On June 26, 2017 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes (MDS), reported demonstrating responses of oral rigosertib with azacitidine in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), as well as oral rigosertib as a single agent (Press release, Onconova, JUN 26, 2017, View Source [SID1234519691]). The findings were presented by Onconova, Mount Sinai, and SymBio at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place on June 22-24 in Madrid, Spain. Schedule your 30 min Free 1stOncology Demo! "Advancing oral rigosertib in the clinic as a stand-alone agent, and providing further evidence for activity of rigosertib in combination with azacitidine in patients with MDS and AML represents an extension of our pipeline," said Dr. Ramesh Kumar, CEO of Onconova. "We are positioned for multiple key milestones in 2017 and beyond, beginning with the interim analysis of our pivotal Phase 3 INSPIRE trial later this year."
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Full copies of the posters and oral presentations can be accessed by visiting "Scientific Presentations" in the Investors section of Onconova’s website.
Oral Presentation: Oral Rigosertib Combined with Azacitidine in Patients with AML and MDS; Effects in Treatment Naive and Relapsed/Refractory Patients
A novel combination therapy of oral rigosertib plus injectable azacitidine was tested in this trial (09-08) at three sites in the U.S. and Europe, representing a first-in-man study of this approach. Eight AML patients were evaluable for response, with an overall response rate (ORR) of 37.5%, and responses in both secondary and refractory AML. Two additional patients had stable disease (25%). Responses were durable, with the longest response in AML approaching one year.
Among 33 evaluable MDS patients, ORR was 76%. Complete remission (CR) in eight (24%), concurrent marrow CR (mCR) and hematologic improvement (HI) in 10 (30%), mCR alone in six (18%), and HI alone in 1 (3%). ORR was 85% in hypomethylating agent (HMA) naïve patients and 62% in HMA resistant patients.
Earlier, Phase 1 and Phase 2 data in first and second-line higher risk (HR)-MDS patients were presented at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and updated at the 2017 ASH (Free ASH Whitepaper) and MDS Foundation meetings. Based on these results, the authors determined that continued study in AML is warranted.
A Phase 3 study of the combination of oral rigosertib and azacitidine in patients with treatment naïve HR-MDS is currently being designed based on an end-of-phase 2 meeting with the Food and Drug Administration.
E-Poster: Rigosertib Combined with Azacitidine Epigenetically Modulates Chromatin and Hematopoietic Stem Cell Populations in MDS
Onconova’s collaborators from the Mount Sinai School of Medicine investigated the in vitro effects of rigosertib combined with azacitidine or vorinostat on two cell lines and on bone marrow samples from patients treated in the Phase 1-2 study, obtained prior to and after one cycle of the combination regimen. Azacitidine is an HMA and vorinostat is an inhibitor of Histone Deacetylase. Rigosertib’s mechanism of action is reported to be mediated by binding to a Ras Binding Domain present in Ras and its effector proteins, including PI3 Kinase and Raf. Chromatin remodeling by changes in methylation and acetylation were noted in cell-lines treated with all three agents, as well as after treatment with the two combinations. The nature of the changes induced with the two combinations was distinct.
The authors propose that rigosertib potentially functions as a chromatin modifying agent in combination with azacitidine and may overcome HMA resistance through chromatin remodeling. Rigosertib alone, and in combination, also leads to epigenetic reprogramming of hematopoietic stem cell populations (HSPCs) that may manifest in hematological improvements in the clinical setting. A U.S. patent describing the synergistic activity of rigosertib in combination with azacitidine has been issued.
SymBio, Onconova’s Partner in Japan and Korea, Presents Phase 1 data Demonstrating Oral Rigosertib as a Single Agent
E-Poster: A Multicenter, Open-label, Phase 1 Clinical Study; Safety, Efficacy, and Pharmacokinetics of Oral Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory MDS
A multicenter, open-label, Phase 1 clinical study of oral rigosertib (primary endpoint was dose-limiting toxicity) indicated that the recommended dose for a Phase 2 clinical study is 560 mg BID in a 2-out-of-3-week administration scheme in Japanese patients with recurrent/relapsed or refractory MDS. This regimen of oral rigosertib was well tolerated.
The primary endpoint of the study was dose-limiting toxicity. The secondary endpoints were 1) safety as assessed by adverse events and laboratory results, 2) efficacy as defined by the International Working Group 2006 Criteria, and 3) pharmacokinetics. Both hematological remission rate and hematological improvement rate were 11.1% of the nine patients with a median age of 70. In this study, the recommended dose was 560 mg BID. This study and a companion Phase 1 study with IV rigosertib were designed to obtain pharmacokinetics, safety, tolerability and efficacy data in MDS patients in Japan. Currently, SymBio is enrolling patients in a pivotal Phase 3 INSPIRE global study to assess the safety and efficacy of IV rigosertib.
Publication: Safety, Efficacy and Pharmacokinetics of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory MDS; A Multicenter, Open-label, Phase 1 Study
A multicenter, open-label, Phase 1 study of intravenous rigosertib was conducted to evaluate its safety, efficacy, and pharmacokinetics and to determine the recommended dose (RD) for Japanese patients.
The Phase 1 study showed that intravenous rigosertib (1,800 mg daily) for consecutive 72 hours was well-tolerated, indicating that this is the RD for Japanese patients with MDS, similar to a Phase 3 study in the U.S. Based on these clinical outcomes, Japanese patients with MDS are participating in a global randomized Phase 3 study to compare rigosertib with physicians’ choice of treatment.