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

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of combined treatment with Ipilimumab and all-trans retinoic acid (ATRA) in melanoma patients.

Detailed Description
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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.

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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: VESANOID
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 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 |
| --- | --- |
| Active Comparator: Ipilimumab<br>Arm A (No VESANOIDTherapy) will receive the standard of care treatment with ipilimumab only, receiving the standard 4 doses of either 3 or 10 mg/kg ipilimumab every 3 weeks. | Drug: Ipilimumab<br>* Ipilimumab is current standard of care treatment for melanoma.<br>* Other names: IPI;|
| Experimental: VESANOID<br>Arm B (VESANOID Therapy) will receive the standard 4 doses of either 3 or 10 mg/kg ipilimumab every three weeks plus the supplemental treatment of 150 mg/m2 of VESANOID orally for 3 days surrounding each dose of ipilimumab (day -1, day 0, day +1) for a total of 12 days of VESANOID treatment. | Drug: VESANOID<br>* All-trans retinoic acid (ATRA) is a vitamin A derivative that binds the retinoic acid receptor on MDSCs and differentiates immature monocytes into more mature dendritic cells (12). VESANOID is a standard treatment for patients with acute promyelocytic leukemia (APL).<br>* Other names: Tretinoin;Drug: Ipilimumab<br>* Ipilimumab is current standard of care treatment for melanoma.<br>* Other names: IPI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | Safety and tolerability of ipilimumab and VESANOID combination therapy in advanced melanoma patients will be established using the Bayesian approach. | Up to 2 years from the time of study enrollment for each patient. | 
| MDSC Frequency | The frequency of circulating MDSCs will be measured by flow cytometry and calculated as a percentage of the total myeloid cell population. This outcome will be measured at the final study blood draw between 84 and 130 days following the first treatment. | 84 and 130 days following the first treatment | 
| MDSC Suppressive Function | MDSC suppressive function in peripheral blood will be measured through the activation and proliferation of T cells in the presence of isolated MDSCs. Functional assays will be performed to assess the ability of isolated MDSCs to suppress T-cell responses. | 4 weeks prior to start, Midway thru and at least 30 days post final infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Frequency of Tumor-specific T Cell Responses | Changes in the frequency of tumor-specific T cell responses attributable to the addition of VESANOID to standard ipilimumab therapy will be determined by the frequency of Interferons (IFN)-gamma producing cells after stimulation with melanoma antigens. | 4 weeks prior to start, Midway thru and at least 30 days post final infusion | 
| Unresectable Stage III and STAGE IV | Subjects will be followed for evidence of disease progression. | Up to 2 years from the time of study enrollment for each patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, Malignant Melanoma