Ipilimumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma
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 Disease | Intervention/Treatment | Phase |
---|---|---|
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
Arms and Interventions
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:
|
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:
Drug: Ipilimumab
Ipilimumab is current standard of care treatment for melanoma.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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.
- 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.
- 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
- 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.
- 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
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
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Colorado Hospital | Aurora | Colorado | United States | 80045 |
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.- 14-0948.cc
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 | ||
STARTED | 6 | 4 |
COMPLETED | 6 | 4 |
NOT COMPLETED | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Ipilimumab | VESANOID | Total |
---|---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 | 10 |
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
Title | Number of Adverse Events |
---|---|
Description | Safety and tolerability of ipilimumab and VESANOID combination therapy in advanced melanoma patients will be established using the Bayesian approach. |
Time Frame | Up to 2 years from the time of study enrollment for each patient. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 |
Number [Number of events in treatment group] |
51
|
45
|
Title | MDSC Frequency |
---|---|
Description | 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. |
Time Frame | 84 and 130 days following the first treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 |
Mean (Standard Error) [% MDSCs of Myeloid Cells] |
34.35
(6.24)
|
7.29
(2.49)
|
Title | MDSC Suppressive Function |
---|---|
Description | 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. |
Time Frame | 4 weeks prior to start, Midway thru and at least 30 days post final infusion |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 |
Mean (Standard Deviation) [Percentage of Proliferating T Cells] |
NA
(NA)
|
NA
(NA)
|
Title | Changes in the Frequency of Tumor-specific T Cell Responses |
---|---|
Description | 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. |
Time Frame | 4 weeks prior to start, Midway thru and at least 30 days post final infusion |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 |
Mean (Standard Deviation) [Percentage of Activated CD8+ T cells] |
6.0975
(4.144)
|
14.2833
(7.2221)
|
Title | Unresectable Stage III and STAGE IV |
---|---|
Description | Subjects will be followed for evidence of disease progression. |
Time Frame | Up to 2 years from the time of study enrollment for each patient. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Ipilimumab | VESANOID |
---|---|---|
Arm/Group Description | 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. 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 Participants | 6 | 4 |
Median (Full Range) [Days] |
776
|
662
|
Adverse Events
Time Frame | Adverse event data was collected for up to 2 years from the time of study enrollment for each patient. | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Ipilimumab | VESANOID | ||
Arm/Group Description | 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. 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 |
||||
Ipilimumab | VESANOID | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/6 (0%) | 0/4 (0%) | ||
Serious Adverse Events |
||||
Ipilimumab | VESANOID | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/6 (33.3%) | 3/4 (75%) | ||
Gastrointestinal disorders | ||||
Colitis or Diarrhea | 2/6 (33.3%) | 2 | 1/4 (25%) | 1 |
Hepatobiliary disorders | ||||
Autoimmune Hepatitis | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 |
Elevated ALT | 1/6 (16.7%) | 1 | 0/4 (0%) | 0 |
Nervous system disorders | ||||
Headache | 0/6 (0%) | 0 | 1/4 (25%) | 1 |
Pseudotumor Cerebri | 0/6 (0%) | 0 | 1/4 (25%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
Ipilimumab | VESANOID | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/6 (100%) | 4/4 (100%) | ||
Endocrine disorders | ||||
Adrenal Insufficiency | 0/6 (0%) | 1/4 (25%) | ||
Eye disorders | ||||
Blurred Vision | 0/6 (0%) | 1/4 (25%) | ||
Eye Crossing | 0/6 (0%) | 1/4 (25%) | ||
Iridocyclitis | 0/6 (0%) | 1/4 (25%) | ||
Itching Eyes | 0/6 (0%) | 1/4 (25%) | ||
Photophobia | 0/6 (0%) | 2/4 (50%) | ||
Redness of the Eyes | 0/6 (0%) | 1/4 (25%) | ||
Uveitis/Iritis | 0/6 (0%) | 1/4 (25%) | ||
Gastrointestinal disorders | ||||
Colitis | 1/6 (16.7%) | 0/4 (0%) | ||
Vomiting | 4/6 (66.7%) | 1/4 (25%) | ||
General disorders | ||||
Abdominal Pain | 2/6 (33.3%) | 0/4 (0%) | ||
Back Pain | 1/6 (16.7%) | 0/4 (0%) | ||
Body Aches (increasing) | 0/6 (0%) | 1/4 (25%) | ||
Decreased Appetite | 2/6 (33.3%) | 0/4 (0%) | ||
Dry Mouth | 0/6 (0%) | 1/4 (25%) | ||
Facial Flushing | 0/6 (0%) | 1/4 (25%) | ||
Fatigue | 3/6 (50%) | 2/4 (50%) | ||
Malaise (increasing) | 0/6 (0%) | 1/4 (25%) | ||
Generalized Flushing | 0/6 (0%) | 1/4 (25%) | ||
Itching Mouth | 0/6 (0%) | 1/4 (25%) | ||
Myalgia | 0/6 (0%) | 1/4 (25%) | ||
Nausea | 4/6 (66.7%) | 1/4 (25%) | ||
Hepatobiliary disorders | ||||
Elevated ALT | 2/6 (33.3%) | 0/4 (0%) | ||
Elevated AST | 2/6 (33.3%) | 0/4 (0%) | ||
Elevated LFT | 2/6 (33.3%) | 1/4 (25%) | ||
Immune system disorders | ||||
Fever | 2/6 (33.3%) | 1/4 (25%) | ||
Arthralgias | 0/6 (0%) | 1/4 (25%) | ||
Musculoskeletal and connective tissue disorders | ||||
Muscle Ache | 0/6 (0%) | 1/4 (25%) | ||
Nervous system disorders | ||||
Headache | 1/6 (16.7%) | 4/4 (100%) | ||
Respiratory, thoracic and mediastinal disorders | ||||
Wheezing | 1/6 (16.7%) | 0/4 (0%) | ||
Skin and subcutaneous tissue disorders | ||||
Pruritus | 6/6 (100%) | 4/4 (100%) | ||
Dry Skin | 1/6 (16.7%) | 1/4 (25%) | ||
Erythematous Rash | 2/6 (33.3%) | 1/4 (25%) | ||
Exfoliation | 0/6 (0%) | 1/4 (25%) | ||
Pruritic Rash | 2/6 (33.3%) | 1/4 (25%) | ||
Rash | 4/6 (66.7%) | 0/4 (0%) | ||
Skin Color Change | 0/6 (0%) | 1/4 (25%) | ||
Skin Peeling | 0/6 (0%) | 1/4 (25%) |
Limitations/Caveats
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/Title | Martin McCarter |
---|---|
Organization | Univesity Colorado Ansshutz Medical Campus |
Phone | 303-724-2728 |
martin.mccarter@ucdenver.edu |
- 14-0948.cc