Safety of ON 01910.Na as a 3-day Infusion in Patients With Advanced Cancer
The primary objective of this study is to determine the largest dose of ON 01910.Na (rigosertib sodium) that can be given safely as a 3-day continuous infusion once every 2 weeks (2-week cycle) in patients with advanced cancer.
Drug: rigosertib sodium
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Escalation Study of ON 01910.Na by 3-day Continuous Infusion in Patients With Advanced Cancer|
- Number of dose limiting toxicities (DLTs) [ Time Frame: 28 days after start of first administration of ON 01910.Na ] [ Designated as safety issue: Yes ]
DLTs are defined as:
- Grade 3 non-hematological toxicity other than nausea, vomiting, diarrhea, fever, stomatitis, esophagitis/dysphagia.
- Grade 3 nausea and vomiting uncontrolled by antiemetics; Grade 3 diarrhea uncontrolled by antidiarrheal agents; Grade 3 drug-induced fever uncontrolled by antipyretics.
- Grade 3 stomatitis and/or esophagitis/dysphagia lasting >3 days.
- Grade 4 neutropenia or thrombocytopenia lasting >5 days.
- Episode of neutropenic fever, as defined in Protocol.
- Failure to recover neutrophils (>1,500 per microliter) or platelets (>75,000 per microliter) by day 28.
- Number of Adverse Events (AEs) [ Time Frame: 30 days after last infusion of study drug ] [ Designated as safety issue: Yes ]All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an intervention), regardless of causal relationship, are recorded in the case report form and source documentation.
- Severity of Adverse Events [ Time Frame: 30 days after last infusion of study drug ] [ Designated as safety issue: Yes ]Severity of AEs are determined according to the NCI Common Terminology Criteria for Adverse Events, Version 3.0.
- Relationship of Adverse Events (AEs) to Study Treatment [ Time Frame: 30 days after last infusion of study drug ] [ Designated as safety issue: Yes ]Relationship assessed as Not related, Unlikely, Possibly, Probably, or, Definitely according to Guidance in Appendix II of Protocol.
- Concentration of ON 01910.Na in plasma versus time [ Time Frame: Up to 72 hours after end of infusion of study drug in Cycles 1 and 4 ] [ Designated as safety issue: No ]Blood samples for subsequent preparation of plasma and determination of concentration of ON 01910.Na will be collected at pre-dose at 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 72 hr (10 min, prior to completion of infusion). After the completion of the infusion, samples will be collected at 10 min, 20 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 24 hr, 48 hr, and 72 hr.
- Change in size of target lesions recorded at baseline [ Time Frame: 30 days after last infusion of study drug ] [ Designated as safety issue: No ]The same method of assessment for each identified and recorded lesion will be used at baseline and each follow-up.
|Study Start Date:||August 2006|
|Study Completion Date:||January 2012|
|Primary Completion Date:||October 2010 (Final data collection date for primary outcome measure)|
Drug: rigosertib sodium
- ON 01910.Na Concentrate
- ON 01910.Na
This was an open-label, single-center, dose-escalating Phase I study to determine the Dose-Limiting Toxicities (DLTs) and Recommended Phase 2 Dose (RPTD) of ON 01910.Na (rigosertib sodium) administered as a 3 day continuous intravenous (CIV) infusion every 2 weeks (2-week cycles) to up to 28 patients with advanced cancer (12 to 16 in the dose escalation phase and up to 12 additional patients in the dose confirmation phase). The dosing of rigosertib was based on body surface area (BSA), with a starting dose of 50 mg/m2/24 hour for 3 consecutive days.
In the absence of toxicity after at least a 3-week observation period, rigosertib doses were escalated following a Fibonacci scheme with an initial accelerated dose-escalation phase in which 1-patient cohorts received rigosertib for 3 weeks until drug-related Grade 2 toxicity (according to Common Toxicity Criteria for Adverse Events [CTCAE] v.3), excluding alopecia, occurred, at which time 2 additional patients were added to subsequent cohorts. If none of the 3 patients in the cohort experienced DLTs, the dose was escalated by a half-Fibonacci step. If a DLT was seen in the first patient of a cohort, dosing went back a half-step. The next dose level occurred if no DLT was reported in the 3 patients or if no more than 1 DLT occurred in an expanded cohort of 6 patients. If a DLT was seen in 1 of the 3 patients, 3 additional patients were enrolled in the cohort. If DLTs were seen in 2 of 6 patients in a cohort, dose escalation was stopped.
Once the maximum administered dose (MAD) was attained and the RPTD was determined, the dose escalation phase was considered complete. Up to 12 additional patients with histologically confirmed malignant tumors were tested at the RPTD dose to confirm its appropriateness.
Secondary objectives were to determine the qualitative and quantitative toxicity and reversibility of toxicity of rigosertib administered in this fashion; to investigate the clinical pharmacology of rigosertib when administered in this fashion, including plasma pharmacokinetics at each dose level; to confirm the appropriateness of the RPTD; to document any observed antitumor activity of rigosertib; and, to evaluate the biological effect of rigosertib in biomarkers in serum and/or peripheral blood mononuclear cells.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01538537
|United States, New York|
|Mount Sinai School of Medicine|
|New York, New York, United States, 10029|
|Principal Investigator:||Takao Ohnuma, MD||Mount Sinai School of Medicine|