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A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML
Alexander J Ambinder1, Kelly Norsworthy1, Daniela Hernandez1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Abstract:
Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.
Insights
This study investigated IRX195183, a novel retinoid receptor agonist, in patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). The drug showed safety and potential efficacy, with some patients achieving stable disease or remission.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Aberrant retinoid signaling is observed in subsets of acute myelogenous leukemia (AML), suggesting potential therapeutic targets.
- Retinoids have demonstrated in vitro sensitivity in certain non-acute promyelocytic leukemia (APL) AML subtypes.
- Relapsed or refractory myelodysplastic syndrome (MDS) and AML represent significant unmet medical needs.
Purpose of the Study:
- To evaluate the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist.
- To determine the maximally tolerated dose (MTD) of IRX195183 in patients with relapsed/refractory MDS or AML.
- To assess the in vivo biological activity and potential clinical benefit of IRX195183.
Main Methods:
- Phase 1, single-center, single-arm dose-escalation study.
- Eleven patients with relapsed or refractory MDS/AML were treated with oral IRX195183 at 50 mg or 75 mg daily for 28-day cycles.
- Pharmacodynamic assessments included CD38 expression and in vitro leukemic cell differentiation assays.
Main Results:
- IRX195183 was generally well-tolerated; the MTD was not reached. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema.
- Four out of eleven patients (36%) achieved stable disease or better, including one complete remission with incomplete hematologic recovery.
- In vivo evidence of leukemic blast maturation (increased CD38) and in vitro leukemic cell differentiation capacity were observed.
Conclusions:
- IRX195183 is a safe investigational drug that achieves biologically active plasma concentrations in patients with MDS/AML.
- IRX195183 demonstrates potential efficacy in a subset of patients with relapsed or refractory MDS/AML.
- Further investigation of IRX195183 in MDS/AML is warranted based on these preliminary findings.
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