Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy.

Abstract

Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment.

• Authors: Lewis R Silverman, Peter Greenberg, Azra Raza, Matthew J Olnes, James F Holland, Premkumar Reddy, Manoj Maniar, Francois Wilhelm
• Journal: Hematological oncology (Hematol Oncol) Vol. 33 Issue 2 Pg. 57-66 (Jun 2015) ISSN: 1099-1069 [Electronic] England
• PMID: 24777753 (Publication Type: Journal Article, Meta-Analysis)
• Copyright: © 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Chemical References

• Cell Cycle Proteins
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Sulfones
• ON 01910
• DNA (Cytosine-5-)-Methyltransferases
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• Glycine

Topics

• Aged
• Aged, 80 and over
• Anemia, Refractory, with Excess of Blasts (drug therapy, enzymology, pathology)
• Bone Marrow (pathology)
• Cell Cycle Proteins (antagonists & inhibitors)
• Clinical Trials, Phase I as Topic (statistics & numerical data)
• Clinical Trials, Phase II as Topic (statistics & numerical data)
• DNA (Cytosine-5-)-Methyltransferases (antagonists & inhibitors)
• DNA Methylation (drug effects)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Glycine (administration & dosage, adverse effects, analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Infusions, Intravenous
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, enzymology, pathology)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Risk
• Signal Transduction (drug effects)
• Sulfones (administration & dosage, adverse effects, pharmacology, therapeutic use)