Am J Cancer Res 2013;3(3):323-338
Original Article
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
Takao Ohnuma, Deborah Lehrer, Chen Ren, Sool Yeon Cho, Manoj Maniar, Lewis Silverman, Max Sung, Herbert F Gretz III,
Vladimir Benisovich, Shyamala Navada, Eugene Akahoho, Eric Wilck, David R Taft, John Roboz, Francois Wilhelm, James F
Holland
Department of Radiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Onconova
Therapeutics, Inc., Newtown, PA, USA; Elmhurst Hospital Center, Elmhurst, NY, USA; Arnold and Marie Schwarz College of
Pharmacy, Long Island, NY, USA
Received March 27, 2013; Accepted May 23, 2013; Epub June 20, 2013; Published June 30, 2013
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/m2/24h) 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/m2/24hr CI x 3 days. (ClinicalTrials.gov identifier: NCT01538537). (ajcr0000194).
Keywords: Rigosertib, ON01910.Na, phase 1 study, polo-like kinase, phosphatidylinositol-3-kinase
Address correspondence to: Dr. Takao Ohnuma, Department of Medicine (Hematology and Oncology) and Tisch Cancer
Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Phone: 212-241-6664;
Fax: 212-860-7186; E-mail: takao.ohnuma@mssm.edu
Original Article
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
Takao Ohnuma, Deborah Lehrer, Chen Ren, Sool Yeon Cho, Manoj Maniar, Lewis Silverman, Max Sung, Herbert F Gretz III,
Vladimir Benisovich, Shyamala Navada, Eugene Akahoho, Eric Wilck, David R Taft, John Roboz, Francois Wilhelm, James F
Holland
Department of Radiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Onconova
Therapeutics, Inc., Newtown, PA, USA; Elmhurst Hospital Center, Elmhurst, NY, USA; Arnold and Marie Schwarz College of
Pharmacy, Long Island, NY, USA
Received March 27, 2013; Accepted May 23, 2013; Epub June 20, 2013; Published June 30, 2013
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/m2/24h) 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/m2/24hr CI x 3 days. (ClinicalTrials.gov identifier: NCT01538537). (ajcr0000194).
Keywords: Rigosertib, ON01910.Na, phase 1 study, polo-like kinase, phosphatidylinositol-3-kinase
Address correspondence to: Dr. Takao Ohnuma, Department of Medicine (Hematology and Oncology) and Tisch Cancer
Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Phone: 212-241-6664;
Fax: 212-860-7186; E-mail: takao.ohnuma@mssm.edu
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American Journal of Cancer Research
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