A Phase I Study With a Personalized NeoAntigen Cancer Vaccine in Melanoma

The study is an open label, phase I trial in which patients with high-risk melanoma are immunized with up to 20 peptides that are both specific to the patient's tumor cells (i.e., not found in their normal cells) and unique to the patient (i.e., "personal"). These peptides are encoded by missense mutations, in-frame gene fusions and novel open reading frame mutations (collectively known as "neoantigens") that have occurred within that patient's tumor cells and are identified through DNA and RNA sequencing. Up to 20 peptides about 20-30 amino acids in length will be prepared for each patient and will be administered together with the immune adjuvant poly-ICLC. The personalized NeoAntigen Cancer Vaccine consists of peptides + poly-ICLC and is called "NeoVax." This phase 1 study is designed to demonstrate that the combination of personalized neoantigen peptides and poly-ICLC is safe, feasible, and induces strong tumor-specific T cell immunity.

The trial has a two-stage enrollment process. Eligible patients will be initially entered into the trial to undergo surgery with the intent to resect all melanoma detectable clinically and on radiographic scans. Patients will be reassessed for eligibility prior to the first vaccination and will continue onto the treatment phase of the trial if secondary eligibility criteria are met. Patients with tumors that are not completely resected and/or that provide inadequate DNA and/or RNA for sequencing will be removed from the trial and replaced. After NeoVax has been prepared, the vaccine will be administered on days 1, 4, 8, 15, and 22 (priming phase), and on days 78 and 134 (booster phase).

Five patients will be entered for the initial safety evaluation (Cohort 1). If none or only 1 patient experiences a DLT on Cohort 1, an additional 10 patients will be treated at this dose to increase the likelihood of detecting serious toxicities, to complete biologic correlative endpoints, and to gain preliminary experience with clinical tumor activity. If two or more patients in Cohort 1 experience dose limiting toxicity (DLT) during the first 7 weeks of treatment, then the dose of poly-ICLC will be reduced by 50% and 5 patients will be enrolled into Cohort -1. If none or only 1 patient experiences a DLT on Cohort -1, then an additional 10 patients will be enrolled as described above. If two or more patients in Cohort -1 experience a DLT, then the study will be stopped. If four or more patients in the expansion cohort experience dose limiting toxicity (DLT) during the first 7 weeks of treatment, then the dose expansion cohort will be determined to have unacceptable toxicity and the study will be stopped prior to completion of enrollment of the expansion cohort.