SY-1425 (tamibarotene) is an oral, potent and selective synthetic RARα agonist previously approved for the treatment of relapsed/refractory acute promyelocytic leukemia (APL) in Japan. Given preclinical evidence of SY-1425 sensitive AML cell lines and patient samples with RARA pathway activation defined by elevated RARA or IRF8, SY-1425 is being investigated in a Phase 2 study of biomarker selected non-APL AML and MDS patients. DHRS3 is a direct RARα target gene with rapid and robust mRNA upregulation in both AML blasts and PBMCs in response to SY-1425. Here we present the first report of SY-1425 plasma levels with DHRS3 based evidence of RARα target engagement from AML and MDS patients enrolled in the Phase 2 study (NCT02807558).
Patients positive for RARA pathway biomarkers (RARA, IRF8, or both) initiated oral daily treatment with SY-1425 at 6 mg/m2/day in two divided doses. Sparse PK was collected twice on day 1 and twice on day 15. PD was sampled before the first dose and at 5-8 hours post dose on day 1 and once on day 15. DHRS3 expression was assessed by qPCR in PBMCs.
PK data in 16 patients showed SY-1425 plasma levels were consistent with those observed in Japanese APL patients based on day 1 Cmax and day 15 steady state exposure. In 19 PD evaluable patients, upregulation of DHRS3 at 5-8 hours had a greater than 2-fold increase in 84% (16/19). Induction was consistent for AML and MDS, including patients positive for RARA, IRF8, or both biomarkers. DHRS3 expression remained elevated after 15 days of continuous treatment in evaluable patients. Using a parallel exploratory ex vivo flow cytometry assay from screening samples, SY-1425 induced differentiation and blast reduction that was correlated with biomarker status.
In a biomarker-selected AML and MDS patients with evidence of RARA pathway activation, SY-1425 causes strong transcriptional upregulation of the DHRS3 target gene, consistent with SY-1425 induced differentiation through myeloid gene activation. The dosing regimen of SY-1425 achieves plasma exposures sufficient to elicit a PD response with direct evidence of RARα target engagement.
Clinical trial identification
NCT02807558 received by on June 13, 2016
Legal entity responsible for the study
J. Jurcic: Research funding from Syros Pharmaceuticals, Astellas Pharma, Daiichi Sankyo, Actinium Pharmaceuticals, Forma Therapeutics, Genetech, Seattle Genetics, Celgene, Kura Oncology. Advisor to Novartis. D. Rizzieri: Consultant for Abbvie, Novartis, Pfizer, Spectrum, Teva; speakers\' bureau for Incyte, Celgene, Gilead, Seattle Genetics. J. Cortes: Research support from Syros Pharmaceuticals. R. Redner: Research funding from Bristol-Myers Squib; Stock or other ownership from Merk, Glaxo, JNJ, MDT, BIIB. G. Roboz: Advisory & funding: Agios, Astex, Celgene, CTI, MedImmune, MEI, Novartis, Onconova, Pfizer, Cellectis; funding: Abbvie, Karyopharm, Moffit, Tensha; Advisory:Amphivena, AstraZeneca, Boerhinger, GSK, Janssen, Roche, Shire, Amgen, Celator, Genoptix, Juno, Sunesis. M. McKeown, N. Waters, K. Stephens: Employee and stock holder of Syros. E. di Tomaso: Employee and stock holder from Syros Pharmaceuticals. D.A. Roth: Employee and stock holder of Syros Pharmaceuticals. E. Stein: Consulting for Agios, Pfizer, Celgene; research funding from Agios, Celgene, GSK, Seattle Genetics, Syros. All other authors have declared no conflicts of interest.