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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ipilimumab | Active Comparator | 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. |
|
| VESANOID | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| VESANOID | Drug | 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). |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Martin McCarter, MD | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Hospital | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30121453 | Result | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | VESANOID |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Number | Number of events in treatment group | Up to 2 years from the time of study enrollment for each patient. |
|
Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | CTCAE (Unspecified) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Colitis | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Martin McCarter | Univesity Colorado Ansshutz Medical Campus | 303-724-2728 | martin.mccarter@ucdenver.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 7, 2016 | Dec 21, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D014212 | Tretinoin |
| D000074324 | Ipilimumab |
| ID | Term |
|---|---|
| D014801 | Vitamin A |
| D012176 | Retinoids |
| D002338 | Carotenoids |
| D011090 | Polyenes |
| D000475 |
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|
|
| Ipilimumab | Drug | Ipilimumab is current standard of care treatment for melanoma. |
|
|
| 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. |
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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| 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. | Posted | Mean | Standard Error | % MDSCs of Myeloid Cells | 84 and 130 days following the first treatment |
|
|
|
| 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. | Posted | Mean | Standard Deviation | Percentage of Proliferating T Cells | 4 weeks prior to start, Midway thru and at least 30 days post final infusion |
|
|
|
| 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. | Posted | Mean | Standard Deviation | Percentage of Activated CD8+ T cells | 4 weeks prior to start, Midway thru and at least 30 days post final infusion |
|
|
|
| Secondary | Unresectable Stage III and STAGE IV | Subjects will be followed for evidence of disease progression. | Posted | Median | Full Range | Days | Up to 2 years from the time of study enrollment for each patient. |
|
|
|
| 0 |
| 6 |
| 2 |
| 6 |
| 6 |
| 6 |
| EG001 | 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. | 0 | 4 | 3 | 4 | 4 | 4 |
| Pseudotumor Cerebri | Nervous system disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Colitis or Diarrhea | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Autoimmune Hepatitis | Hepatobiliary disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Elevated ALT | Hepatobiliary disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Fever | Immune system disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Headache | Nervous system disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Abdominal Pain | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Adrenal Insufficiency | Endocrine disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Arthralgias | Immune system disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Back Pain | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Blurred Vision | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Body Aches (increasing) | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Decreased Appetite | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Dry Mouth | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Dry Skin | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Elevated ALT | Hepatobiliary disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Elevated AST | Hepatobiliary disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Elevated LFT | Hepatobiliary disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Erythematous Rash | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Exfoliation | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Eye Crossing | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Facial Flushing | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Malaise (increasing) | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Generalized Flushing | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Iridocyclitis | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Itching Eyes | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Itching Mouth | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Muscle Ache | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Myalgia | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Nausea | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Photophobia | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Pruritic Rash | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Redness of the Eyes | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Skin Color Change | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Skin Peeling | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Uveitis/Iritis | Eye disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| Alkenes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D053138 | Cyclohexenes |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D013729 | Terpenes |
| D004224 | Diterpenes |
| D010860 | Pigments, Biological |
| D001685 | Biological Factors |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |