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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Melanoma (Skin)

Intervention / Treatment
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* Biological: incomplete Freund's adjuvant
* Biological: melanoma helper peptide vaccine
* Biological: multi-epitope melanoma peptide vaccine
* Biological: tetanus toxoid helper peptide
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed melanoma Cutaneous, mucosal, or primary melanoma Stage IIB-IV disease Has undergone surgical resection or stereotactic radiosurgery for malignant melanoma ≥ 1 week but ≤ 6 months ago No clinical or radiological evidence of disease after surgical resection or stereotactic radiosurgery by chest x-ray or CT scan*, abdominal and pelvic CT scan*, and head CT scan or MRI NOTE: *Positron emission tomography scan/CT fusion scan may replace scans of the chest, abdomen, and pelvis Must have ≥ 2 intact (undissected) axillary and/or inguinal lymph node basins HLA-A1, -A2, or -A3 positive AND HLA-DR1, -DR4, -DR11, -DR13, or -DR15 positive Ineligible for OR refused interferon No ocular melanoma Brain metastases allowed provided all of the following criteria are met: No more than 3 total brain metastases Each metastasis ≤ 2 cm in diameter at the time of study entry Each metastasis was completely removed by surgery or treated with stereotactic radiosurgery No evidence of brain metastasis progression since the most recent treatment PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 9 g/dL Hepatic AST and ALT ≤ 2.5 times upper limit of normal (ULN) Bilirubin ≤ 2.5 times ULN Lactic dehydrogenase ≤ 1.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Hepatitis C negative Renal Creatinine ≤ 1.5 times ULN Cardiovascular No New York Heart Association class III or IV heart disease Immunologic HIV negative No known or suspected allergy to any component of the study vaccines No autoimmune disorder with visceral involvement No prior or active autoimmune disorder requiring cytotoxic or immunosuppressive therapy The following immunologic conditions are allowed: Laboratory evidence of autoimmune disease (e.g., positive anti-nuclear antibody titer) without symptoms Clinical evidence of vitiligo Other forms of depigmenting illness Mild arthritis requiring non-steroidal anti-inflammatory drugs Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Weight ≥ 110 lbs No uncontrolled diabetes Hemoglobin A1C < 7% No medical contraindication or potential problem that would preclude study compliance No other malignancy except squamous cell or basal cell skin cancer without known metastasis, carcinoma in situ of the breast (ductal or lobular) or cervix, or other successfully treated cancer without distant metastasis with no evidence of recurrence or metastasis for > 5 years No known active addiction to alcohol or drugs No recent (within the past year) or ongoing illicit IV drug use PRIOR CONCURRENT THERAPY: Biologic therapy No prior vaccination with any of the synthetic peptides used in this study Prior vaccinations (containing agents other than the synthetic peptides used in this study) that resulted in recurrent disease during or after vaccine administration allowed provided the last vaccination was administered more than 12 weeks ago More than 4 weeks since prior and no concurrent interferon (e.g., Intron-A®), interleukins (e.g., Proleukin®), or growth factors (e.g., Procrit®, Aranesp®, or Neulasta®) More than 4 weeks since prior and no concurrent allergy desensitization injections No influenza vaccines for at least 2 weeks before or after study vaccine administration Chemotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) No concurrent chemotherapy, including nitrosoureas Endocrine therapy More than 4 weeks since prior and no concurrent oral or parenteral corticosteroids No prior or concurrent inhaled steroids (e.g., Advair®, Flovent®, or Azmacort®) Prior or concurrent topical corticosteroids allowed Radiotherapy See Disease Characteristics More than 4 weeks since other prior and no concurrent radiotherapy Surgery See Disease Characteristics Other More than 4 weeks since prior and no other concurrent investigational agents More than 30 days since prior and no concurrent participation in another clinical study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Biological: incomplete Freund's adjuvant<br>* Given intradermally and subcutaneously<br>Biological: multi-epitope melanoma peptide vaccine<br>* Given intradermally and subcutaneously<br>Biological: tetanus toxoid helper peptide<br>* Given intradermally and subcutaneously<br>|
| Experimental: Arm II<br>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. | Biological: incomplete Freund's adjuvant<br>* Given intradermally and subcutaneously<br>Biological: multi-epitope melanoma peptide vaccine<br>* Given intradermally and subcutaneously<br>Biological: tetanus toxoid helper peptide<br>* Given intradermally and subcutaneously<br>Drug: cyclophosphamide<br>* Given IV<br>|
| Experimental: Arm III<br>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. | Biological: incomplete Freund's adjuvant<br>* Given intradermally and subcutaneously<br>Biological: melanoma helper peptide vaccine<br>* Given intradermally and subcutaneously<br>Biological: multi-epitope melanoma peptide vaccine<br>* Given intradermally and subcutaneously<br>|
| Experimental: Arm IV<br>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. | Biological: incomplete Freund's adjuvant<br>* Given intradermally and subcutaneously<br>Biological: melanoma helper peptide vaccine<br>* Given intradermally and subcutaneously<br>Biological: multi-epitope melanoma peptide vaccine<br>* Given intradermally and subcutaneously<br>Drug: cyclophosphamide<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the Peptide Vaccines | Number of participants with dose-limiting toxicities | 30 days after receiving the last dose of study drug, up to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 50 | 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). | 50 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II melanoma, stage III melanoma, stage IV melanoma