TY - JOUR
T1 - A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML
AU - Ambinder, Alexander J.
AU - Norsworthy, Kelly
AU - Hernandez, Daniela
AU - Palau, Laura
AU - Paun, Bogdan
AU - Duffield, Amy S
AU - Chandraratna, Rosh
AU - Sanders, Martin
AU - Varadhan, Ravi
AU - Jones, Richard J.
AU - Douglas Smith, B.
AU - Ghiaur, Gabriel
N1 - Funding Information:
This project was supported by the National Heart, Lung, and Blood Institute (grants K08-HL127269, R03 HL145226, T32-HL007525) (GG, LP), the National Cancer Institute (grants P01-CA225618, P30-CA00793, 5T32-CA009071) (BS, RJ, GG, AA), The Leukemia and Lymphoma Society (LLS TRP 14086277) (RJ), and The Augustine Fellowship (KN). IRX195183 was provided by Io Therapeutics, Inc.
Publisher Copyright:
© Copyright © 2020 Ambinder, Norsworthy, Hernandez, Palau, Paun, Duffield, Chandraratna, Sanders, Varadhan, Jones, Douglas Smith and Ghiaur.
PY - 2020/10/23
Y1 - 2020/10/23
N2 - 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.
AB - 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.
KW - acute myeloid leukemia
KW - differentiation therapy
KW - microenvironment niche
KW - phase 1 clinical trial
KW - retinoic acid receptor agonist
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UR - http://www.scopus.com/inward/citedby.url?scp=85095604487&partnerID=8YFLogxK
U2 - 10.3389/fonc.2020.587062
DO - 10.3389/fonc.2020.587062
M3 - Article
C2 - 33194741
AN - SCOPUS:85095604487
SN - 2234-943X
VL - 10
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 587062
ER -