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Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies

Leukemia volume 27, pages 1920–1923 (2013)Cite this article

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Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are incurable B-cell malignancies usually responsive to initial immunochemotherapy, but virtually all patients experience relapse. Salvage therapy choices for relapsed/refractory disease are often limited by resultant cytopenias and acquired drug resistance. The current priority in these B-cell malignancies, therefore, is to develop agents with novel mechanisms of action that are selective for tumor cells, overcome shared patterns of acquired drug resistance and exhibit limited toxicities.

Styrylbenzylsulfones are a new family of non-ATP-competitive anticancer agents that induce apoptosis in a variety of tumor cell lines, including those resistant to many chemotherapy agents.1, 2 As a class, styrylbenzylsulfones inhibit cell cycle progression and induce mitotic arrest of tumor cells with less toxicity to normal human cells.3, 4 ON 01910.Na (rigosertib) is a styryl sulfonyl compound that demonstrated inhibition of phosphatidylinositol-3-kinase (PI3K), preferentially targeting the PI3Kα and PI3Kβ isoforms, and triggered apoptosis via the release of cytochrome c from mitochondria in MCL cell lines.3 Rigosertib’s mechanism of action was initially considered to include inhibition of polo-like 1 kinase,4 but evidence for direct inhibition was not confirmed in subsequent studies5 and its antimitotic activity may rely on the phosphorylation of mitosis coordinator RanGAP1 SUMO1.6 First-in-man studies of rigosertib in solid tumors demonstrated excellent tolerability with limited hematologic toxicity.7 Rigosertib has also demonstrated preclinical and early clinical activities in myelodysplastic syndromes (MDS),8, 9 and it is currently being tested in a randomized phase III trial in patients with relapsed/refractory MDS (NCT01241500).

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Acknowledgements

We would like to thank all the patients for their willingness to participate in this study protocol; Clifton Mo and Janet Valdez for management of patients; and Susan Soto for clinical research support; This work was supported by the Intramural Research Program of National, Heart, Lung, and Blood Institute at the National Institutes of Health (NIH). The study was monitored by Onconova Therapeutics Inc. in accordance with good clinical practice requirements.

Author contributions

The design of this scientific work was done by MR and AW. MR, MF, GA and AW were responsible for care of all patients. Data analysis was done by MR, FW and AW. The manuscript was written by MR and AW, and submitted after critical review by all authors.

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Authors and Affiliations

  1. Metabolism Branch, National Cancer Institute, NIH, Bethesda, MD, USA

    M Roschewski

  2. Hematology Branch, National Heart, Lung, Blood Institute, NIH, Bethesda, MD, USA

    M Roschewski, M Farooqui, G Aue & A Wiestner

  3. Onconova Therapeutics Inc, Newton, PA, USA

    F Wilhelm

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  1. M Roschewski
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  2. M Farooqui
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  4. F Wilhelm
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Corresponding author

Correspondence to A Wiestner.

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Competing interests

Francois Wilhelm is the Chief Medical Officer and Senior Vice President at Onconova Therapeutics Inc. The remaining authors declare no conflict of interest.

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Roschewski, M., Farooqui, M., Aue, G. et al. Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies. Leukemia 27, 1920–1923 (2013). https://doi.org/10.1038/leu.2013.79

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