Melanoma
Conditions
Keywords
Melanoma, Malignant Melanoma
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.
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.
Interventions
DRUGVESANOID
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).
DRUGIpilimumab
Ipilimumab is current standard of care treatment for melanoma.
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Ipilimumab: Ipilimumab is current standard of care treatment for melanoma. | 6 |
| 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.
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. | 4 |
| Total | 10 |
Baseline characteristics
| Characteristic | VESANOID | Total | Ipilimumab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 9 Participants | 6 Participants |
| Age, Continuous | 50.4 years | 52.1 years | 54.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment United States | 4 participants | 10 participants | 6 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 6 / 6 | 4 / 4 |
| serious Total, serious adverse events | 2 / 6 | 3 / 4 |
Outcome results
Primary
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.
Time frame: 84 and 130 days following the first treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab | MDSC Frequency | 34.35 % MDSCs of Myeloid Cells | Standard Error 6.24 |
| VESANOID | MDSC Frequency | 7.29 % MDSCs of Myeloid Cells | Standard Error 2.49 |
Primary
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.
Time frame: 4 weeks prior to start, Midway thru and at least 30 days post final infusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ipilimumab | MDSC Suppressive Function | NA Percentage of Proliferating T Cells |
| VESANOID | MDSC Suppressive Function | NA Percentage of Proliferating T Cells |
Primary
Number of Adverse Events
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab | Number of Adverse Events | 51 Number of events in treatment group |
| VESANOID | Number of Adverse Events | 45 Number of events in treatment group |
Secondary
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.
Time frame: 4 weeks prior to start, Midway thru and at least 30 days post final infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ipilimumab | Changes in the Frequency of Tumor-specific T Cell Responses | 6.0975 Percentage of Activated CD8+ T cells | Standard Deviation 4.144 |
| VESANOID | Changes in the Frequency of Tumor-specific T Cell Responses | 14.2833 Percentage of Activated CD8+ T cells | Standard Deviation 7.2221 |
Secondary
Unresectable Stage III and STAGE IV
Subjects will be followed for evidence of disease progression.
Time frame: Up to 2 years from the time of study enrollment for each patient.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab | Unresectable Stage III and STAGE IV | 776 Days |
| VESANOID | Unresectable Stage III and STAGE IV | 662 Days |