Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine

Inclusion Criteria:

   - Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria
   or French-American-British (FAB) classification.

   - MDS classified as follows, according to WHO criteria and FAB classification:

      - RAEB-1 (5% to 9% BM blasts)

      - RAEB-2 (10% to 19% BM blasts)

      - CMML (10% to 20% BM blasts) and white blood cells (WBC) < 13,000/μL

      - RAEB-t (20% to 30% BM blasts), meeting the following criteria: WBC < 25,000/μL at
      study entry; or, Stable White Blood Cell (WBC) at least 4 weeks prior to
      Screening and not requiring intervention for WBC control with hydroxyurea,
      chemotherapy, or leukopheresis.

   - At least one cytopenia (Absolute Neutrophil Count (ANC) < 1800/μL or Platelet (PLT)
   count < 100,000/μL or hemoglobin (Hgb) < 10 g/dL).

   - Progression (according to 2006 IWG criteria) at any time after initiation of
   subcutaneous or intravenous azacitidine or decitabine treatment per labeling during
   the past 2 years, defined as follows:

      - For patients with ˂ 5% BMBL, ≥ 50% increase in BMBL to ˃ 5% BMBL

      - For patients with 5-10% BMBL, ≥ 50% increase in BMBL to ˃ 10% BMBL

      - For patients with 10-20% BMBL, ≥ 50% increase in BMBL to ˃ 20% BMBL

      - For patients with 20-30% BMBL, ≥ 50% increase in BMBL to ˃ 30% BMBL

      - Any of the following: ≥ 50% decrease from maximum remission/response levels in
      granulocytes or PLT; Decrease in Hgb concentration by ≥ 2 g/dL; or, Transfusion
      dependence, defined as administration of at least 4 RBC units in the past 8 weeks
      before Screening (patients must have Hgb values ˂ 9 g/dL prior to transfusion to
      be considered), in the absence of another explanation.

   - Has failed to respond to, relapsed following, not eligible, or opted not to
   participate in bone marrow transplantation.

   - Off all other treatments for MDS for at least 4 weeks, except for azacitidine or
   decitabine. Filgrastim (G-CSF) and erythropoietin are allowed before and during the
   study as clinically indicated.

   - No medical need for induction chemotherapy.

   - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

   - Willing to adhere to the prohibitions and restrictions specified in this protocol.

   - Patient must signed an informed consent form.

Exclusion Criteria:

   - Previous participation in a clinical study of IV or oral rigosertib.

   - Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI]
   bleeding) unless stabilized for 1 week after RBC transfusion.

   - 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.

   - 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, or 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 (βHCG) pregnancy test at Screening.

   - Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle
   1 Day 1 visit.

   - Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic
   pressure ≥ 110 mmHg).

   - New onset seizures (within 3 months prior to Baseline) or poorly controlled seizures.

   - Any other concurrent investigational agent or chemotherapy, radiotherapy, or
   immunotherapy.

   - Prior treatment with low-dose cytarabine during the past 2 years.

   - Investigational therapy within 4 weeks of Baseline/Day 1 visit.

   - Psychiatric illness or social situation that would limit the patient's ability to
   tolerate and/or comply with study requirements.