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

Intralesional Influenza Vaccine for Patients With Melanoma

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma; 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
• Intervention / Treatment: Procedure: Resection; Biological: Ipilimumab; Biological: Nivolumab; Biological: Pembrolizumab; Biological: Quadrivalent Inactivated Influenza Vaccine; Biological: Nivolumab + Relatlimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Contact: Carlo M. Contreras, MD; Phone Number: 614-366-3681; Email: Carlo.Contreras@osumc.edu
      • Principal Investigator: Carlo M. Contreras, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or females
• 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
• Absolute neutrophil count (ANC) >= 1.5 x 10^3/mm^3 (drawn at or not more than 30 days prior to the screening visit)
• Hemoglobin (Hgb) >= 9 g/dL (drawn at or not more than 30 days prior to the screening visit)
• Platelet count >= 100 x 10^3/mm^3 (drawn at or not more than 30 days prior to the screening visit)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) or =< 5 x ULN in patients with liver metastases (Cohort 2 only) (drawn at or not more than 30 days prior to the screening visit)
• Prothrombin time =< 1.5 x ULN (drawn at or not more than 30 days prior to the screening visit)
• Total bilirubin =< 1.5 x ULN (unconjugated bilirubin of < 3 x ULN for patients with known Gilbert syndrome) (drawn at or not more than 30 days prior to the screening visit)
• Creatinine clearance of >= 50 ml/min by Cockcroft-Gault equation (drawn at or not more than 30 days prior to the screening visit)

• Women of childbearing potential (WOCBP) must agree to use effective contraceptive methods from screening until at least:

  • Cohort 1: 14 days after the surgical resection for subjects in Cohort 1

  • Cohort 2:

    • Nivolumab: 5 months after the last dose of either nivolumab or intralesional Flucelvax, whichever is later
    • Pembrolizumab: 4 months after the last dose of either pembrolizumab or intralesional Flucelvax, whichever is later
    • Ipilimumab: 3 months after the last dose of either ipilimumab or intralesional Flucelvax, whichever is later
    • Relatlimab + nivolumab (marketed under the trade name Opdualag): 5 months after the last dose of either Opdualag or intralesional Flucelvax, whichever is later.

    • Combination ipilimumab with other checkpoint inhibitor: Whichever is later:

      • 3 months after the last dose of either ipilimumab or intralesional Flucelvax
      • Above-bulleted recommendation for nivolumab or pembrolizumab
• Non-childbearing potential is defined as a woman who meets either of the following criteria: a) postmenopausal state defined as no menses for 12 months without an alternative medical cause, or b) documented hysterectomy, bilateral tubal ligation, or bilateral oophorectomy

• Effective contraception methods are defined as one of the following:

  • True abstinence, defined as refraining from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject
  • Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception
  • Condoms and spermicide
  • Diaphragm and spermicide
  • Oral or implanted hormonal contraceptive
  • An intra-uterine device
• WOCBP must have a negative pregnancy test (serum or urine)

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
• Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to randomization: stable and adequate CD4 counts (≥ 350 mm^3), and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria
• Pregnant or lactating patients
• Patients incapable of independently providing consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort I (resectable Stage I-III melanoma); 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.	Procedure: Resection; Undergo surgical resection; Other Names: Surgical Resection; Biological: Quadrivalent Inactivated Influenza Vaccine; 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).; Other Names: Fluzone Quadrivalent; Quadrivalent Influenza Vaccine; QIV; Fluzone Quadrivalent Influenza Vaccine
Experimental: Cohort II (unresectable Stage IV); 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; immune checkpoint inhibitor; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Nivolumab; immune checkpoint inhibitor; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Biological: Pembrolizumab; immune checkpoint inhibitor; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Biological: Quadrivalent Inactivated Influenza Vaccine; 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).; Other Names: Fluzone Quadrivalent; Quadrivalent Influenza Vaccine; QIV; Fluzone Quadrivalent Influenza Vaccine; Biological: Nivolumab + Relatlimab; immune checkpoint inhibitor; Other Names: Opdualag

What is the study measuring?

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
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
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

Collaborators and Investigators

• Sponsor: Carlo Contreras
• Investigators: Principal Investigator: Carlo M Contreras, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2021
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 5, 2021
• First Submitted That Met QC Criteria: January 5, 2021
• First Posted (Actual): January 6, 2021

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Receptors, Cell Surface; Membrane Proteins; Biological Products; Complex Mixtures; Vaccines; Viral Vaccines; Antigens; Antigens, Surface; Biomarkers; Receptors, Immunologic; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Nivolumab; Ipilimumab; pembrolizumab; relatlimab; Opdualag; Influenza Vaccines; CTLA-4 Antigen
• Other Study ID Numbers: OSU-20221; NCI-2020-13282 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No