Intralesional Influenza Vaccine for the Treatment of Stage I-IV Melanoma

Study Overview
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Brief Summary
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This phase I trial investigates the effects of influenza vaccine in treating patients with stage I-IV melanoma. While intramuscular administration of influenza vaccine provides immunization against the influenza virus, giving influenza vaccine directly into the tumor (intralesional) may decrease the size of the injected melanoma tumor, or the extent of the melanoma within the body.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability and determine the maximum tolerated dose of intralesional (quadrivalent inactivated influenza vaccine (unadjuvanted influenza vaccine) for patients with a) resectable melanoma as monotherapy, and b) metastatic melanoma, concurrent with standard of care (single- or dual-agent) checkpoint inhibition. SECONDARY OBJECTIVES: I. To evaluate tumor dimensions of injected (Cohorts #1-2) and non-injected lesions (Cohort #2 only), by caliper or ultrasound measurement. (Clinical endpoint) II. To determine time to disease progression (local or distant). (Clinical endpoint) III. To evaluate immunohistochemistry density, cells/mm^2: CD4, CD8, PD-L1, PD1, CD56, CD20, CD45RO, FOXP3. (Tumor-based endpoint) IV. To evaluate granzyme B H-score. (Tumor-based endpoint) V. To evaluate NanoString Pan Cancer Immune Profiling Panel. (Tumor-based endpoint) VI. To evaluate tumor-infiltrating lymphocytes: not identified, present (non-brisk), present (brisk), cannot be determined. (Tumor-based endpoint) VII. To evaluate degree of tumor regression (percent). (Tumor-based endpoint) VIII. To evaluate changes in micro ribonucleic acid (microRNA) expression. (Tumor-based endpoint) IX. To evaluate of flow cytometry for T-cell subset evaluation and changes in circulating microRNA. (Blood draw endpoint) EXPLORATORY OBJECTIVE: I. To evaluate the evidence of immunologic activation in blood and tissue specimens. OUTLINE: This is dose-escalation study. Patients are assigned to 1 of 2 cohorts. COHORT I: Patients receive quadrivalent inactivated influenza vaccine intramuscularly (IM) on day 0 and intratumorally on days 2 and 14 in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery on day 28. COHORT II: Patients receive quadrivalent inactivated influenza vaccine IM on day 0 and intratumorally on days 2, 14, 28, 42, 56, 70, 84, and 98 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care ipilimumab, nivolumab, pembrolizumab, or Opdualag. After completion of study treatment, patients are followed up for up to 1 year.

Official Title
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Intralesional Influenza Vaccine for Patients With Melanoma

Conditions
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Clinical Stage I Cutaneous Melanoma AJCC v8, Clinical Stage IA Cutaneous Melanoma AJCC v8, Clinical Stage IB Cutaneous Melanoma AJCC v8, Clinical Stage II Cutaneous Melanoma AJCC v8, Clinical Stage IIA Cutaneous Melanoma AJCC v8, Clinical Stage IIB Cutaneous Melanoma AJCC v8, Clinical Stage IIC Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma

Intervention / Treatment
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* Biological: Ipilimumab
* Biological: Nivolumab
* Biological: Pembrolizumab
* Biological: Quadrivalent Inactivated Influenza Vaccine
* Procedure: Resection
* Biological: Nivolumab + Relatlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 99 years of age Histologically confirmed cutaneous melanoma by historical pathology report review, clinical Stage I-III (Cohort #1), or Stage IV (Cohort #2) cutaneous melanoma At least one, biopsy-proven, palpable melanoma tumor deposit suitable for intralesional injection measuring ≥ 1 cm by digital caliper (with digital photography documentation) or ultrasound (with ultrasound image documentation) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Exclusion Criteria: Known allergy or intolerance to influenza vaccination Subjects with condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone/equivalent) or other immunosuppressive medications within 14 days of study drug administration Active, known or suspected autoimmune disease Active brain metastasis or leptomeningeal metastasis Diagnostic biopsy of ocular or mucosal melanoma Any melanoma therapy within 6 months of enrollment; though prior surgical resection is permitted Incarcerated patients Human immunodeficiency virus (HIV) positive patients Pregnant or lactating patients Patients incapable of independently providing consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Cohort I (resectable Stage I-III melanoma)<br>Patients receive an influenza vaccine IM on day 0 and intratumorally on days 2 and 14 in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery on day 28. | Biological: Quadrivalent Inactivated Influenza Vaccine<br>* Given IM and intratumorally. For this protocol the U.S. F.D.A recently approved the use of recently expired influenza vaccine (only until new seasonal vaccine is available anticipated Sept 1). Use of expired vaccine will not exceed 4 months past June 30th expiry date (October 30th).<br>* Other names: Quadrivalent Influenza Vaccine;Procedure: Resection<br>* Undergo surgical resection<br>* Other names: Surgical Resection;|
| Experimental: Cohort II (unresectable Stage IV)<br>Patients receive an influenza vaccine IM on day 0 and intratumorally on days 2, 14, 28, 42, 56, 70, 84, and 98 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care (single- or dual-agent) ipilimumab, nivolumab, relatlimab, or pembrolizumab. | Biological: Ipilimumab<br>* immune checkpoint inhibitor<br>* Other names: Yervoy;Biological: Nivolumab<br>* immune checkpoint inhibitor<br>* Other names: Opdivo;Biological: Pembrolizumab<br>* immune checkpoint inhibitor<br>* Other names: SCH 900475;Biological: Quadrivalent Inactivated Influenza Vaccine<br>* Given IM and intratumorally. For this protocol the U.S. F.D.A recently approved the use of recently expired influenza vaccine (only until new seasonal vaccine is available anticipated Sept 1). Use of expired vaccine will not exceed 4 months past June 30th expiry date (October 30th).<br>* Other names: Quadrivalent Influenza Vaccine;Biological: Nivolumab + Relatlimab<br>* immune checkpoint inhibitor<br>* Other names: Opdualag;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability. | Up to 1 year after the last intra-tumoral dose | 
| Maximum tolerated dose (MTD) in Cohorts #1 and #2 | Will employ the Bayesian optimal interval design to find the MTD. | Up to 98 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor dimensions of injected (Cohorts #1) | Will be assessed by caliper or ultrasound measurement. Tumor dimensions will be summarized using descriptive statistics (i.e. mean with standard deviations, or median with range). | Up to 1 year after the last intra-tumoral dose | 
| Tumor dimensions of non-injected lesions (Cohort #2) | Will be assessed by caliper or ultrasound measurement. Tumor dimensions will be summarized using descriptive statistics (i.e. mean with standard deviations, or median with range). | Up to 1 year after the last intra-tumoral dose | 
| Time to disease progression (local or distant) | Time to disease progression will be analyzed using Kaplan-Meier method, resulting in median survival times with 95% confidence interval, assuming sufficient events have occurred. | From the start of treatment until the documentation of local or distant disease progression, assessed up to 1 year | 
| Biomarker analysis | Will analyze immunohistochemistry density, cells/mm^2 of CD4, CD8, PD-L1, PD1, CD56, CD20, CD45RO, FOXP3. Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose | 
| Granzyme B H-score | Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose | 
| NanoString Pan Cancer Immune Profiling Panel | Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose | 
| Tumor-infiltrating lymphocytes analysis | Will analyze tumor-infiltrating lymphocytes: not identified, present (non-brisk), present (brisk), cannot be determined. Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose | 
| Degree of tumor regression (percent) | Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose | 
| Changes in micro ribonucleic acid (RNA) expression | Summary statistics will be used. | Baseline up to 1 year after the last intra-tumoral dose | 
| T-cell subset evaluation and changes in circulating microRNA | Summary statistics will be used. | Up to 1 year after the last intra-tumoral dose |