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

Phase IIIB, Open-label, Multi-Center Study of the Efficacy and Safety of Rigosertib Administered as 72-hour Continuous Intravenous Infusions in Patients With Myelodysplastic Syndrome With Excess Blasts Progressing On or After Azacitidine or Decitabine

This study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (MDS) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with 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.