Efficacy and Safety of Oral Rigosertib in Transfusion-dependent, Low or Int-1 or Trisomy 8 Int-2 Myelodysplastic Syndrome

A Phase II, Multicenter, Single-arm Study to Assess the Efficacy and Safety of Oral Rigosertib in Transfusion-dependent Low or Intermediate-1 (Any Cytogenetics) or Trisomy 8 Intermediate-2 Myelodysplastic Syndrome Patients Based on IPSS Classification

The primary objectives of this study are to determine if rigosertib sodium, given orally in the form of soft gel capsules, is safe and is associated with a reduction in the number of blood transfusion units that are needed in patients with myelodysplastic syndrome (MDS) classified as Low or Intermediate-1 (Int-1) (any cytogenetics) or trisomy 8 Intermediate 2 (Int-2) in the International Prognostic Scoring System (IPSS) who are transfusion-dependent. Rigosertib will be taken on days 1 to 21 of a 21-day cycle.

This will be a Phase II open-label, multicenter (up to 5 centers), single-arm study. Sixty transfusion-dependent patients with MDS classified as Low or Int-1 risk (any cytogenetics) or trisomy 8 Int-2 by International Prognostic Scoring System (IPSS) will be enrolled to receive rigosertib BID for 21 consecutive days of a 21-day cycle.

Patients will be stratified on prior treatment with azacitidine and/or decitabine and/or lenalidomide and/or erythropoietin.

Patients will remain treated on study until 2006 Internation Working Group (IWG) progression criteria are met or until death from any cause.

All study participants will be allowed, as medically justified, access to RBC and platelet transfusions, and to filgrastim [G-CSF]. Erythropoiesis-stimulating agents (ESAs) will not be allowed during the initial 3 cycles. Rigosertib dosing adjustment policies are described in Protocol.

Inclusion Criteria:

• Diagnosis of MDS confirmed by bone marrow aspirate and/or biopsy within 6 weeks prior to first dose of study drug according to World Health Organization (WHO) or French-American-British (FAB) classification
• MDS classified as Low risk or Int-1 risk (any cytogenetics) or Trisomy 8 Int-2 risk, according to IPSS classification
• Transfusion dependency defined by at least 4 units of RBC administered within 8 weeks before baseline
• Off all other treatments for MDS (azacitidine, decitabine, lenalidomide, chemotherapy, immunosuppressive agents) for at least 4 weeks
• ECOG performance status of 0, 1 or 2

Exclusion Criteria:

• Ongoing clinically significant anemia due to factors such as iron, B12, or folate deficiencies, auto-immune or hereditary hemolysis, or gastrointestinal (GI) bleeding, unless stabilized for 1 week after RBC transfusion
• Serum ferritin <50 ng/mL
• Hypoplastic MDS (cellularity <10%)
• Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
• 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
• Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease
• ALT/AST ≥2.5 x upper limit of normal (ULN)
• Serum creatinine ≥2.0 mg/dL
• Ascites requiring active medical management including paracentesis
• Hyponatremia (defined as serum sodium value of <130 mEq/L)
• Female patients who are pregnant or lactating
• Patients who are unwilling to follow strict contraception requirements
• Female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (bHCG) pregnancy test at Screening
• Major surgery without full recovery or major surgery within 3 weeks of rigosertib treatment start
• Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥110 mmHg)
• New onset seizures (within 3 months prior to the first dose of rigosertib) or poorly controlled seizures
• Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
• Chronic use (>2 weeks) of corticosteroids (>10 mg/24 hr equivalent prednisone) within 4 weeks of starting rigosertib
• Investigational therapy within 4 weeks of starting rigosertib
• Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements