Efficacy, Safety, and Tolerability of Gebasaxturev (V937) Administered Intravenously or Intratumorally With Pembrolizumab (MK-3475) Versus Pembrolizumab Alone in Participants With Advanced/Metastatic Melanoma (V937-011)

Study Overview
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Brief Summary
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This is a Phase 2 study to assess the efficacy, safety, and tolerability of gebasaxturev administered both intratumorally (ITu) and intravenously (IV) as combination therapy with pembrolizumab (MK-3475) versus pembrolizumab alone in anti-programmed cell death ligand 1 (anti-PD-L1)-treatment-naive participants with advanced/metastatic melanoma. The primary hypothesis of the study is that gebasaxturev administered either ITu or IV in combination with pembrolizumab results in a superior objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review (BICR), compared to pembrolizumab alone. This study will be terminated once all participants finish treatment with V937. Participants eligible to continue to receive pembrolizumab will be transferred to MK-3475-587 study.

Official Title
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A Phase 2, Randomized Clinical Study of Intravenous or Intratumoral Administration of V937 in Combination With Pembrolizumab (MK-3475) Versus Pembrolizumab Alone in Participants With Advanced/Metastatic Melanoma

Conditions
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Advanced/Metastatic Melanoma

Intervention / Treatment
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* Biological: Gebasaxturev IV
* Biological: Gebasaxturev ITu
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically or cytologically confirmed diagnosis of advanced/metastatic melanoma. Has Stage III or Stage IV melanoma. Must be naive to anti-PD-L1 treatment, talimogene laherparepvec (TVEC) and other oncolytic viruses. Has 2 lesions as defined below: At least 1 cutaneous or subcutaneous lesion that is amenable to IT injection and biopsy and measurable per RECIST 1.1 At least 1 distant and/or discrete noninjected lesion that is amenable to biopsy and measurable per RECIST 1.1 Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale Demonstrates adequate organ function Male participants refrain from donating sperm during the intervention period and for at least 120 days after the last dose of study intervention PLUS are either abstinent from heterosexual intercourse OR agree to use approved contraception during that period Female participants are not pregnant or breastfeeding and are not a woman of childbearing potential (WOCBP) OR are a WOCBP that agrees to use contraception during the treatment and for at least 120 days after the last dose of study intervention Has measurable disease per RECIST 1.1 Is able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated Human Immunodeficiency Virus (HIV)-infected participants must have well controlled HIV on anti-retroviral therapy (ART), defined as: Must have Cluster of Differentiation 4 (CD4)+ T-cell count >350 cells/mm^3 at time of screening Must have achieved and maintained virologic suppression Must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry The combination ART regimen must not contain any antiretroviral medication other than abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenofovir Exclusion Criteria: Has had chemotherapy, definitive radiation, or biological cancer therapy or an investigational agent or investigational device within 4 weeks prior to the first dose of study intervention or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier Has ocular melanoma Has radiographic evidence of major blood vessel infiltration Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the study requirements Has undergone allogeneic hematopoietic stem cell transplantation within the last 5 years Has not fully recovered from major surgery without significant detectable infection Active cardiovascular disease (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure or serious cardiac arrhythmia requiring medication Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or other agents such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), OX-40, Cluster of Differentiation 137 (CD137) Has received a live vaccine within 30 days prior to the first dose of study drug Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug Has a known additional malignancy that is progressing or has required active treatment within the past 2 years Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has hypersensitivity to pembrolizumab and/or any of its excipients Has hypersensitivity to gebasaxturev or any of its excipients Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis Has an active infection requiring systemic therapy Has a known history of Hepatitis B or known active Hepatitis C virus infection Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 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: IV Gebasaxturev + Pembrolizumab<br>Participants receive gebasaxturev at a dose of 1 X 10^9 TCID50 by IV infusion on Days 1, 3, 5, and 8 of Cycle 1 (28-day cycle) and Day 1 of Cycles 2-8 (21-day cycles) plus pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Gebasaxturev will be administered for up to 8 cycles (up to 6 months). Pembrolizumab will be administered for up to 35 cycles (up to 2 years). | Biological: Gebasaxturev IV<br>* Administered as an IV infusion of 1 X 10^9 TCID50<br>* Other names: V937;Drug: Pembrolizumab<br>* Administered as an IV infusion of 200 mg<br>* Other names: Keytruda®;|
| Experimental: ITu Gebasaxturev + Pembrolizumab<br>Participants receive gebasaxturev at a dose of 3 X 10^8 TCID50 by ITu injection on Days 1, 3, 5, and 8 of Cycle 1 (28-day cycle) and Day 1 of Cycles 2-8 (21-day cycles) plus pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Gebasaxturev will be administered for up to 8 cycles (up to 6 months). Pembrolizumab will be administered for up to 35 cycles (up to 2 years). | Biological: Gebasaxturev ITu<br>* Administered as an ITu injection of 3 X 10^8 TCID50<br>* Other names: V937;Drug: Pembrolizumab<br>* Administered as an IV infusion of 200 mg<br>* Other names: Keytruda®;|
| Experimental: Pembrolizumab<br>Participants receive pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Pembrolizumab will be administered for up to 35 cycles (up to 2 years). | Drug: Pembrolizumab<br>* Administered as an IV infusion of 200 mg<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | ORR is defined as the percentage of participants who have a Complete Response (CR: disappearance of all lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions, without evidence of progression based on non-target or new lesions) as assessed by BICR per RECIST 1.1 which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experience a CR or PR based on modified RECIST 1.1 will be presented. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) per RECIST 1.1 as Assessed by BICR | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as either a 20% increase from nadir in target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions. PFS will be assessed by BICR for this outcome measure. | Up to 3 years | 
| Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR | For participants who demonstrate a confirmed complete response (CR: disappearance of all lesions) or confirmed Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions, without evidence of progression based on non-target or new lesions.) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and will be assessed by BICR for this outcome measure. | Up to 3 years | 
| ORR per RECIST 1.1 as Assessed by the Investigator | ORR is defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, without evidence of progression based on non-target or new lesions.) as assessed by the investigator per RECIST 1.1, which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experience a CR or PR based on modified RECIST 1.1 will be presented. | Up to 3 years | 
| PFS per RECIST 1.1 as Assessed by the Investigator | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as either a 20% increase from nadir in target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions. PFS will be assessed by the investigator for this outcome measure. | Up to 3 years | 
| DOR per RECIST 1.1 as Assessed by the Investigator | For participants who demonstrate a confirmed complete response (CR: disappearance of all lesions) or confirmed Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. DOR will be assessed by the investigator for this outcome measure. | Up to 3 years | 
| Overall Survival (OS) | OS is defined as the time from the date of study treatment to the date of death due to any cause. | Up to 3 years | 
| Number of Participants with One or More Adverse Events (AEs) | 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 at least one AE will be reported. | Up to 30 days after last dose (up to 3 years) | 
| Number of Participants who Discontinue Study Drug 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 2 years | 

 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), programmed cell death ligand 2 (PD-L2, PDL2), Coxsackievirus A21, Intracellular Adhesion Molecule-1 (ICAM-1)