Safety of ON 01910.Na as a 3-day Infusion in Patients With Advanced Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I Dose Escalation Study of ON 01910.Na by 3-day Continuous Infusion in Patients With Advanced Cancer

Conditions
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Advanced Cancer, Solid Tumors, Cancer, Neoplasms

Intervention / Treatment
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* Drug: rigosertib sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. At least 4 weeks since the last dose of other potentially myelosuppressive treatment (at least 6 weeks since last dose of nitrosoureas or mitomycin C) and recovery from manifestations of reversible drug toxicity (except alopecia, stable residual neuropathy, and residual hand and foot syndrome). Among patients with prior doxorubicin chemotherapy, only those with no more than 450 mg/m2 of the drug will be entered. It must be at least 4 weeks since prior chemotherapy or radiation therapy, 6 weeks if the last regimen included nitrosoureas or mitomycin C. Patients with prior radiotherapy are eligible provided that a minimum of 4 weeks have passed and that the maximal area of hematopoietic active bone marrow treated was less than 25%. ECOG performance status < 2. Hgb > 10 gm/dl WBC > 4,000 per microliter Absolute neutrophil count > 1,500 per microliter Platelets >100,000 per microliter Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) values within limits defined by Protocol Creatinine within normal institutional limits or creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Women of child-bearing potential and men must agree to use adequate contraception. Ability to understand and the willingness to sign a written informed consent document. Inclusion Criteria - Dose Confirmation Phase Same inclusion criteria as in the Dose Escalation phase described above, except Patients must have an ECOG performance of 0 or 1. Exclusion Criteria: Patients who have had recent major surgery (within the past 14 days), chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (except alopecia, stable residual neuropathy, and residual hand and foot syndrome) due to previously administered agents. Patients may not be receiving any other investigational agents or concurrent chemotherapy, radiotherapy, hormonal treatments, or immunotherapy while on study. Patients with known or clinical evidence of central nervous system metastasis, except brain metastases that have been previously removed or irradiated and currently have no clinical impact. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ON 01910.Na. The patient should have no major 3rd space fluid, ascites requiring active medical management including paracentesis, peripheral bilateral edema, or hyponatremia (serum sodium value less than 134 Meq/L). Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, bleeding, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and nursing women are excluded from this study. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: rigosertib sodium|ON 01910.Na will be supplied as a sterile, concentrated solution (75 mg/ml) in labeled, sealed glass vials. ON 01910.Na concentrated solution (75 mg/ml) must be diluted before intravenous administration. The starting dose will be 50 mg/m2 over 24 hour infusion daily for 3 days. A fresh infusion must be prepared for each day of the 3-day continuous infusion. This 3-day continuous treatment followed by 11 days without administration of study drug will constitute 1 Cycle. Cycles can be repeated every 2 weeks. The dosing of ON 01910.Na will be based on body surface area (BSA). In the absence of toxicity that would cause accelerated dose escalation to cease, drug doses are planned to escalate every 3 weeks.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) | 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. | 30 days after last infusion of study drug | 
| Severity of Adverse Events | Severity of AEs are determined according to the NCI Common Terminology Criteria for Adverse Events, Version 3.0. | 30 days after last infusion of study drug | 
| Relationship of Adverse Events (AEs) to Study Treatment | Relationship assessed as Not related, Unlikely, Possibly, Probably, or, Definitely according to Guidance in Appendix II of Protocol. | 30 days after last infusion of study drug | 
| Concentration of ON 01910.Na in plasma versus time | 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. | Up to 72 hours after end of infusion of study drug in Cycles 1 and 4 | 
| Change in size of target lesions recorded at baseline | The same method of assessment for each identified and recorded lesion will be used at baseline and each follow-up. | 30 days after last infusion of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ON 01910.Na, rigosertib Sodium, rigosertib