efficacy of investigational treatment arms in participants with 1L advanced melanoma and to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/pembrolizumab monotherapy. Arm 1: Pembrolizumab + Vibostolimab was added in the base protocol on 13-Nov-2019, and enrollment into this arm has been completed. Arm 2: Pembrolizumab was added in the base protocol on 13-Nov-2019, and enrollment stopped prematurely on 15-Aug-2022. Arm 3: Coformulation Pembrolizumab/Quavonlimab was added in Amendment 01 on 20-Oct-2020, and enrollment stopped prematurely on 15-Aug-2022. Arm 4: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib was added in Amendment 01 on 20-Oct-2020, and enrollment is ongoing. Arm 5: Coformulation Favezelimab/Pembrolizumab, Arm 6: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA), and Arm 7: Coformulation Favezelimab/Pembrolizumab + Vibostolimab were added in Amendment 04 on 10-May-2023, and enrollment for these arms will be initiated in July 2023.

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 02B

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Vibostolimab
* Biological: Pembrolizumab/Quavonlimab
* Drug: Lenvatinib
* 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 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

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>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. | 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;|
| Active Comparator: Pembrolizumab<br>Participants will receive pembrolizumab IV at a specified dose on specified days for a total treatment duration of up to approximately 2 years. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;|
| Experimental: Coformulation Pembrolizumab/Quavonlimab<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Pembrolizumab/Quavonlimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-1308A;|
| Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Pembrolizumab/Quavonlimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-1308A;Drug: Lenvatinib<br>* Administered via oral capsule at a specified dose on specified days<br>* Other names: LENVIMA®;|
| Experimental: Coformulation Favezelimab/Pembrolizumab<br>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 | Biological: Favezelimab/Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-4280A;|
| Experimental: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA)<br>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). | Drug: ATRA<br>* Administered via oral capsule at a specified dose on specified days<br>|
| Experimental: Coformulation Favezelimab/Pembrolizumab + Vibostolimab<br>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. | Biological: Vibostolimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-7684;Biological: Favezelimab/Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-4280A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who experience a dose-limiting toxicity (DLT): Safety lead-in phase | The percentage of participants who experience 1 or more protocol-defined DLTs during the safety lead-in period will be reported. | Up to  3 weeks | 
| Percentage of participants who experience an adverse event (AE): Safety lead-in | 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 during the safety lead-in period will be reported. | Up to  3 weeks | 
| Percentage of participants who discontinue study treatment due to an AE: Safety lead-in | 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 during the safety lead-in will be reported. | Up to  3 weeks | 
| 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 demonstrate 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 | 

 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), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT), Cytotoxic T lymphocyte associated protein 4 (CTLA4)