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)

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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 02A

Conditions
-----------------
Melanoma

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


Participation Criteria
=================
Eligibility Criteria
-----------------
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

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 + Quavonlimab + Vibostolimab<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Quavonlimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-1308;Biological: Vibostolimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-7684;|
| Experimental: Pembrolizumab + Quavonlimab + Lenvatinib<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: KEYTRUDA®;Biological: Quavonlimab<br>* Administered via IV infusion at a specified dose on specified days<br>* Other names: MK-1308;Drug: Lenvatinib<br>* Administered via oral capsules at a specified dose on specified days<br>* Other names: LENVIMA®;|
| Experimental: Pembrolizumab + all-trans retinoic acid (ATRA)<br>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 | Drug: ATRA<br>* Administered via oral capsules at a specified dose on specified days<br>* Other names: VESANOID;|

What is the study measuring?
-----------------
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  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 show 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
receptor tyrosine kinase inhibitor, 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)