NY-ESO-1 Protein Vaccine With Imiquimod in Melanoma (Adjuvant Setting)

Phase 1

Completed

Conditions: Malignant Melanoma

Interventions: Drug: Imiquimod
Biological: NY-ESO-1 protein

Registration Number: NCT00142454

Lead Sponsor: Ludwig Institute for Cancer Research

Brief Summary: This was a Phase 1, single-arm, open-label, pilot study of NY-ESO-1 protein vaccination with imiquimod as an adjuvant in patients with resected Stage IIB, IIC, and III malignant melanoma. The primary study objective was to determine the safety of NY-ESO-1 protein/imiquimod treatment, and the secondary objective was to evaluate the immunogenicity of treatment.

Detailed Description: Patients applied imiquimod (250 mg) topically to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). The NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.

Safety was monitored continuously. Immunization was assessed by the generation of NY-ESO-1-specific cluster of differentiation (CD)4+ and CD8+ T cell responses in enzyme-linked immunosorbent spot (ELISPOT) assays and by the development or augmentation of NY-ESO-1-specific antibody titers, assessed by enzyme-linked immunosorbent assay (ELISA).

Blood samples were obtained for the assessment of clinical biochemistry and hematology, and physical examinations were performed at baseline, on Day 1 of each cycle, and at a follow-up visit at Week 13.

Skin biopsies of the vaccinated area were obtained 48 hours after the last injection (Day 5 of Cycle 4). To avoid irritation, imiquimod was not applied after the biopsies.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Had histologically confirmed, resected American Joint Committee on Cancer Stage IIB, IIC or III malignant melanoma
Fully recovered from surgery
Age ≥ 18 years; children were excluded from this study, as the safety of imiquimod had not been established in patients below the age of 18
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Adequate organ and marrow function as defined below:
- absolute neutrophil count: ≥ 1500/μL
- hemoglobin: ≥ 9 g/dL
- platelets: ≥ 100,000/μL
- total bilirubin: ≤ 1.5 × institutional upper limit of normal (ULN)
- aspartate aminotransferase/alanine aminotransferase (AST/ALT): ≤ 2.5 × institutional ULN
- creatinine: ≤ 1.5 × institutional ULN
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Received chemotherapy, immunotherapy (including interferon), or radiotherapy within 4 weeks prior to first dosing of study agent
Prior treatment with NY-ESO-1 vaccines
Known human immunodeficiency virus infection or autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus), as these conditions could have interfered with the evaluation of the induced immune response; patients with vitiligo or melanoma-associated hypopigmentation were not excluded
History of allergic reactions attributed to compounds of similar chemical or biologic composition to imiquimod or other agents used in the study
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would have limited compliance with study requirements
Pregnancy or lactation
Women of childbearing potential not using a medically acceptable means of contraception
Known history of inflammatory skin disorders, as imiquimod might have exacerbated these conditions
Chronic corticosteroid or immunosuppressive therapies, as these might have interfered with the evaluation of the induced immune response
Lack of availability for immunological and clinical follow-up assessments

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Imiquimod + NY-ESO-1	NY-ESO-1 protein	Patients applied topical imiquimod followed by vaccination with intradermal injections of the NY-ESO-1 protein.
Imiquimod + NY-ESO-1	Imiquimod	Patients applied topical imiquimod followed by vaccination with intradermal injections of the NY-ESO-1 protein.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Treatment-emergent Adverse Events (TEAEs)	Up to 4 months	Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (fatal). Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, and any other medically indicated assessments, including patient interviews, from the time informed consent was signed through the last follow-up visit. AEs were considered to be treatment emergent (TEAE) if they occurred or worsened in severity after the first dose of study treatment.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Cellular Antibody Response to NY-ESO-1 at Two or More Post-vaccination Time Points	Up to 4 months	Assays to assess cluster of differentiation (CD)8+ and CD4+ antigen-specific responses were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immune absorbent spot (ELISPOT) assay following prior in vitro sensitization. A 3-fold increase in spot-forming cells over baseline defined a positive response. Suitable antigens may have included recombinant viral vectors encoding NY-ESO-1, or NY-ESO-1 overlapping peptides, depending upon availability.
Number of Patients With Humoral Antibody Response to NY-ESO-1	Up to 4 months	Assays to assess NY-ESO-1 specific antibodies were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immunosorbent assay (ELISA). Samples were diluted serially. The induction and augmentation of immunity were defined as an increase in antibody titer of ≥ 3× over buffer alone or ≥ 4× the pre-vaccination titer, respectively. Sera from the responding patients were tested a second time against a pool of NY-ESO-1 overlapping peptides to confirm NY-ESO-1 specificity; the number of patients in the table reflect the patients with confirmed NY-ESO-1 specificity.