Trial Outcomes & Findings for Ipilimumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma (NCT NCT02403778)

Last Updated: 2023-09-21

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

10 participants

Primary outcome timeframe

Up to 2 years from the time of study enrollment for each patient.

Results posted on

2023-09-21

Participant Flow

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	6	4
Overall Study COMPLETED	6	4
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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 n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age, Continuous	54.8 years n=5 Participants	50.4 years n=7 Participants	52.1 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants	4 participants n=7 Participants	10 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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.
Number of Adverse Events	51 Number of events in treatment group	45 Number of events in treatment group

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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.
MDSC Frequency	34.35 % MDSCs of Myeloid Cells Standard Error 6.24	7.29 % MDSCs of Myeloid Cells Standard Error 2.49

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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.
MDSC Suppressive Function	NA Percentage of Proliferating T Cells Standard Deviation NA Assay not indicative of function no T cell proliferation in controls.	NA Percentage of Proliferating T Cells Standard Deviation NA Assay not indicative of function no T cell proliferation in controls.

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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.
Changes in the Frequency of Tumor-specific T Cell Responses	6.0975 Percentage of Activated CD8+ T cells Standard Deviation 4.144	14.2833 Percentage of Activated CD8+ T cells Standard Deviation 7.2221

SECONDARY outcome

Timeframe: Up to 2 years from the time of study enrollment for each patient.

Subjects will be followed for evidence of disease progression.

Outcome measures

Outcome measures
Measure	Ipilimumab n=6 Participants 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.	VESANOID n=4 Participants 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.
Unresectable Stage III and STAGE IV	776 Days Interval 258.0 to 912.0	662 Days Interval 566.0 to 758.0

Adverse Events

Ipilimumab

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

VESANOID

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Ipilimumab n=6 participants at risk 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.	VESANOID n=4 participants at risk 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.
Nervous system disorders Headache	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Number of events 1 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Nervous system disorders Pseudotumor Cerebri	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Number of events 1 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Gastrointestinal disorders Colitis or Diarrhea	33.3% 2/6 • Number of events 2 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Number of events 1 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Hepatobiliary disorders Autoimmune Hepatitis	16.7% 1/6 • Number of events 1 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Hepatobiliary disorders Elevated ALT	16.7% 1/6 • Number of events 1 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.

Other adverse events

Additional Information

Martin McCarter

Univesity Colorado Ansshutz Medical Campus

Phone: 303-724-2728

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Ipilimumab n=6 participants at risk 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.	VESANOID n=4 participants at risk 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.
Gastrointestinal disorders Colitis	16.7% 1/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Pruritus	100.0% 6/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	100.0% 4/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Immune system disorders Fever	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Nervous system disorders Headache	16.7% 1/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	100.0% 4/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Abdominal Pain	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Endocrine disorders Adrenal Insufficiency	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Immune system disorders Arthralgias	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Back Pain	16.7% 1/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Blurred Vision	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Body Aches (increasing)	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Decreased Appetite	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Dry Mouth	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Dry Skin	16.7% 1/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Hepatobiliary disorders Elevated ALT	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Hepatobiliary disorders Elevated AST	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Hepatobiliary disorders Elevated LFT	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Erythematous Rash	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Exfoliation	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Eye Crossing	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Facial Flushing	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Fatigue	50.0% 3/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	50.0% 2/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Malaise (increasing)	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Generalized Flushing	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Iridocyclitis	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Itching Eyes	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Itching Mouth	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Musculoskeletal and connective tissue disorders Muscle Ache	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Myalgia	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
General disorders Nausea	66.7% 4/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Photophobia	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	50.0% 2/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Pruritic Rash	33.3% 2/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Rash	66.7% 4/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Redness of the Eyes	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Skin Color Change	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Skin and subcutaneous tissue disorders Skin Peeling	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Eye disorders Uveitis/Iritis	0.00% 0/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Gastrointestinal disorders Vomiting	66.7% 4/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	25.0% 1/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.
Respiratory, thoracic and mediastinal disorders Wheezing	16.7% 1/6 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.	0.00% 0/4 • Adverse event data was collected for up to 2 years from the time of study enrollment for each patient.