Vaccination With 6MHP, With or Without Systemic CDX-1127, in Patients With Stage II-IV 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 (6MHP) with adjuvants and the CDX-1127 monoclonal antibody, and whether the adjuvants and the CDX-1127 monoclonal antibody boost immune responses to the vaccine. In this study, the adjuvants are Montanide ISA-51 and polyICLC. The investigators will monitor these effects by performing tests in the laboratory on participants' blood and tissue from a vaccine site.

Official Title
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Evaluation of Safety and Durable Immunogenicity of Melanoma Vaccination, With or Without Systemic CDX-1127, in Patients With Stage II-IV Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: 6MHP
* Drug: Montanide ISA-51
* Drug: polyICLC
* Drug: CDX-1127


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Patients with stage IIB, IIC, III, or IV melanoma at original diagnosis or at restaging after recurrence, rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration. Patients with small radiologic or clinical findings of an indeterminate nature may be eligible. Patients with high-risk stage IIA melanoma (by DecisionDx Melanoma test, Castle Biosciences, Inc., Friendswood, TX) may be eligible. 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 8 AJCC staging system. 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. No brain metastasis is > 2 cm in diameter at the time of registration. Any neurologic symptoms attributable to brain metastases have returned to baseline.There is no evidence of new or enlarging brain metastases. The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed ≥ 1 week and ≤ 6 months prior to registration. ECOG performance status of 0 or 1. Ability and willingness to give informed consent. Adequate organ function Age 18 years or older at registration. Main Exclusion Criteria: 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 Growth factors (e.g. Procrit®, Aranesp®, Neulasta®) Interleukins (e.g. Proleukin®) Any investigational medication Targeted therapies specific for mutated BRAF or for MEK Nitrosoureas within 6 weeks of registration. Checkpoint molecule blockade therapy within 12 weeks of registration. Known or suspected allergies to any component of the vaccine. Previous vaccination with 6MHP. Prior treatment with CDX-1127 or other CD27 agonistic antibody. Pregnancy. HIV positivity or evidence of active Hepatitis C virus. Female participants must not be breastfeeding. A medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator. New York Heart Association classification as having Class III or IV heart disease. Uncontrolled diabetes, defined as having an HgbA1c > 8.5%. 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. 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. Participants who have received a live vaccine within 30 days of registration. Body weight < 110 pounds at registration, due to the amount and frequency with which blood will be drawn. Participants with prior autoimmune pneumonitis.

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 + polyICLC + CDX-1127<br>200 mcg of 6MHP plus 0.9 mg of polyICLC emulsified in Montanide ISA-51 adjuvant will be administered subcutaneously on days 1, 8, 15, and 36. 200 mcg of 6MHP in Montanide ISA-51 adjuvant (without polyICLC) will be administered subcutaneously/intradermally on day 176. CDX-1127 (3mg/kg) will be administered intravenously on days 1, 36, 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>Drug: CDX-1127<br>* CDX-1127, anti-CD27 monoclonal antibody<br>* Other names: Varlilumab;|
| Experimental: Arm B: 6MHP/Montanide ISA-51 + polyICLC<br>200 mcg of 6MHP plus 0.9 mg of polyICLC emulsified in Montanide ISA-51 adjuvant will be administered subcutaneously on days 1, 8, 15, and 36. 200 mcg of 6MHP in Montanide ISA-51 adjuvant (without polyICLC) will be administered subcutaneously/intradermally on day 176. | 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CDX-1127 administered with a melanoma vaccine | Number of participants with dose-limiting toxicities based on CTCAE v5.0 | 30 days after receiving the last dose of study drug | 
| Immunogenicity-Percent of patients with persistent CD4+ T cell responses to the 6MHP vaccine | Number of participants with CD4+ T cell responses to 6 MHP persisting to day 127 or later. | Day 127 or Day 176 or both | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunologic effect of CDX-1127 - Impact on regulatory T cells | Number of regulatory T cells per mm2 in the vaccine site microenvironment | Day 22 and Day 85 (Note: Day 85 biopsy not required for participants whose Day 85 visit would be due after IRB approval of Protocol v12-03-2020) | 
| Immunologic effect of CDX-1127 - Percent of circulating regulatory T cells | Percent of circulating regulatory T cells among CD4+ T cells | through day 176 | 
| Immunogenicity - Frequency of circulating CD4+ Th1 responses | Number of participants with circulating CD4+ Th1 responses to vaccine antigens | through day 176 | 
| Immunogenicity-Frequency of durable CD4+ Th1 memory responses | Number of participants with durable CD4+ Th1 memory response to vaccine antigens, measured as response at two or more consecutive time points | Day 8 to Day 85 | 
| Immunogenicity-Frequency of CD4+ Th1 memory responses | Number of participants with CD4+ Th1 memory response to vaccine antigens a week after the Day 176 booster vaccine. | Day 183 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peptide, vaccine, adjuvant, 6MHP, polyICLC, varlilumab, CDX-1127, Montanide ISA-51