Neoantigen Vaccine Plus Locally Administered Ipilimumab and Systemic Nivolumab in Advanced Melanoma

This is a Phase I clinical trial to assess the safety of an investigational personalized neoantigen vaccine, NeoVax, consisting of personalized neoantigen peptides and Hiltonol® plus Montanide®, in combination with Nivolumab and Ipilimumab. The study also seeks to define the appropriate dose of investigational Ipilimumab administered subcutaneously (under the skin) to use for further studies. "Investigational" means that the combination is being studied. The FDA (the U.S. Food and Drug Administration) has not approved personalized neoantigen peptides, Hiltonol®, or Montanide® as a treatment for any disease. The combination is an investigational therapy being developed for use in the treatment of certain cancers. The FDA has approved Nivolumab (Opdivo®) and intravenous Ipilimumab (Yervoy™) as a treatment option for melanoma. Subcutaneous administration of Ipilimumab has not been approved by the FDA for treatment of melanoma. It is known that melanoma cancers have mutations (changes in genetic material) that are specific to each patient and tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that the proteins used in a vaccine may cause strong immune responses, which may help the body fight any tumor cells that could allow the melanoma to come back in the future. In this study, melanoma cells will be obtained either by tumor surgery or tumor biopsy. The genetic material contained in the melanoma cells will be examined for the presence of tumor-specific mutations. This information will be used to prepare small protein fragments, which are called "peptides". Each NeoVax vaccine will consist of up to 20 peptides mixed with two drugs that activate the immune system called Poly-ICLC (Hiltonol®) and Montanide®. A 5-patient dose escalation design will be implemented with up to three cohorts of patients. Each cohort of patients (5 patients/cohort) will begin treatment with Nivolumab (480 mg intravenously every 4 weeks). The NeoVax vaccine will be prepared during the initial 12 weeks of Nivolumab therapy. Any patient for whom vaccine cannot be made will be replaced within a cohort. Vaccine will be administered on weeks 12, 15, 18, and 21 with Hiltonol, Montanide, and concurrent Ipilimumab. The protocol specifies that the dose of Ipilimumab will begin at 2.5 mg per injection site. If the number of dose-limiting toxicities (DLTs) occurring within 7 weeks of NeoVax initiation is 0 or 1 (i.e., in no more than 20% of patients) the dose of Ipilimumab will be increased to 5 mg per injection site in the next cohort. If the number of DLTs is 2 or more, the dose of Ipilimumab will be decreased to 1.25 mg per injection site in the next cohort. The maximum tolerated dose (MTD) will be the highest dose of Ipilimumab in which the DLT rate is 20% or less. Toxicities will be graded using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). A DLT is defined as: 1. Grade 3 or 4 toxicity that is definitely, probably, or possibly related to administration of vaccine, excluding transient (≤ 72 hours) flu-like symptoms; grade 3 nausea, vomiting, diarrhea, or constipation that returns to grade 2 (or lower) within 48 hours; any grade 3 rash that resolves to grade 2 or lower within 14 days; any grade 3 endocrine abnormality that is corrected with hormonal therapy within 4 weeks. 2. Grade 3 or 4 abnormal laboratory value that is at least possibly related to the administration of vaccine lasting for more than 7 days and requires hospitalization or medical intervention. Excludes any grade 3 electrolyte abnormality that: lasts ≤ 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical intervention. 3. Any grade 3 or grade 4 toxicity that is considered, in the opinion of the Principal Investigator, to be dose-limiting. 4. Any death related to study treatment. Health status assessments, including physical exams and blood chemistry, will be conducted every 4 weeks. Leukapheresis will occur at the time of enrollment, prior to administration of the first dose of NeoVax, and at week 20. For patients with unresectable melanoma, tumor biopsies will be obtained prior to the first dose of vaccine, at week 20, and at the time of disease progression. Vaccine site biopsies will be obtained at weeks 15 and 18 (i.e., at the times of the second and third vaccine administration).