Ipilimumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma

The successful treatment of melanoma with immune checkpoint inhibitors, such as
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed cell death protein 1
(PD-1) antibodies, has altered our thinking and approach to immunotherapy for solid tumors.
Despite these advances, only a portion of patients experience a durable response suggesting
that there is room for improvement via enhanced immunomodulatory approaches. Anti-CTLA-4
(Ipilimumab) significantly improves overall survival and achieves long-lasting complete
responses in some melanoma patients, the number of patients that achieve durable clinical
benefit is limited and could be improved by a combined immunomodulatory approach. The
objectives of this study are to assess the safety and efficacy of combined treatment with
Ipilimumab and all-trans retinoic acid (ATRA) in melanoma patients. We hypothesize that
combined treatment with Ipilimumab and ATRA will improve patient responses, increase tumor
antigen-specific T cell responses, and decrease immunosuppressive myeloid-derived suppressor
cells (MDSCs) in melanoma patients compared to patients treated with Ipilimumab alone.

Inclusion Criteria:

- Patients over the age of 18 year.

- Patients diagnosed with advanced melanoma.

- Patients that are considered candidates for ipilimumab therapy.

- Patients able to understand and willing to sign a written informed consent documents.

- Patients willing to have regular blood draws, one before treatment and four during or
after treatment.

Exclusion Criteria:

- Patients under the age of 18.

- Patients with Stage I or II, melanoma who are not candidates for Ipilimumab.

- Patients that have received systemic treatments within four weeks prior to the
beginning of treatment.

- Women that are pregnant or nursing.

- Patients taking immunosuppressive medications.

- Patients with active autoimmune disease.

- Patients with known sensitivity to retinoic acid derivatives.

- Patients with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or
bilirubin > 2.5 × ULN.