Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Vaccines

Monatide (IMS 3015)

Freund's Adjuvant

Immunologic Factors

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Adjuvants, Immunologic

Patients receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

Patients receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

incomplete Freund's adjuvant

melanoma helper peptide vaccine

multi-epitope melanoma peptide vaccine

tetanus toxoid helper peptide

cyclophosphamide

Craig L. Slingluff, MD

RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cyclophosphamide may also stimulate the immune system in different ways and stop tumor cells from growing. Giving vaccine therapy together with cyclophosphamide after surgery may cause a stronger immune response to kill any remaining tumor cells. It may also prevent or delay the recurrence of melanoma.

PURPOSE: This randomized phase I/II trial is studying the side effects of vaccine therapy when given with or without cyclophosphamide and to see how well they work in treating patients who have undergone surgery for stage II, stage III, or stage IV melanoma.

OBJECTIVES:

Primary

* Determine the safety of adjuvant vaccine therapy comprising multi-epitope melanoma peptides (MP) and multi-epitope melanoma helper peptides (MHP) emulsified in Montanide ISA-51 in patients with resected stage IIB-IV melanoma.
* Determine the safety of administering cyclophosphamide before vaccination in these patients.
* Compare the magnitude of immune response against vaccination comprising MP in combination with either MHP or tetanus toxoid helper peptide (TET) emulsified in Montanide ISA-51 with vs without cyclophosphamide in these patients.

Secondary

* Compare the response rate and persistence of immune responses in patients treated with these regimens.
* Compare the magnitude of immune response against vaccination comprising TET or MHP with vs without cyclophosphamide in these patients.
* Compare the response rate and persistence of immune response against vaccination comprising TET or MHP with vs without cyclophosphamide in these patients.
* Determine the delayed-type hypersensitivity response to the peptide components of these vaccines in these patients.
* Compare, preliminarily, disease-free survival of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to HLA-type (HLA-A1 positive vs HLA-A2 positive, HLA-A1 negative, or -A3 negative vs HLA-A3 positive, or -A1 negative) and participating center (University of Virginia \[UVA\] vs non-UVA). Patients are randomized to 1 of 4 treatment arms.

* Arm I: Patients receive vaccine comprising multi-epitope melanoma peptides (MP) and tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally (ID) and subcutaneously (SC) on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.
* Arm II: Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine as in arm I.
* Arm III: Patients receive vaccine comprising MP and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 ID and SC on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.
* Arm IV: Patients receive cyclophosphamide as in arm II. Patients then receive vaccine as in arm III.

Treatment in all arms continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 173 patients will be accrued for this study within 2 years.

Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Who Have Undergone Surgery for Stage II, Stage III, or Stage IV Melanoma

A Multicenter Trial to Evaluate the Effects of Administration of Cyclophosphamide and Melanoma-Derived Helper Peptides on the Immunogenicity of a Class I MHC-Restricted Peptide-Based Vaccine in Participants With Resected Melanoma

Number of participants with dose-limiting toxicities

The primary end point was the maximum cumulative circulating CD8+ T cell response to 12 melanoma peptides (12MP) measured by ELISpot assay over the first six vaccines (to day 50).

National Cancer Institute (NCI)

Craig L Slingluff, Jr

Professor of Surgery

Patients receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

incomplete Freund's adjuvant: Given intradermally and subcutaneously

multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously

tetanus toxoid helper peptide: Given intradermally and subcutaneously

Arm I

Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

incomplete Freund's adjuvant: Given intradermally and subcutaneously

multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously

tetanus toxoid helper peptide: Given intradermally and subcutaneously

cyclophosphamide: Given IV

Arm II

Patients receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

incomplete Freund's adjuvant: Given intradermally and subcutaneously

melanoma helper peptide vaccine: Given intradermally and subcutaneously

multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously

Arm III

Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365.

incomplete Freund's adjuvant: Given intradermally and subcutaneously

melanoma helper peptide vaccine: Given intradermally and subcutaneously

multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously

cyclophosphamide: Given IV

Arm IV

Total

Age, Categorical

Sex: Female, Male

Dr. Craig Slingluff

Intent to treat population including 167 eligible and 3 ineligible.

Safety of the Peptide Vaccines

Immunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 50

Overall Study

Symptoms and General Pathology

Recurrence

Molgramostim

Sargramostim

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.

sargramostim

tetanus peptide melanoma 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)

Age, Continuous

United States

Region of Enrollment

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	Link
Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Who Have Undergone Surgery for Stage II, Stage III, or Stage IV Melanoma	NCT00118274	Melanoma (Skin)	incomplete Freu... melanoma helper... multi-epitope m... tetanus toxoid ... cyclophosphamid...	18 Years - 120 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 melanoma helper peptide vaccine