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

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.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Drug: Ipilimumab; Drug: VESANOID

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ipilimumab; 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; Ipilimumab is current standard of care treatment for melanoma.; Other Names: IPI
Experimental: VESANOID; 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: Ipilimumab; Ipilimumab is current standard of care treatment for melanoma.; Other Names: IPI; Drug: VESANOID; 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).; Other Names: ATRA; Tretinoin

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Martin McCarter, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Tobin RP, Jordan KR, Robinson WA, Davis D, Borges VF, Gonzalez R, Lewis KD, McCarter MD. Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int Immunopharmacol. 2018 Oct;63:282-291. doi: 10.1016/j.intimp.2018.08.007. Epub 2018 Aug 16.

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2015
• Primary Completion (Actual): August 1, 2018
• Study Completion (Actual): January 18, 2023

Study Registration Dates

• First Submitted: February 23, 2015
• First Submitted That Met QC Criteria: March 25, 2015
• First Posted (Estimated): March 31, 2015

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Melanoma; Malignant Melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Dermatologic Agents; Immune Checkpoint Inhibitors; Keratolytic Agents; Ipilimumab; Tretinoin
• Other Study ID Numbers: 14-0948.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO