Phase I Dose Escalation Study of ON 01910.Na by 3-day Continuous Infusion in Patients With Advanced Cancer
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of dose limiting toxicities (DLTs)
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.
28 days after start of first administration of ON 01910.Na
Takao Ohnuma, MD
Mount Sinai School of Medicine
United States: Food and Drug Administration
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