Effect of 2-h Infusion of ON 01910.Na in Ovarian Cancer Patients

This is a Phase II single arm study of ON 01910.Na to be administered as a 2-hour infusion biweekly to patients with progressive ovarian cancer resistant to platinum-based therapy.

The primary objective is to evaluate progression-free survival (PFS). The secondary objectives are to document other measures of outcome [objective response rate (ORR), duration of response, duration of stable disease, and overall survival (OS)], and tolerability of study drug.

Thirty-seven (37) patients with progressive ovarian cancer resistant to platinum-based therapy will be enrolled in a single arm study and treated with ON 01910.Na administered as a 2-hour infusion on Days 1, 4, 8, 11, 15 and 18 of a 28-day cycle. Patients will be treated until disease progression or withdrawal for other causes (unacceptable toxicity, patient or investigator decision) with ON 01910.Na. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0). Progression-free survival, objective response, duration of response, and duration of stable disease will be assessed using RECIST (Response Evaluation Criteria in Solid Tumor) guidelines, as well as overall survival. Grades 3 and 4 hematologic toxicities, grade >2 non-hematologic toxicities will be monitored. A futility analysis will be performed after 17 evaluable patients are enrolled and evaluated for overall objective response. If 3 or fewer objective response (CR and PR) are observed, the study will be closed to further accrual and deemed futile. An extension study for an additional 25 weeks with complete monitoring will be considered for patients who have not progressed by week 25.

The ON 01910.Na dose to be used in this study (2-hour infusions of 2400 or 3200 mg twice weekly for 3 weeks of a 4-week cycle) was selected based on the maximum tolerated doses and activities documented in phase 1 protocols.

Inclusion criteria

• Women with ovarian cancer at least 18 years old with measurable disease who have shown recurrent disease within 6 months of the last dose of cisplatin- or carboplatin-based chemotherapy. Measurable disease will be defined as lesions that can be accurately measured in at least one dimension with longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2.
• No more than 3 prior chemotherapy regimens.
• Disease-free period of more than 5 years from prior malignancies other than ovarian (except curatively treated basal cell carcinoma, squamous cell carcinoma of the skin,or carcinoma in situ of the cervix).
• All female patients of childbearing potential must use at least one form of contraception as approved by the Investigator prior to study entry and for up to 30 days beyond the last administration of study drug.
• Women of childbearing potential must have a negative serum βHCG pregnancy test at screening.
• Willing to adhere to the prohibitions and restrictions specified in this protocol.
• Patient (or her legally authorized representative) must have signed an informed consent document.

Exclusion criteria

• Evidence of complete or partial bowel obstruction.
• Need for IV hydration or Total Parenteral Nutrition.
• Inability to comply with study and/or follow-up procedures.
• Life expectancy of less than 12 weeks.
• Prior radiotherapy to greater than one third of hematopoietic sites.
• Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.
• Active infection not adequately responding to appropriate therapy.
• Hyponatremia (defined as serum sodium value of <134 mEq/L).
• Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease, AST/ALT or alkaline phosphatase ≥ 2 X ULN.
• Serum creatinine ≥ 2.0 mg/dL.
• ANC < 1500/mm3, platelets < 100,000/mm3; hemoglobin less than 9 g/dL.
• Ascites requiring active medical management including paracentesis for more than twice a month.
• Women patients who are pregnant or lactating or have a positive serum βHCG pregnancy test at screening.
• Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start.
• Uncontrolled hypertension (defined as a systolic pressure ≥ 160 and/or a diastolic pressure ≥ 110).
• New onset seizures (within 3 months prior to the first dose of ON 01910.Na) or poorly controlled seizures.
• Brain metastases including any of the following:

• Evidence of cerebral edema by CT scan or MRI.
• Evidence of disease progression on prior imaging studies.
• Requirement for steroids.
• Clinical symptoms of brain metastases.
• Any concurrent and/or within 4 weeks of the first dose of study drug investigational agent or chemotherapy, radiotherapy or immunotherapy.
• Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.