A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML

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.

Keywords: acute myeloid leukemia; differentiation therapy; microenvironment niche; phase 1 clinical trial; retinoic acid receptor agonist.

Figure 1

Treatment schema of phase I clinical trial using IRX195183 in patients with high risk MDS and relapsed/refractory AML.

Figure 2

Flow chart diagramming patient enrollment. DLT, Dose-limiting toxicity.

Figure 3

Differentiation activity of plasma from patients treated with IRX195183. (A) Representative flow plots of CD11b expression of NB4 cells cultured in the presence of 10% plasma from patients treated with ATRA (1^st and 3^rd) or IRX195183 (2^nd and 4^th) in the presence or absence of bone marrow stroma. (B, C) Differentiation activity on plasma from patients treated with either ATRA or IRX195183 as measured by upregulation of CD11b expression (B) and decreased clonogenic activity (C) of NB4 cells. Data represents mean ± SEM, n = 4 independent patients, *p < 0.05, **p < 0.01. P was calculated using unpaired, 2-tailed Student’s t test. (D) CD38 expression on the leukemic blasts from patient #3 and patient #5 treated with IRX195183.