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.