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

Official title

Intralesional Influenza Vaccine for Patients With Melanoma

Overview

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

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.

Interventions

• Biological Ipilimumab
  immune checkpoint inhibitor
• Biological Nivolumab
  immune checkpoint inhibitor
• Biological Pembrolizumab
  immune checkpoint inhibitor
• 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).
• Procedure Resection
  Undergo surgical resection
• Biological Nivolumab + Relatlimab
  immune checkpoint inhibitor

Primary outcome measures

• Incidence of adverse events (AEs) [Time frame: Up to 1 year after the last intra-tumoral dose]
• Maximum tolerated dose (MTD) in Cohorts #1 and #2 [Time frame: Up to 98 days]

Secondary outcome measures (10)

• Tumor dimensions of injected (Cohorts #1) [Time frame: Up to 1 year after the last intra-tumoral dose]
• Tumor dimensions of non-injected lesions (Cohort #2) [Time frame: Up to 1 year after the last intra-tumoral dose]
• Time to disease progression (local or distant) [Time frame: From the start of treatment until the documentation of local or distant disease progression, assessed up to 1 year]
• Biomarker analysis [Time frame: Up to 1 year after the last intra-tumoral dose]
• Granzyme B H-score [Time frame: Up to 1 year after the last intra-tumoral dose]
• NanoString Pan Cancer Immune Profiling Panel [Time frame: Up to 1 year after the last intra-tumoral dose]
• Tumor-infiltrating lymphocytes analysis [Time frame: Up to 1 year after the last intra-tumoral dose]
• Degree of tumor regression (percent) [Time frame: Up to 1 year after the last intra-tumoral dose]
• Changes in micro ribonucleic acid (RNA) expression [Time frame: Baseline up to 1 year after the last intra-tumoral dose]
• T-cell subset evaluation and changes in circulating microRNA [Time frame: Up to 1 year after the last intra-tumoral dose]

Eligibility criteria

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) >= 8 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Ohio State University Comprehensive Cancer Center — Columbus

Identifiers

NCT: NCT04697576 · OSU-20221 · NCI-2020-13282

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗