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

Phase 1
18 Years
Not Enrolling
Advanced Cancer, Solid Tumors, Cancer, Neoplasms

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Trial Information

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.

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of dose limiting toxicities (DLTs)

Outcome Description:

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.

Outcome Time Frame:

28 days after start of first administration of ON 01910.Na

Safety Issue:


Principal Investigator

Takao Ohnuma, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mount Sinai School of Medicine


United States: Food and Drug Administration

Study ID:

Onconova 04-02



Start Date:

August 2006

Completion Date:

January 2012

Related Keywords:

  • Advanced Cancer
  • Solid Tumors
  • Cancer
  • Neoplasms
  • ON 01910.Na
  • rigosertib Sodium
  • rigosertib
  • Neoplasms



Mount Sinai School of Medicine New York, New York  10029