Safety Study of a Helper Peptide Vaccine Plus Adjuvant Combinations for the Treatment of Melanoma

Study Overview
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Brief Summary
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This study evaluates whether it is safe to administer a peptide vaccine in combination with different adjuvants. Adjuvants are substances that may boost immune responses vaccines. In this study, the adjuvants are Montanide ISA-51, polyICLC and cyclophosphamide. This study will also evaluate the effects of the combination of the peptide vaccine and the adjuvants on the immune system. The investigators will monitor these effects by performing tests in the laboratory on participants' blood, a lymph node, and tissue from the sites of vaccination.

Official Title
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A Trial to Evaluate the Immunogenicity and Safety of a Melanoma Helper Peptide Vaccine Plus Novel Adjuvant Combinations (MEL63)

Conditions
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Melanoma

Intervention / Treatment
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* Biological: 6MHP
* Drug: Montanide ISA-51
* Drug: polyICLC
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1 only: Participants with stage IIB, IIC, III, or IV melanoma at original diagnosis or at restaging after recurrence. Patients with high-risk stage IIA melanoma (by DecisionDx Melanoma test, Castle Biosciences, Inc,;Friendswood, TX) also may be eligible. These participants may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. Diagnosis of melanoma must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on version 7 AJCC staging system. Part 2 only: Patients with a diagnosis of stage IIIB-IV melanoma with one or more tumor deposits accessible for biopsy and/or excision. These participants may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. Diagnosis of melanoma must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on version 7 AJCC staging system. Patients must have adequate cutaneous, subcutaneous, soft tissue, or nodal metastases of melanoma readily accessible for biopsy Participants will be required to have radiological studies to rule out radiologically evident disease. Required studies include: Chest CT scan, Abdominal and pelvic CT scan, and Head CT scan or MRI PET/CT fusion scan may replace scans of the chest, abdomen, and pelvis. Participants who have had brain metastases will be eligible if all of the following are true: Each brain metastasis must have been completely removed by surgery or each unresected brain metastasis must have been treated with stereotactic radiosurgery. There has been no evident growth of any brain metastasis since the most recent treatment. No brain metastasis is > 2 cm in diameter at the time of registration. The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed ≥ 1 week and for Part 1, ≤ 6 months prior to registration. All participants must have: ECOG performance status of 0 or 1 (Appendix 3) Ability and willingness to give informed consent Laboratory parameters as follows: ANC > 1000/mm3 Platelets > 100,000/mm3 Hgb > 9 g/dL HgbA1c ≤ 7.5% Hepatic: AST and ALT ≤ 2.5 x upper limits of normal (ULN) Bilirubin ≤ 2.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 4x ULN is allowed) Alkaline phosphatase ≤ 2.5 x ULN Renal Creatinine ≤ 1.5 x ULN Serology (within 6 months of study entry) HIV negative Hepatitis C negative (no evidence of active virus) Blood is to be collected for HLA typing (Class I and Class II), which will be analyzed as part of the immunologic endpoints, but HLA type will not be an inclusion/exclusion criterion. Age 18 years or older at registration. Part 1 only: Participants must have at least two intact (undissected) axillary and/or inguinal lymph node basins. Part 2 only: Participants must have at least one intact (undissected) axillary and/or inguinal lymph node basin. Exclusion Criteria: Participants who have received the following medications or treatments at any time within 4 weeks of registration: Chemotherapy Interferon (e.g. Intron-A®) Radiation therapy (Stereotactic radiotherapy, such as gamma knife, can be used ≥ 1 week and ≤ 6 months prior to registration) Allergy desensitization injections High doses of systemic corticosteroids, with the following qualifications and exceptions: In patients with adrenal or pituitary insufficiency replacement steroid doses are allowed; however, daily doses of 10 mg or more of prednisone (or equivalent) per day administered parenterally or orally are not allowed in patients with normal adrenal and pituitary function. Inhaled steroids (e.g.: Advair®, Flovent®, Azmacort®) are permitted at low doses (less than 500 mcg fluticasone per day, or equivalent) (76,77). Topical, nasal, and intra-articular corticosteroids are acceptable. Growth factors (e.g. Procrit®, Aranesp®, Neulasta®) Interleukins (e.g. Proleukin®) Any investigational medication Targeted therapies specific for mutated BRAF or for MEK Participants who are currently receiving nitrosoureas or who have received this therapy within the preceding 6 weeks Participants who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within the preceding 12 weeks. Participants with known or suspected allergies to any component of the vaccine. Participants may not have been vaccinated previously with any of the synthetic peptides included in this protocol. Participants who have received vaccinations containing agents other than the synthetic peptides included in this protocol and have recurred during or after administration of the vaccine will be eligible to enroll 12 weeks following their last vaccination. Pregnancy. Female participants of childbearing potential must have a negative pregnancy test (urinary or serum beta-HCG) obtained within 2 weeks prior to registration. Males and females must agree, in the consent form, to use effective birth control methods during the course of vaccination. Female participants must not be breastfeeding Participants in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator. Participants classified according to the New York Heart Association classification as having Class III or IV heart disease (Appendix 4). Participants with uncontrolled diabetes, defined as having a HgbA1c ≥ 7.5%. Participants must not have had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement. Participants with an active autoimmune disorder requiring these therapies are also excluded. The following will not be exclusionary: The presence of laboratory evidence of autoimmune disease (e.g. positive ANA titer) without symptoms Clinical evidence of vitiligo Other forms of depigmenting illness Mild arthritis requiring NSAID medications Participants who have another cancer diagnosis, except that the following diagnoses will be allowed: squamous cell cancer of the skin without known metastasis basal cell cancer of the skin without known metastasis carcinoma in situ of the breast (DCIS or LCIS) carcinoma in situ of the cervix any cancer without distant metastasis that has been treated successfully, without evidence of recurrence or metastasis for over 5 years Participants with known addiction to alcohol or drugs who are actively taking those agents, or participants with recent (within 1 year) or ongoing illicit IV drug use. Body weight < 110 pounds (without clothes) at registration, due to the amount and frequency with which blood will be drawn.

Ages Eligible for Study
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Minimum Age: 18 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 A:6MHP + Montanide ISA-51<br>Part 1: 200 mcg of 6MHP emulsified in Montanide ISA-51 adjuvant will be administered on 1, 8, 15, 36, 57 and 78. | Biological: 6MHP<br>* 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides<br>* Other names: 6 melanoma helper peptide vaccine;Drug: Montanide ISA-51<br>* Montanide ISA-51 (Incomplete Freund's Adjuvant), local adjuvant<br>|
| Experimental: Arm B:6MHP + Montanide ISA-51 + Cyclophosphamide<br>Part 1: 200 mcg of 6MHP emulsified in Montanide ISA-51 adjuvant will be administered on 1, 8, 15, 36, 57 and 78. Cyclophosphamide (50 mg) will be taken orally once a day for 7 days followed by a 7 day rest period. This will be repeated for 5 cycles. Cycles will begin on the following days: Day -6 (Cycle 1) Day 8 (Cycle 2) Day 22 (Cycle 3) Day 36 (Cycle 4) Day 50 (Cycle 5) | Biological: 6MHP<br>* 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides<br>* Other names: 6 melanoma helper peptide vaccine;Drug: Montanide ISA-51<br>* Montanide ISA-51 (Incomplete Freund's Adjuvant), local adjuvant<br>Drug: Cyclophosphamide<br>* Cyclophosphamide, systemic adjuvant<br>|
| Experimental: Arm C:6MHP + polyICLC + Montanide ISA-51<br>Part 1: 200 mcg of 6MHP plus 1 mg of polyICLC emulsified in Montanide ISA-51 adjuvant will be administered on 1, 8, 15, 36, 57 and 78. | Biological: 6MHP<br>* 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides<br>* Other names: 6 melanoma helper peptide vaccine;Drug: Montanide ISA-51<br>* Montanide ISA-51 (Incomplete Freund's Adjuvant), local adjuvant<br>Drug: polyICLC<br>* polyICLC, local adjuvant<br>|
| Experimental: Arm D:6MHP + polyICLC + Montanide ISA-51 + Cyclophosphamide<br>Parts 1 and 2: 200 mcg of 6MHP plus 1 mg of polyICLC emulsified in Montanide ISA-51 adjuvant will be administered on 1, 8, 15, 36, 57 and 78. Cyclophosphamide (50 mg) will be taken orally once a day for 7 days followed by a 7 day rest period. This will be repeated for 5 cycles. Cycles will begin on the following days: Day -6 (Cycle 1) Day 8 (Cycle 2) Day 22 (Cycle 3) Day 36 (Cycle 4) Day 50 (Cycle 5) | Biological: 6MHP<br>* 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides<br>* Other names: 6 melanoma helper peptide vaccine;Drug: Montanide ISA-51<br>* Montanide ISA-51 (Incomplete Freund's Adjuvant), local adjuvant<br>Drug: polyICLC<br>* polyICLC, local adjuvant<br>Drug: Cyclophosphamide<br>* Cyclophosphamide, systemic adjuvant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Treatment-related adverse events, by CTCAE v4, Dose-limiting toxicities. | 30 days after administration of the last dose of 6MHP or cyclophosphamide | 
| Immunogenicity-CD4+ T Cell Responses | CD4+ T cell responses to 6 MHP: durable helper T cell response to 6MHP at 2 or more consecutive timepoints in the PBMC. | through day 85 | 
| Immunogenicity-modification of the Tumor Microenvironment (Part 2 Only) | increased infiltration of CD4+ and CD8+ T lymphocytes into melanoma metastases | through day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity-CD8+ T Cell Responses | CD8+ T cell responses to defined melanoma antigens | through day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peptide, vaccine, adjuvant, polyICLC, cyclophosphamide, Montanide ISA-51