A Study of Gebasaxturev (V937) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors (V937-013)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy in participants with advanced/metastatic or recurrent malignancies who receive gebasaxturev (V937) in combination with pembrolizumab (MK-3475). The primary objective for Part 1 is to evaluate the objective response rate, and the primary objective for Part 2 is to determine the safety and tolerability of gebasaxturev administered in combination with pembrolizumab. With Amendment 4, this study will be terminated once all participants who have completed or discontinued gebasaxturev treatment and are only receiving pembrolizumab may be enrolled in a pembrolizumab extension study, if available, to continue pembrolizumab monotherapy for up to 35 cycles from first pembrolizumab dose on V937-013.

Official Title
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A Phase 1b/2 Clinical Study of Intratumoral Administration of V937 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Biological: Gebasaxturev
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally-advanced disease that is not amenable to surgery or radiation, or Stage IV advanced/metastatic solid tumor malignancies Histologically- or cytologically-confirmed diagnosis of an advanced/metastatic solid tumor. Measurable disease by RECIST 1.1 criteria as assessed by investigator. Target lesions in a previously irradiated area will be considered measurable if progression has been demonstrated in such lesions Submitted a baseline tumor sample for analysis. Participants enrolling in Part 2 Cohorts D-F may enroll without submitting a tumor sample if all other enrollment criteria are met. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale obtained within 72 hours prior to the first dose of study intervention If participant has known human immunodeficiency virus (HIV)-positive disease, participant must have well-controlled HIV on antiretroviral therapy (ART), per study criteria. Adequate organ function Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent, OR must agree to use contraception unless confirmed to be azoospermic. Female participants are eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) Is a WOCBP and using a contraceptive method that is highly effective, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days after the last dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Part 1, All Cohorts: participants must have at least one injectable lesion amenable to injection and/or biopsy. Part 1, Cohort A: Locally recurrent, inoperable OR metastatic breast cancer treated with at least 1 prior line of therapy in the metastatic setting with skin involvement and/or subcutaneous lesions or accessible lymph nodes amenable to local injection. An exception would be allowed for participants who are not eligible to receive chemotherapy. Diagnosis of triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2-receptor negative status) Part 1, Cohort B: Histologically confirmed advanced or metastatic head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx considered incurable and/or treated with no more than 1 previous line of therapy Tumors must be PD-L1+ Documentation of HPV status for oropharyngeal cancers. Other HNSCC subtypes may submit HPV testing, but is not required. Part 1, Cohort C: Histologically confirmed cutaneous squamous cell carcinoma (cSCC) as the primary site of malignancy Recurrent/metastatic disease only: Has metastatic disease defined as disseminated disease distant from the initial/primary site of diagnosis and/or with a history of locally-recurrent disease previously treated with surgery and/or radiotherapy, which is now incurable Locally-advanced disease only: Must be ineligible for surgical resection per study criteria, and must have received prior radiation therapy to the index site or deemed ineligible for radiation therapy Part 2, Solid Tumors+Liver Metastases Dose Level 1-3 arms: Histologically-confirmed advanced/metastatic solid tumor that has progressed on all treatment known to confer clinical benefit Metastatic liver lesion(s) not exceeding one-third of the total liver volume AND a minimum of one injectable liver lesion Part 2, Cohort D: Advanced hepatocellular carcinoma (HCC) following progression on, or intolerance to, sorafenib or lenvatinib with no curative options Diagnosis of HCC confirmed by radiology, histology, or cytology Child-Pugh Class A score If a participant has a history of hepatitis C virus (HCV) infection, then the participant must have been successfully treated for this condition Controlled (treated) hepatitis B participants will be allowed if they meet protocol-specified criteria Participants who are anti-hepatitis B core (HBc) positive, negative for hepatitis B surface antigen (HBsAg), negative or positive for anti-hepatitis B surface (HBs), and who have an HBV viral load under 100 IU/mL, do not require HBV anti-viral prophylaxis Part 2, Cohort E: Histologically- or cytologically-confirmed diagnosis of locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma Received at least one prior line of therapy that includes a platinum/fluoropyrimidine doublet or triplet regimen Had proven clinical progression 6 months following (or during) last dose of adjuvant or neo-adjuvant therapy Human epidermal growth factor receptor 2 (HER2) negative status; or, those with HER2 positive status AND documented disease progression on a prior regimen containing trastuzumab Exclusion Criteria: Chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to first dose of study intervention, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better If major or minor surgery was performed at/near the area being considered for injection, participant must be recovered from toxicity and/or complications of intervention If participant has had injection or radiation therapy, participant must be recovered from toxicity and/or complications of intervention History of second malignancy, unless potentially curative treatment has been completed with no further evidence of disease for ≥5 years. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with treated brain metastases may participate if lesions are radiologically stable. Active infection requiring therapy, except HIV criteria as stated above, and HBV and HCV criteria for HCC cohort as stated above History of interstitial lung disease History of noninfectious pneumonitis requiring active steroid therapy or ongoing pneumonitis Active autoimmune disease that required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy Known Hepatitis B or C infections or known to be positive for HBsAg/HBV deoxyribonucleic acid (DNA) or Hepatitis C Antibody or ribonucleic acid (RNA) History of Kaposi's sarcoma and/or Multicentric Castleman's Disease Known hypersensitivity to gebasaxturev and/or pembrolizumab or any of their excipients Received prior therapy with anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1) agents, Talimogene Laherparepvec (T-VEC), or any other oncolytic virus therapies Received a live or live-attenuated vaccine within 30 days prior to first dose of study intervention. Administration of killed vaccines is allowed. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention Part 2, Cohort D: Has had esophageal or gastric variceal bleeding within the last 6 months Has had clinically diagnosed hepatic encephalopathy in the 6 months prior to initiation of study intervention Part 2, Cohort E: Squamous cell or undifferentiated gastric cancer

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Cohort A: Triple-Negative Breast Cancer<br>This arm will enroll participants with triple-negative breast cancer (TNBC) solid tumors. Participants receive gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 1, Cohort B: Head and Neck Squamous Cell Carcinoma<br>This arm will enroll participants with head and neck squamous cell carcinoma (HNSCC) solid tumors. Participants receive gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 1, Cohort C: Cutaneous Squamous Cell Carcinoma<br>This arm will enroll participants with cutaneous squamous cell carcinoma (cSCC) solid tumors. Participants receive gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 2 Dose Level 1, Solid Tumors + Liver Metastases<br>This arm will enroll participants with solid tumors with liver metastases. Participants receive dose level 1 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 2 Dose Level 2, Solid Tumors + Liver Metastases<br>This arm will enroll participants with solid tumors with liver metastases. Participants receive dose level 2 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 2 Dose Level 3, Solid Tumors + Liver Metastases<br>This arm will enroll participants with solid tumors with liver metastases. Participants receive dose level 3 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 2, Cohort D: Hepatocellular Carcinoma (HCC)<br>This arm will enroll participants with hepatocellular carcinoma (HCC) solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|
| Experimental: Part 2, Cohort E: Gastric Carcinoma<br>This arm will enroll participants with gastric carcinoma solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. | Biological: Gebasaxturev<br>* Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles.<br>* Other names: V937;Drug: Pembrolizumab<br>* Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Investigator | ORR is defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions and no new lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 
| Number of Participants who Experience a Dose-Limiting Toxicity (DLT) | DLTs are defined as toxicities that: are possibly, probably, or definitely related to study intervention administration; and meet pre-defined study criteria. | Up to approximately 4 weeks | 
| Part 2: Number of Participants Who Experienced One or More Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Only the Part 2 arms will be analyzed in this outcome measure. | Up to approximately 107 weeks | 
| Part 2: Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Only the Part 2 arms will be analyzed in this outcome measure. | Up to approximately 103 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants Who Experienced One or More Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 107 weeks | 
| Part 1: Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 103 weeks | 
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Investigator | PFS is defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by investigator. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 
| Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Investigator | For participants who demonstrate a confirmed immune-based Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics (iRECIST) as Assessed by Investigator | PFS is defined as the time from first dose of study treatment to the first documented immune-based confirmed progressive disease (iCPD) or death due to any cause, whichever occurs first as assessed by investigator. Per iRECIST, iCPD is defined as worsening of any existing cause of progression, or the appearance of any other cause of progression, relative to the initial appearance of progressive disease by RECIST 1.1. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 
| Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics (iRECIST) as Assessed by Investigator | For participants who demonstrate a confirmed immune-based Complete Response (iCR: Disappearance of all target lesions) or an immune-based Partial Response (iPR: ≥30% decrease in the sum of diameters of target lesions) per iRECIST 1.1 as assessed by investigator, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Only the Part 1 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 
| Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics (iRECIST) as Assessed by Investigator | ORR is defined as the percentage of participants in the analysis population who had an immune-based Complete Response (iCR: Disappearance of all target lesions) or an immune-based Partial Response (iPR: ≥30% decrease in the sum of diameters of target lesions) per iRECIST 1.1 as assessed by investigator. | Up to approximately 44 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 44 months | 
| Solid Tumors + Liver Metastases Arms: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Investigator | ORR is defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions and no new lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Only the Solid Tumors+Liver Metastases Dose Level 1-3 arms will be analyzed in this outcome measure. | Up to approximately 44 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)