Effects of a Novel Benzyl Styryl Sulfone Derivative ON 01910.Na On the Myelodysplastic Syndrome (MDS) Derived Clone in Patients Relapsing Following Response to Azacitidine (AzaC) Therapy.
Authors: Silverman Lewis R. , Odchimar-Reissig Rosalie , Navada Shyamala C. , Ohnuma Takao , Najfeld Vesna , Wilhelm Francois , Reddy E. Premkumar , Holland James F 
Published: October 2019

Abstract 4839

Background

ON 01910.Na, a novel benzyl styryl sulfone derivative is currently under clinical development as an anticancer agent in solid tumors and hematologic malignancies. ON 01910.Na selectively targets tumor cells at the mitotic phase of the cell cycle, arrests leukemia cells at the G2/M stage and induces apoptosis in a time and dose dependent manner. ON 01910.Na affects multiple cellular pathways, has multikinase activity and has been shown to target multiple genetic pathways, including those that are regulated by cyclin dependent kinases. Our studies indicate that leukemic cells exhibit significantly higher levels of sensitivity of ON01910.Na compared to normal marrow progenitors and increasing cytotoxicity upon prolonged and repetitive exposure (Skidan Proc AACR 2006; Chen Proc AACR 2008). AzaC alters the natural history of higher risk MDS with effects on marrow function, reduction in the risk of leukemic transformation and increased overall survival (Silverman JCO 2002, 2006; Fenaux Lancet 2009). However, 50% of patients (pts) do not respond to AzaC and upon progression after treatment their prognosis is poor, thus, a need for alternative agents.

Methods

A phase I/II study of ON 01910.Na is being conducted in pts with heme malignancies. In the phase I component pts are entered in cohorts of escalating doses in a classic 3+3 design in doses ranging from 650 up to 1700 mg/m2/d continuous IV infusion (CI) for durations from 72 hours up to 144 hours every 2 weeks (1 cycle) for 4 cycles of treatment during the induction phase. Subsequent treatments are administered every 3 to 4 weeks.

Results

This report details two pts with progressive disease following treatment for MDS with AzaC at a dose of 75mg/m2/d x 7 days SC every 4 weeks. Upon progression they were treated with ON 01910.Na at 1050 mg/m2/d CI x 72h to 144 hours. Patient 002 presented with MDS int-2 with myelofibrosis and mild splenomegaly, 8% marrow blasts, normal karyotype, and RBC transfusion dependence. AzaC therapy was initiated in 9/2004. A hematologic improvement (HI) was achieved according to modified IWG criteria with marrow myeloblasts < 5%, RBC transfusion independence and a persistence of mild splenomegaly. A stable HI was maintained for 4 years on monthly AzaC therapy until relapse. At progression (10/2008), marrow myeloblasts increased to 11%, RBC transfusion requirement resumed, platelets fell to 20 × 109/L, the spleen enlarged and a new cytogenetically abnormal clone emerged, 46,XY,del(20)(q11q13),i(21)(q10),der(21)t(1;21)(q12;p11) resulting in trisomy for 1q. Administration of ON 01910.Na 1050 mg/m2/d x 72 hours CI was initiated 3 months after the last dose of AzaC. After 2 cycles of treatment evaluation demonstrated a reduction in: marrow myeloblast to 1%, spleen size by 50% and the MDS clone by 74% by standard cytogenetic analysis. Following the 4th and 7th cycles of treatment with ON 01910.Na, marrow myeloblasts ranged from 1 to 3%, palpable splenomegaly resolved, RBC transfusions decreased by 33% and platelets rose to 80 × 109/L. Although the conventional karyotype normalized after the 4th cycle, all 3 abnormalites were detected by FISH in 30% of cells following the 4th and 7th cycles suggesting a loss of proliferative capacity of the MDS clone. Patient 004 presented with high risk MDS, 19% marrow blasts, pancytopenia and a complex karyotype. AzaC treatment was initiated in 9/2002 leading to a stable HI, with marrow myeloblasts < 5%, RBC transfusion independence, and persistence of the MDS clone with no change in the complex karyotype, including deletion of the MLL locus. The HI was maintained for 6.5 years with monthly AzaC therapy until progression. At relapse marrow myeloblasts increased to 19%, and the complex karyotype persisted unchanged from initial diagnosis. ON 01910.Na treatment started (3/2009) and evaluations at the 2nd, 4th and 7th cycles revealed: a) reduction in % marrow myeloblasts to 12%, 8% and 7% respectively; b) persistence of abnormal karyotype in over 90% of metaphase and interphase cells, irrespective of the decreased % blasts; c) increased platelets from 20 to 40 × 109/L. Patient 002 and 004 remain on treatment with ON 01910.Na at 8+ and 5+ months, respectively.

Conclusions

Preliminary data suggest that ON 01910.Na has an anti-proliferative modulatory effect on the MDS clone in pts progressing after AzaC therapy and should be explored in a broader MDS population.

Disclosures

Silverman: Onconova Therapeutics: Research Funding. Off Label Use: ON01910Na is investigational and not FDA approved. Wilhelm:Onconova: Employment. Reddy:Onconova Therapeutics Inc.: Consultancy, Equity Ownership, Grantee, Membership on an entity's Board of Directors or advisory committees. Holland:Onconova Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.