title: Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer.
abstract: BACKGROUND
  Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies.
  
  
  OBJECTIVE
  To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD).
  
  
  METHODS
  Phase 1, open-label, dose-escalation study in men and women ≥18 years of age.
  
  
  METHODS
  An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD).
  
  
  METHODS
  All data summaries were descriptive. PK parameters were estimated using compartmental analysis.
  
  
  RESULTS
  25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days.
  
  
  CONCLUSIONS
  2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.
authors.forename: S H
authors.initials: SH
authors.lastname: Advani
authors.forename: S D
authors.initials: SD
authors.lastname: Achrekar
authors.forename: D C
authors.initials: DC
authors.lastname: Doval
authors.affiliation: Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, India.
authors.forename: D
authors.initials: D
authors.lastname: Raghunadharao
authors.forename: F E
authors.initials: FE
authors.lastname: Wilhelm
authors.forename: M
authors.initials: M
authors.lastname: Acharya
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D013450:Sulfones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D013450:Sulfones; C507134:ON 01910; D005998:Glycine