Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Patients After Failure of an HMA

Inclusion Criteria: * MDS classified as follows: * RAEB-1 per World Health Organization (WHO) MDS criteria (5% to \<10% BM blasts) * RAEB-2 per WHO MDS criteria (10% to \<20% BM blasts) * RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts) * At least one cytopenia (ANC \< 1800/µL or platelet count \< 100,000/µL or hemoglobin \[Hgb\] \< 10 g/dL) * Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment or Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria) * Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months * Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization * Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation * Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 * Willing to adhere to protocol prohibitions and restrictions * Patient must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate. Should patient be incapable of giving consent, the patient's legally authorized representative (as defined by local regulation) must give consent. However, should patient, in any manner, choose not to participate this takes precedence and will be respected. * Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated Exclusion Criteria: * Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation * Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3 days of an anthracycline, or high-dose cytarabine * Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found * Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris * Active infection not adequately responding to appropriate therapy * Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease * Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN) * Serum creatinine ≥2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) \< 40 mL/min. * Known active HIV, hepatitis B or hepatitis C, where active is defined as follows: * HIV or hepatitis C - presence of viral load * Hepatitis B - antigen positive * Uncorrected hyponatremia (defined as serum sodium value of \<130 mEq/L) * Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period. Examples of acceptable contraception methods include: * estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal), * gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable), * intra-uterine devices (IUDs), * intra-uterine hormone-releasing systems (IUSs), * bilateral tubal occlusion * vasectomized partner * sexual abstinence in accordance with an individual's lifestyle * Female patients of child-bearing potential (pre-menopausal and not surgically sterilized) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin pregnancy test at Screening * Major surgery without full recovery or within 3 weeks before planned randomization; * Uncontrolled hypertension * New onset seizures (within 3 months before planned randomization) or poorly controlled seizures * Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions) * Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization * Investigational therapy within 4 weeks of planned randomization * Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements. * Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage of \>30%).