Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Combination with Azacitidine or Daratumumab in Non-APL Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Authors: Cook Rachel J. , Moyo Tamara , Liesveld Jane L. , Rizzieri David A. , Stein Eytan M. , De Botton Stephane , Roboz Gail J. , Sekeres Mikkael A. , Jurcic Joseph G. , Raza Azra , Redner Robert L. , Bixby Dale L. , Cortes Jorge E. , Stephens Kristin , Volkert Angela , Kang Qing , Di Tomaso Emmanuelle , Roth David A. , Vigil Carlos E 
Published: October 2019

Abstract
Introduction: SY-1425 (tamibarotene) is an orally available, synthetic retinoid in Phase 2 development for non-APL AML and MDS patients (pts) positive for the RARA and/or IRF8 biomarkers of RARA pathway activation (McKeown et al, Cancer Discovery, 2017). Biomarker-selected pts treated with SY-1425 single agent showed myeloid differentiation, improved blood counts and reduced bone marrow blasts, and treatment was generally well tolerated with manageable and/or reversible side effects (Jurcic et al, ASH 2017). SY-1425 showed evidence of combination activity in preclinical models. Synergy was observed with HMAs, with DNA damage and apoptosis in vitro, and in an AML PDX model the combination of SY-1425 and azacitidine (Aza) demonstrated increased tumor reduction, deeper, more durable responses and improved survival relative to Aza or SY-1425 alone (McKeown et al, ASH 2016). SY-1425 induced CD38 expression in preclinical models and the combination with daratumumab (Dara), a CD38 targeting antibody indicated for multiple myeloma (MM), induced immune-mediated cell death ex vivo (Austgen et al, AACR 2017). SY-1425 also increased CD38 expression in bone marrow blasts in AML/MDS pts (Jurcic et al, ASH 2017). These data support the ongoing investigation of the efficacy and safety of SY-1425 in non-APL AML and MDS pts, in combination with Aza or Dara (NCT02807558).
Methods: Biomarker positive (Bm+), unfit pts with newly-diagnosed (ND) AML received SY-1425 + Aza. The SY-1425 + Aza combination arm was recently expanded to include biomarker negative pts. Bm+ pts with relapsed/refractory (R/R) AML or R/R higher-risk MDS received SY-1425 + Dara. All enrolled pts received SY-1425 at 6 mg/m2/day PO with twice daily dosing. Aza (75 mg/m2 IV/SC) and Dara (16 mg/kg IV) were dosed as approved in MDS and MM, respectively. Objectives included characterization of activity by overall response rate (per IWG), duration of response, event-free, relapse-free and overall survival, hematologic improvement, and assessment of safety. For pts treated with SY-1425 + Dara, the kinetics and magnitude of CD38 increases were evaluated on peripheral blasts using a centralized assay.
Results: With 10 ND AML pts currently enrolled to receive SY-1425 + Aza, 6 were Bm+. Data through 9 July 2018 were available for 5 Bm+ pts, 4 (80%) male and median age 76 years (64-83). Pts were reported to have poor (3 pts) and intermediate (2 pts) ELN genetic risk. Median time on treatment was 25.4 weeks (9.7-42.1). Early clinical responses at 4 weeks (C2D1) were reported in 4 of 5 pts. Best responses were CR (1 pt), CRi (1 pt) and PRi (2 pts), defined as PR with incomplete blood count recovery. A 5th pt with ND AML developing from prior CMML with 2 distinct blast populations had stable disease (AML blasts), but with CR of CMML marrow blasts by flow at 8 weeks (C3D1). 2 pts remained on treatment, including 1 with CR at 9 months (C10D1). 3 pts discontinued due to PD/lack of efficacy (2 pts) and AE (1 pt).
10 Bm+ pts have enrolled to receive SY-1425 + Dara. Data were available for 4 pts (3 R/R AML and 1 R/R MDS), 4 (100%) female and median age 60 years (36-68). Pt risk was poor (2 pts) and intermediate (1 pt) per ELN for AML, and good (1 pt) per IPSS-R for MDS. Median time on treatment was 5.9 weeks (0.7-8.9). 1 of 3 evaluable pts achieved a PRi at 4 weeks (C2D1) but progressed at C3D1. Initial data demonstrate that 3 of 4 pts showed an increase in CD38 expression levels in peripheral AML blasts as early as 3 days following SY-1425 treatment, up to 2.6-fold by 1 week. All 4 pts discontinued treatment due to disease progression.
AEs (most common, all causality) reported in >2 pts receiving SY-1425 combination treatment included febrile neutropenia (44%), and hypertriglyceridemia, pruritus, abdominal pain and peripheral edema (33% each). Overall, AEs, including AEs ≥ grade 3 and SAEs, were consistent with those of single agent SY-1425, Aza or Dara.
Conclusion: SY-1425 in combination with Aza in non-APL AML shows preliminary evidence of clinical activity with early objective responses observed. CD38 expression increased in 3 of 4 pts with R/R AML or R/R MDS within 3 days of SY-1425 treatment and reduction in marrow blasts was observed in 1 pt treated with SY-1425 in combination with Dara. No new safety signals have been identified with either combination regimen. In summary, early data suggest SY-1425 in combination has clinical potential in pts with non-APL AML and MDS. Updated results will be presented.

Disclosures
Cook: Syros Pharmaceuticals: Consultancy. Liesveld:Abbvie: Honoraria; Onconova: Other: DSMB. Rizzieri:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy. Stein:Novartis: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Bayer: Consultancy. Roboz:Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Sandoz: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Jurcic:Actinium Pharmaceuticals, Inc: Research Funding; Daiichi-Sankyo: Research Funding; Forma Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Genetech: Research Funding; Incyte: Consultancy; Celgene: Research Funding; Astellas: Research Funding. Raza:Kura Oncology: Research Funding; Geoptix: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Research Funding; Janssen: Research Funding; Onconova: Research Funding, Speakers Bureau; Syros: Research Funding. Bixby:GlycoMimetics: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Stephens:Syros Pharmaceuticals: Employment, Equity Ownership. Volkert:Syros Pharmaceuticals: Employment, Equity Ownership. Kang:Syros Pharmaceuticals: Employment, Equity Ownership. Di Tomaso:Syros Pharmaceuticals: Employment, Equity Ownership. Roth:Syros Pharmaceuticals: Employment, Equity Ownership.