Phase 3, Multi-Center, International, Randomized, Double-Blind, Placebo Controlled Study of Oral Rigosertib + Injectable Azacitidine (AZA) Versus Injectable Azacitidine in Treatment-Naive Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS)
Authors: Garcia-Manero Guillermo , Navada Shyamala C. , Fenaux Pierre , Zbyszewski Patrick S. , Adesanya Afoluso Ronnee , Azarnia Nozar , Fruchtman Steven M. , Silverman Lewis R. 
Published: November 2019

Background
The only approved medications for treatment of first line HR-MDS are HMAs (AZA & decitabine (DEC) in US, AZA only in EU). It is estimated that progression to Acute Myeloid Leukemia (AML) as well as median OS for these pts is <1-3 yrs (Greenberg 2012). Although AZA monotherapy demonstrated improvement in OS in HR-MDS, clinically meaningful & durable responses continue to be limited to a subset of pts (Silverman 2006). One obvious strategy is to identify a novel drug that can be administered effectively in combo with AZA & has minimal overlapping toxicity with AZA. Based on this current approach & favorable results of the Ph2 study (Navada EHA 2019) the 1st pivotal Ph3 randomized study of oral rigosertib in combo with AZA has been developed as part of an effort to increase overall responses as well as reduce risk of transformation to AML for pts with treatment-naive HR-MDS.
Studies have demonstrated that rigosertib binds directly to the Ras-Binding Domains (RBD) found in Ras effector proteins, such as the Raf kinases & PI3K & inhibits the RAS-RAF-MEK & the PI3Ks pathways (Athuluri-Divakar 2016 Cell 2016). In vitro, the combo of rigosertib with AZA synergistically inhibits growth & induces apoptosis of leukemic cells in a sequence-dependent fashion. Sequential exposure with rigosertib followed by AZA achieved maximum synergy with clinically achievable concentrations (Skiddan AACR 2006, Silverman EHA 2019). In a ph2 study (09-08) oral rigosertib at doses ≥ 840 mg/d administered in combo with AZA demonstrated efficacy in HMA-naive MDS pts with an ORR of 90% & a CR rate of 34%. The combo administered in repetitive cycles for more than 2 yrs was well tolerated & the observed GU toxicity was mitigated using specific management guidelines. Based on the efficacy data & favorable safety profile, the pivotal Ph3 trial presented here in treatment-naive HR-MDS population has been developed. (Navada EHA 2019).
Study Design & Methods
Ph3, multi-center, international, randomized, double-blind, placebo-controlled study to be conducted in treatment-naive pts with HR-MDS who will receive oral rigosertib 1120mg/d (560 mg morning & 560 mg afternoon) or placebo in combo with AZA 75mg/m2 daily (SC or IV). Pts will take rigosertib/placebo on days 1-21 of a 28-day cycle & starting on Day 8, AZA will be administered by SC injection or IV infusion at a 75 mg/m2 daily dose for 7 days of a 28-day cycle according to the approved label. 400 pts are anticipated for enrollment. Major inclusion criteria are shown in Figure 1. Major exclusion criteria are prior treatment with rigosertib or HMA; chronic myelomonocytic leukemia; & prior BMT.
Treatment will continue until disease progression as defined by IWG 2006, or unacceptable toxicity. Treatment will continue until PD as defined by IWG 2006 or unacceptable toxicity, after which pts will be followed for survival every 2 mos until death or 3 yrs, whichever occurs first. The primary analysis of all efficacy endpoints will be in the intention-to-treat population. The safety population will include all pts classified according to the protocol treatment they received, regardless of random assignment. Randomized pts who receive no treatment will be excluded. Management guidelines for treatment emergent adverse events requiring dose adjustments, either dose delay or dose modification at time of AE, is provided in protocol.
The final analysis of response rate will be conducted using IWG 2006.
Endpoints
All endpoints for the study are provided in Table 1.
Conclusion
This pivotal Phase 3 trial in treatment-naive HR-MDS population has been developed based on efficacy data & favorable safety profile from 09-08. The Intergroup randomized ph2 combo study in pts with HR-MDS treated with AZA + lenalidomide (ORR 49%), or AZA + vorinostat (ORR 27%) had a similar ORR to pts treated with AZA monotherapy (ORR 38%) (Sekeres 2017). In contrast, the ph2 study of oral rigosertib in combo with AZA had an ORR of 90% & a CR rate of 34% (Navada EHA 2019). This proposed study is the 1st ph3 combo study of oral rigosertib with AZA & may provide a potential new treatment for first line in a pt population with poor prognosis & limited therapeutic options.

Disclosures
Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Navada:Onconova Therapeutics Inc: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Adesanya:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Silverman:Medimmune: Research Funding; Celgene: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.