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Adjuvants, Immunologic

4 melanoma peptides pulsed on monocyte-derived dendritic cells

4 melanoma peptides administered as an emulsion with GM-CSF and Montanide ISA-51 adjuvant.

Systemic subcutaneous delivery of low-dose IL-2.

aldesleukin

gp100 antigen

incomplete Freund's adjuvant

sargramostim

tetanus peptide melanoma vaccine

tyrosinase peptide

Craig L. Slingluff, MD

RATIONALE: Vaccines made from melanoma cells may make the body build an immune response to and kill tumor cells. Colony-stimulating factors such as GM-CSF may increase the number of immune cells found in the bone marrow or peripheral blood. Interleukin-2 may stimulate a person's white blood cells to kill melanoma cells. Combining vaccine therapy with GM-CSF and interleukin-2 may be kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of vaccines made from melanoma cells with or without GM-CSF followed by interleukin-2 in treating patients with stage III or stage IV melanoma.

OBJECTIVES: I. Compare the effectiveness of vaccination with synthetic melanoma peptides pulsed on autologous dendritic cells versus vaccination with synthetic melanoma peptides plus sargramostim (GM-CSF) in decreasing tumor burden in patients with high risk melanoma (pulsed autologous dendritic cell arm closed 1/8/2001). II. Determine whether these regimens result in increased tumor specific immune responses as measured in vitro and in vivo. III. Determine whether these regimens stimulate T-cell responses in these patients.

OUTLINE: This is an open label study. Patients are included in treatment arm II only (arm I closed 1/8/2001): Arm I: Patients undergo leukapheresis to collect dendritic cells. Patients receive a mixture of synthetic melanoma peptides (gp100 antigen, tyrosinase, and tetanus peptides) pulsed on autologous dendritic cells IV and subcutaneously (SC). Arm II: Patients receive a mixture of synthetic melanoma peptides (gp100 antigen, tyrosinase, and tetanus peptides) and sargramostim (GM-CSF) emulsified in Montanide ISA-51 SC and intradermally. Patients receive vaccination during weeks 0, 1, 2, 4, 5, and 6 for a total of 6 doses and interleukin-2 SC daily on days 7-49. Patients receive 3 additional vaccinations at different sites not involved with the tumor concurrently with the first 3 vaccinations. Patients are evaluated at 8 weeks, 12 weeks, 6 months, 12 months, and 24 months.

PROJECTED ACCRUAL: A total of 27-54 patients will be accrued for this study within 2 years.

Vaccine Therapy Plus Interleukin-2 in Treating Patients With Stage III or Stage IV Melanoma

Phase II Trial for the Evaluation of the Efficacy of Vaccination With Synthetic Melanoma Peptides Either Pulsed on Dendritic Cells, or Administered With GM-CSF-in-Adjuvant, Plus Administration of Sustemic IL-2, in Patients With Advanced Melanoma.

The primary end point for this trial was clinical response. This was assessed by measurement of assessable metastatic deposits by CT, MRI, or direct measure of cutaneous deposits. Baseline tumor measurements used for assessment of clinical response were those obtained most immediately before the first vaccine administration and within 6 weeks of protocol entry. Measurements were made and reviewed by a multidisciplinary team. The original protocol defined tumor response on the basis of changes in cross-sectional area calculated as the product of two perpendicular measures. However, since the initiation of this study, the Response Evaluation Criteria in Solid Tumors Group (RECIST) system was employed as the current standard for clinical trials, in which response is based on changes in maximum cross-sectional dimensions. Computed tomography scans of clinical responders were reviewed again by a senior faculty radiologist not otherwise involved in the study.

National Cancer Institute (NCI)

University of Virginia

Principal Investigator

Toxicity was recorded with a daily diary of toxicities, reviewed by the research team and supplemented by direct questioning, for the as treated population. Among patients assigned to arm 1, 3 patients progressed rapidly during DC preparation and required other interventions that caused removal from this study before the first vaccine.

Peptides Pulsed on Dendritic Cells

Peptides in GMCSF-in-adjuvant

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Complete Response

Partial Response

Stable Disease

Progressive Disease

The analysis of this outcome measure was performed on subjects enrolled in Stage I of the trial, which included 13 subjects in each arm.

Evaluation of Objective Clinical Response (CR/PR/SD)

This is a test for differences between the response rates of the two arms. The null hypothesis is that the arms have equal response rates and the alternative hypothesis is that they are different.

The analysis of this outcome measure was performed on subjects enrolled in Stage I of the trial, which included 13 subjects in each arm. Some patients were not evaluable because of inadequate sample availability.

Measure of Tumor-antigen-specific Immunity in Peripheral Blood Mononuclear Cells (PBMC) by Elispot Assay

Analysis of this outcome measure was performed on subjects in Stage I of the trial. Sentinel immunized nodes (SIN) were not evaluable for early tumor progression (5 arm 1, 2 arm 2) and patient refusal (1 arm 2). Thus, SINs were evaluable from 8 in arm 1 and 10 on arm 2, exceeding the protocol requirement for at least 6 subjects on each arm.

Measure of Tumor-antigen-specific Immunity in Sentinel Immunized Node (SIN) by Elispot Assay

---peptides were pulsed on monocyte-derived dendritic cells cultures in GM-CSF and IL-4

---Peptides were administered in an emulsion of sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's) adjuvant

Peptides in Sargramostim (GMCSF)-In-Montanide ISA-51 Adjuvant

Overall Study

Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

melanoma helper peptide vaccine

multi-epitope melanoma peptide vaccine

RATIONALE: Vaccines made from peptides may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying four different vaccines using melanoma peptides from cytotoxic T cells and helper T cells to see how well they work in treating patients with metastatic melanoma.

OBJECTIVES:

* Compare the cytotoxic T-cell response to each of 12 melanoma peptides restricted by Human Leukocyte Antigen (HLA)-A1, -A2, or -A3 in patients with metastatic melanoma vaccinated with or without these 12 melanoma peptides and with or without helper peptides.
* Compare the helper T-cell response to each of 6 melanoma helper peptides restricted by HLA-DR molecules in patients treated with these vaccinations.
* Determine whether the addition of 6 melanoma helper peptides to a vaccine containing multiple class I Major histocompatibility complex (MHC)-restricted peptides augments T-cell responses to the class I restricted peptides in these patients.
* Determine, preliminarily, whether booster vaccination maintains immune response in patients treated with these vaccinations.
* Compare the rates of clinical response and survival in patients treated with these vaccinations.
* Determine, preliminarily, whether cellular immune response correlates with clinical response and survival rates in patients treated with these vaccinations.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to HLA type (HLA-A1 vs HLA-A2 vs HLA-A1 and -A2 vs HLA-A3) and planned sentinel immunized node biopsy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

* Arm I: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (Granulocyte-macrophage colony-stimulating factor, GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
* Arm II: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
* Arm III (closed to accrual as of 5/19/08): Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.
* Arm IV: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

In all arms, patients continue therapy in the absence of unacceptable toxicity or disease progression necessitating other urgent therapy.

Patients are evaluated at 8 and 12 weeks. Beginning 2-3 weeks after the week-12 evaluation, patients with no evidence of disease progression may receive booster vaccinations according to their randomized treatment arm. Patients receive booster vaccination ID and SC once weekly for 3 weeks. Treatment repeats every 9 weeks for 1 course, every 12 weeks for 2 courses, and then every 24 weeks for 2 courses OR for up to 2 years (whichever comes first) provided the patient does not require an urgent change in therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then for survival for 5 years from study randomization.

ACTUAL ACCRUAL: A total of 175 patients were accrued for this study during March 2005 and January 2009.

Vaccine Therapy Using Melanoma Peptides for Cytotoxic T Cells and Helper T Cells in Treating Patients With Metastatic Melanoma

A Randomized Phase II Trial of Multi-Epitope Vaccination With Melanoma Peptides For Cytotoxic T Cells And Helper T Cells For Patients With Metastatic Melanoma

Assessment of CTL response was based on a fold-increase in T cell response measure by interferon-gamma ELIspot assay.

Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.

Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate is calculated as the number of patients with complete response (disappearance of all lesions) or partial response () divided by total number of evaluable patients.

OS was defined as the time from registration to death from any cause.

Eastern Cooperative Oncology Group

All patients who received protocol therapy were evaluated for toxicity, regardless of eligibility.

Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

multi-epitope melanoma peptide vaccine : Given by injection

incomplete Freund's adjuvant : Given by injection

sargramostim : Given by injection

Arm I (12MP)

Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

multi-epitope melanoma peptide vaccine : Given by injection

incomplete Freund's adjuvant : Given by injection

sargramostim : Given by injection

tetanus peptide melanoma vaccine : Given by injection

Arm II (12MP/Tet)

Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

multi-epitope melanoma peptide vaccine : Given by injection

incomplete Freund's adjuvant : Given by injection

sargramostim : Given by injection

melanoma helper peptide vaccine : Given by injection

Arm III (12MP/6MHP)

Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

incomplete Freund's adjuvant : Given by injection

sargramostim : Given by injection

melanoma helper peptide vaccine : Given by injection

Arm IV (6MHP)

Study Statistician

Compare CTL response rate among four arms. The null hypothesis is that CTL response is same in all four arms. Alternative hypothesis is that CTL response rate is different in at least one arm compared to other arms.

140 eligible and treated patients who had CTL response data were included in the analysis

Cytotoxic T-cell Lymphocytes (CTL) Response Rate

Compare HTL response rate to 6MHP among four arms. The null hypothesis is that HTL response is same in all four arms. Alternative hypothesis is that HTL response rate is different in at least one arm compared to other arms.

128 eligible and treated patients who had data about helper T cell response were included in the analysis

Helper T-cells Response to 6MHP

Compare HTL response rate to tetanus peptide among four arms. The null hypothesis is that HTL response is same in all four arms. Alternative hypothesis is that HTL response rate is different in at least one arm compared to other arms.

128 eligible and treated patients who had data about HTL response to tetanus peptide were included in the analysis

Helper T Cell Response to Tetanus

Compare objective response rate among four arms. The null hypothesis is that objective response rate is same in all four arms. Alternative hypothesis is that objective response rate is different in at least one arm compared to other arms.

148 eligible and treated patients were included in the analysis

Objective Response Rate

Compare overall survival curves among four arms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Vaccine Therapy Plus Interleukin-2 in Treating Patients With Stage III or Stage IV Melanoma	NCT00003222	Melanoma (Skin)	aldesleukin gp100 antigen incomplete Freu... sargramostim tetanus peptide... tyrosinase pept...	18 Years - 79 Years	University of Virginia
Vaccine Therapy Plus Interleukin-2 in Treating Patients With Stage III or Stage IV Melanoma	NCT00003222	Melanoma (Skin)	aldesleukin gp100 antigen incomplete Freu... sargramostim tetanus peptide... tyrosinase pept...	18 Years - 79 Years	University of Virginia
Vaccine Therapy Using Melanoma Peptides for Cytotoxic T Cells and Helper T Cells in Treating Patients With Metastatic Melanoma	NCT00071981	Melanoma (Skin)	incomplete Freu... melanoma helper... multi-epitope m... sargramostim tetanus peptide...	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for tetanus peptide melanoma vaccine