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

Sponsor
University of Colorado, Denver (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02403778
Collaborator
(none)
10
Enrollment
1
Location
2
Arms
108.5
Anticipated Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
10 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Ipilimumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma
Actual Study Start Date :
Dec 17, 2015
Actual Primary Completion Date :
Aug 1, 2018
Anticipated Study Completion Date :
Jan 1, 2025

Arms and Interventions

ArmIntervention/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: 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
  • Drug: Ipilimumab
    Ipilimumab is current standard of care treatment for melanoma.
    Other Names:
  • IPI
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Adverse Events [Up to 2 years from the time of study enrollment for each patient.]

      Safety and tolerability of ipilimumab and VESANOID combination therapy in advanced melanoma patients will be established using the Bayesian approach.

    2. MDSC Frequency [84 and 130 days following the first treatment]

      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.

    3. MDSC Suppressive Function [4 weeks prior to start, Midway thru and at least 30 days post final infusion]

      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.

    Secondary Outcome Measures

    1. Changes in the Frequency of Tumor-specific T Cell Responses [4 weeks prior to start, Midway thru and at least 30 days post final infusion]

      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.

    2. Unresectable Stage III and STAGE IV [Up to 2 years from the time of study enrollment for each patient.]

      Subjects will be followed for evidence of disease progression.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 89 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Colorado HospitalAuroraColoradoUnited States80045

    Sponsors and Collaborators

    • University of Colorado, Denver

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Colorado, Denver
    ClinicalTrials.gov Identifier:
    NCT02403778
    Other Study ID Numbers:
    • 14-0948.cc
    First Posted:
    Mar 31, 2015
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of Colorado, Denver
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Period Title: Overall Study
    STARTED64
    COMPLETED64
    NOT COMPLETED00

    Baseline Characteristics

    Arm/Group TitleIpilimumabVESANOIDTotal
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.Total of all reporting groups
    Overall Participants6410
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    6
    100%
    3
    75%
    9
    90%
    >=65 years
    0
    0%
    1
    25%
    1
    10%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    54.8
    50.4
    52.1
    Sex: Female, Male (Count of Participants)
    Female
    3
    50%
    3
    75%
    6
    60%
    Male
    3
    50%
    1
    25%
    4
    40%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    6
    100%
    4
    100%
    10
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    6
    100%
    4
    100%
    10
    100%

    Outcome Measures

    1. Primary Outcome
    TitleNumber of Adverse Events
    DescriptionSafety and tolerability of ipilimumab and VESANOID combination therapy in advanced melanoma patients will be established using the Bayesian approach.
    Time FrameUp to 2 years from the time of study enrollment for each patient.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Measure Participants64
    Number [Number of events in treatment group]
    51
    45
    2. Primary Outcome
    TitleMDSC Frequency
    DescriptionThe 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.
    Time Frame84 and 130 days following the first treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Measure Participants64
    Mean (Standard Error) [% MDSCs of Myeloid Cells]
    34.35
    (6.24)
    7.29
    (2.49)
    3. Primary Outcome
    TitleMDSC Suppressive Function
    DescriptionMDSC 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.
    Time Frame4 weeks prior to start, Midway thru and at least 30 days post final infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Measure Participants64
    Mean (Standard Deviation) [Percentage of Proliferating T Cells]
    NA
    (NA)
    NA
    (NA)
    4. Secondary Outcome
    TitleChanges in the Frequency of Tumor-specific T Cell Responses
    DescriptionChanges 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.
    Time Frame4 weeks prior to start, Midway thru and at least 30 days post final infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Measure Participants64
    Mean (Standard Deviation) [Percentage of Activated CD8+ T cells]
    6.0975
    (4.144)
    14.2833
    (7.2221)
    5. Secondary Outcome
    TitleUnresectable Stage III and STAGE IV
    DescriptionSubjects will be followed for evidence of disease progression.
    Time FrameUp to 2 years from the time of study enrollment for each patient.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    Measure Participants64
    Median (Full Range) [Days]
    776
    662

    Adverse Events

    Time FrameAdverse event data was collected for up to 2 years from the time of study enrollment for each patient.
    Adverse Event Reporting Description
    Arm/Group TitleIpilimumabVESANOID
    Arm/Group DescriptionArm 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. Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.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. 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). Ipilimumab: Ipilimumab is current standard of care treatment for melanoma.
    All Cause Mortality
    IpilimumabVESANOID
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/6 (0%) 0/4 (0%)
    Serious Adverse Events
    IpilimumabVESANOID
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total2/6 (33.3%) 3/4 (75%)
    Gastrointestinal disorders
    Colitis or Diarrhea2/6 (33.3%) 21/4 (25%) 1
    Hepatobiliary disorders
    Autoimmune Hepatitis1/6 (16.7%) 10/4 (0%) 0
    Elevated ALT1/6 (16.7%) 10/4 (0%) 0
    Nervous system disorders
    Headache0/6 (0%) 01/4 (25%) 1
    Pseudotumor Cerebri0/6 (0%) 01/4 (25%) 1
    Other (Not Including Serious) Adverse Events
    IpilimumabVESANOID
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total6/6 (100%) 4/4 (100%)
    Endocrine disorders
    Adrenal Insufficiency0/6 (0%) 1/4 (25%)
    Eye disorders
    Blurred Vision0/6 (0%) 1/4 (25%)
    Eye Crossing0/6 (0%) 1/4 (25%)
    Iridocyclitis0/6 (0%) 1/4 (25%)
    Itching Eyes0/6 (0%) 1/4 (25%)
    Photophobia0/6 (0%) 2/4 (50%)
    Redness of the Eyes0/6 (0%) 1/4 (25%)
    Uveitis/Iritis0/6 (0%) 1/4 (25%)
    Gastrointestinal disorders
    Colitis1/6 (16.7%) 0/4 (0%)
    Vomiting4/6 (66.7%) 1/4 (25%)
    General disorders
    Abdominal Pain2/6 (33.3%) 0/4 (0%)
    Back Pain1/6 (16.7%) 0/4 (0%)
    Body Aches (increasing)0/6 (0%) 1/4 (25%)
    Decreased Appetite2/6 (33.3%) 0/4 (0%)
    Dry Mouth0/6 (0%) 1/4 (25%)
    Facial Flushing0/6 (0%) 1/4 (25%)
    Fatigue3/6 (50%) 2/4 (50%)
    Malaise (increasing)0/6 (0%) 1/4 (25%)
    Generalized Flushing0/6 (0%) 1/4 (25%)
    Itching Mouth0/6 (0%) 1/4 (25%)
    Myalgia0/6 (0%) 1/4 (25%)
    Nausea4/6 (66.7%) 1/4 (25%)
    Hepatobiliary disorders
    Elevated ALT2/6 (33.3%) 0/4 (0%)
    Elevated AST2/6 (33.3%) 0/4 (0%)
    Elevated LFT2/6 (33.3%) 1/4 (25%)
    Immune system disorders
    Fever2/6 (33.3%) 1/4 (25%)
    Arthralgias0/6 (0%) 1/4 (25%)
    Musculoskeletal and connective tissue disorders
    Muscle Ache0/6 (0%) 1/4 (25%)
    Nervous system disorders
    Headache1/6 (16.7%) 4/4 (100%)
    Respiratory, thoracic and mediastinal disorders
    Wheezing1/6 (16.7%) 0/4 (0%)
    Skin and subcutaneous tissue disorders
    Pruritus6/6 (100%) 4/4 (100%)
    Dry Skin1/6 (16.7%) 1/4 (25%)
    Erythematous Rash2/6 (33.3%) 1/4 (25%)
    Exfoliation0/6 (0%) 1/4 (25%)
    Pruritic Rash2/6 (33.3%) 1/4 (25%)
    Rash4/6 (66.7%) 0/4 (0%)
    Skin Color Change0/6 (0%) 1/4 (25%)
    Skin Peeling0/6 (0%) 1/4 (25%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleMartin McCarter
    OrganizationUnivesity Colorado Ansshutz Medical Campus
    Phone303-724-2728
    Emailmartin.mccarter@ucdenver.edu
    Responsible Party:
    University of Colorado, Denver
    ClinicalTrials.gov Identifier:
    NCT02403778
    Other Study ID Numbers:
    • 14-0948.cc
    First Posted:
    Mar 31, 2015
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021