1032P - Pharmacodynamic and pharmacokinetic evaluation of SY-1425 (tamibarotene) in biomarker-selected acute myeloid leukemia (AML) and myelodysplastic syn...

Date 09 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cancer in Adolescents
Leukaemia
Haematologic Malignancies
Presenter Dale Bixby
Citation Annals of Oncology (2017) 28 (suppl_5): v355-v371. 10.1093/annonc/mdx373
Authors D. Bixby1, C.E. Vigil2, J. Jurcic3, R. Cook4, M.A. Sekeres5, D. Rizzieri6, J. Cortes7, R. Redner8, D. Steensma9, G. Roboz10, T. Moyo11, M. McKeown12, N. Waters12, K. Stephens12, E. di Tomaso12, D.A. Roth12, E. Stein13
  • 1Hematology, University of Michigan Comprehensive Cancer Center, 48109 - Ann Arbor/US
  • 2Hematology, University of Iowa, Iowa city/US
  • 3Hematology, Columbia University Medical Center, New York/US
  • 4Hematology, Oregon Health Science University, Portland/US
  • 5Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 44195 - Cleveland/US
  • 6Hematology/oncology, Duke University Medical Center, 27522 - Durham/US
  • 7Department Of Leukemia, MD Anderson Cancer Center, 77090 - Houston/US
  • 8Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh/US
  • 9Hematology Oncology, Dana Farber Cancer Institute, boston/US
  • 10Hematology Oncology, Weill Cornell Medical College, 10065 - New York/US
  • 11Hematology Oncology, Vanderbilt University Medical Center, Nashville/US
  • 12Clinical Development, Syros Pharmaceuticals, 02139 - Cambridge/US
  • 13Hematology Oncology, Memorial Sloan Kettering Cancer Center, New York/US

Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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

Syros Pharmaceuticals

Funding

Syros Pharmaceuticals

Disclosure

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.