title: Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer.
abstract: Rigosertib (ON 01910.Na), a synthetic novel benzyl styryl sulfone, was administered to 28 patients with advanced cancer in a Phase I trial in order to characterize its pharmacokinetic profile, determine the dose-limiting toxicities (DLT), define the recommended phase II dose (RPTD) and to document any antitumor activity. Patients with advanced malignant neoplasms refractory to standard therapy were given escalating doses of rigosertib (50, 100, 150, 250, 325, 400, 650, 850, 1,050, 1,375, 1,700 mg/m(2)/24h) as a 3-day continuous infusion (CI) every 2 weeks. An accelerated Fibonacci titration schedule with specified decreases for toxicities was used for escalation until grade ≥2 toxicity occurred. Intrapatient dose escalation was allowed if toxicity was grade ≤2 and the disease remained stable. Plasma pharmacokinetics (PK) and urinary PK assessments were studied in the 1st and 4th cycles. Twenty-nine patients (12 men and 17 women; age 36-87 y with a median of 63 y) were registered, but one died before study drug was given. Twenty-eight patients received a median of 3 cycles of therapy. Most common grade ≥2 toxicities attributable to rigosertib included fatigue, anorexia, vomiting and constipation. DLTs included muscular weakness, hyponatremia, neutropenia, delirium and confusional state. Risk factors for severe toxicities include pre-existing neurological dysfunction or advanced gynecologic cancer after pelvic surgery. Rigosertib pharmacokinetics showed rapid plasma distribution phases and urinary excretion. Elevations in plasma Cmax and AUC due to decreases in plasma clearance were associated with acute grade ≥3 toxicities. Of 22 evaluable patients, 9 (41%) achieved a best overall response of stable disease; all other patients (n=13; 59%) progressed. The median progression-free survival time was 50 days (95% confidence interval [CI]: 37-80 days). Nine (41%) patients survived for over 1 y. In summary, prolonged IV infusions of rigosertib were generally well tolerated. Nine (41%) patients achieved stable disease and 9 (41%) patients survived for over 1 year. The RPTD appears to be 850 mg/m(2)/24hr CI x 3 days. (ClinicalTrials.gov identifier: NCT01538537).
authors.affiliation: Department of Radiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York, NY, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Ohnuma
authors.forename: Deborah
authors.initials: D
authors.lastname: Lehrer
authors.forename: Chen
authors.initials: C
authors.lastname: Ren
authors.forename: Sool Yeon
authors.initials: SY
authors.lastname: Cho
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
authors.forename: Lewis
authors.initials: L
authors.lastname: Silverman
authors.forename: Max
authors.initials: M
authors.lastname: Sung
authors.forename: Herbert F
authors.initials: HF
authors.lastname: Gretz
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benisovich
authors.forename: Shyamala
authors.initials: S
authors.lastname: Navada
authors.forename: Eugene
authors.initials: E
authors.lastname: Akahoho
authors.forename: Eric
authors.initials: E
authors.lastname: Wilck
authors.forename: David R
authors.initials: DR
authors.lastname: Taft
authors.forename: John
authors.initials: J
authors.lastname: Roboz
authors.forename: Francois
authors.initials: F
authors.lastname: Wilhelm
authors.forename: James F
authors.initials: JF
authors.lastname: Holland
keywords: ON01910.Na; Rigosertib; phase 1 study; phosphatidylinositol-3-kinase; polo-like kinase