Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts (ONTIME)

• Overall response (complete and partial remission) according to 2006 IWG criteria [ Time Frame: Changes measured at Week 4 from Baseline and every 8 Weeks thereafter ] [ Designated as safety issue: No ]
  Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts, hemoglobin, peripheral neutrophils, platelets and blasts.
• Complete bone marrow response according to 2006 IWG criteria [ Time Frame: Changes measured at Week 4 from Baseline and every 8 Weeks thereafter ] [ Designated as safety issue: No ]
  Compare the BSC + ON 01910.Na group to the BSC group with respect to changes in bone marrow myeloblasts.
• Hematological improvements according to 2006 IWG criteria [ Time Frame: Weekly ] [ Designated as safety issue: No ]
  Compare the BSC + ON 01910.Na group to the BSC group with respect to in absolute neutrophil count (ANC), platelet count, and erythroid responses.
• Scores of Quality of Life Questionnaire [ Time Frame: Measured at Baseline and every 4 Weeks ] [ Designated as safety issue: No ]
  Compare the BSC + ON 01910.Na group to the BSC group with respect to scores of Quality-of-life (QOL)(using the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 version 3.
• Adverse events [ Time Frame: Weekly ] [ Designated as safety issue: Yes ]
  Record adverse events according to CTCAE v4.
• Change in Aneuploidy [ Time Frame: Baseline and, only if abnormal at Baseline, Week 4 and every 8 Weeks thereafter ] [ Designated as safety issue: No ]
  Improvements of cytogenetics as evaluated by the change in aneuploidy in bone marrow according to 2006 IWG criteria.
• Transition time to AML [ Time Frame: Measured at Week 4 from date of randomization and every 8 Weeks thereafter ] [ Designated as safety issue: No ]
  Transition time to AML: Defined for RAEB-1 and RAEB-2 MDS and chronic myelomonocytic leukemia (CMML) patients (with BM blasts from 10% to 20% for CMML) by an increase of at least 50% BM blasts and more than 20% BM blasts; Defined for RAEB-t by an increase of at least 50% BM blasts.
• Incidence of infections and bleeding episodes. [ Time Frame: Every 4 Weeks ] [ Designated as safety issue: Yes ]
  Incidence of infections (treated with intravenous antimicrobials) and bleeding episodes.

The primary objective of this study is to compare overall survival (OS) in patients receiving ON 01910.Na + best supportive care (BSC) to OS of patients receiving BSC in a population of patients with myelodysplastic syndrome (MDS) with excess blasts (5% to 30% bone marrow blasts) who have failed azacitidine or decitabine treatment. This patient population has no available therapy and a short life expectancy (approximately 4 months). The high level of bone marrow activity of ON 01910.Na documented in Phase 1 and 2 studies has the potential to delay substantially the transition of MDS to Acute Myeloid Leukemia(AML), a very significant and severe complication, which shortens survival of these MDS patients.

This is a Phase III open-label, randomized, controlled, multicenter study (up to 50 centers). Approximately 270 patients with MDS classified as RAEB-1 and RAEB-2 using the WHO classification and as RAEB-t and chronic myelomonocytic leukemia (CMML) using the FAB classification who failed, became intolerant to, or progressed after treatment with 5-azacitidine or decitabine administered during the past 2 years, will be randomized in a 2:1 ratio into the following 2 treatment regimens:

• Best Supportive Care (BSC) + ON 01910.Na 1800 mg/24 hr administered as a 72-hr continuous intravenous (CIV) infusion on Days 1, 2, and 3 of a 2-week cycle (N = approximately 180 patients)
• BSC (N = approximately 90 patients).

Patients will be stratified at entry by bone marrow (BM) blasts (5% to 19% vs. 20% to 30%). After completing the first eight 2-week cycles (i.e., after 16 weeks of treatment), the frequency of further 72-hr CIV infusions will be decreased to an administration on Days 1, 2, and 3 of a 4-week cycle.

Patients will remain treated on study until 2006 International Working Group (IWG) progression criteria are met (i.e., 50% increase of BM blasts or worsening of cytopenias) or until death from any cause, whichever comes first.

Patients who progress to Acute Myeloid Leukemia (AML) while on study should be offered either standard treatment for AML or enrollment in an appropriate investigational study if they are eligible. These treatments with their start and end dates should be documented and patient survival time will be documented for all randomized patients.

Cross-over of BSC patients to ON 01910.Na after progression will not be allowed. However, patients in the BSC-only group will be allowed, as medically justified, access to low-dose cytarabine 20 mg/m2 subcutaneously (SC) once daily for the first consecutive 14 days of each 28-day cycle, up to 4 cycles, until progression or unacceptable toxicity develops. Low-dose cytarabine will be delayed as needed until recovery of blood counts. All study participants will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (erythropoietin, Filgrastim [G-CSF]). Hydroxyurea will be allowed to manage blastic crisis with hyperleukocytosis when patients transition to leukemia.

• Myelodysplastic Syndromes
• MDS
• RAEB
• Chronic Myelomonocytic Leukemia

• Experimental: ON 01910.Na + best supportive care (BSC)
  Patients will receive ON 01910.Na 1800 mg/24 hr as a continuous intravenous infusion for 72 hours every other week for the first 16 weeks then every 4 weeks afterwards and best supportive care (BSC).
  Intervention: Drug: ON 01910.Na
• No Intervention: Best supportive care (BSC)
  Patients will receive best supportive care (BSC).

Inclusion Criteria:

• MDS diagnosis confirmed within 6 weeks prior to entry according to WHO or FAB classification

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

  • RAEB-1 (5% - 9% BM blasts)
  • RAEB-2 (10% - 20% BM blasts)
  • CMML (10% - 20% BM blasts) and WBC < 13,000/μL
  • RAEB-t (21% - 30% BM blasts), with following criteria:
  • o WBC < 25 x 10E9/L at entry
  • o Stable WBC at least 4 weeks prior to entry and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.
• At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin <10 g/dL)
• Progression according to 2006 International Working Group (IWG) criteria any time after start of azacitidine or decitabine during past 2 years; or failure to achieve complete or partial response or hematological improvement (according to 2006 IWG) after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria) observed after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine during past 2 years; or, intolerance to azacitidine or decitabine defined by drug-related ≥Grade 3 liver or renal toxicity leading to discontinuation during the past 2 years.
• Did not respond to, relapsed after, not eligible for, or opted not to do bone marrow transplantation
• Off other MDS treatments for at least 4 weeks; Filgrastim (G-CSF) and erythropoietin allowed before and during the study as clinically indicated.
• No need for induction chemotherapy
• ECOG status 0, 1 or 2
• Willing to adhere to protocol prohibitions and restrictions
• Patient (or a legally authorized representative) must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate

Exclusion Criteria:

• Anemia due to factors other than MDS (including hemolysis or gastrointestinal 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, 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.
• Alanine transaminase (ALT)/aspartate transaminase (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)
• Pregnant or lactating females
• Patients unwilling to follow strict contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine device, double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) before entry and throughout the study
• Females with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin pregnancy test at screening
• Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start
• Uncontrolled hypertension (defined as systolic pressure ≥160 mmHg and/or diastolic pressure ≥110 mmHg)
• New onset seizures (within 3 months prior to first dose of ON 01910.Na) or poorly controlled seizures
• Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
• Prior treatment with low-dose cytarabine during past 2 years Investigational therapy within 4 weeks of starting ON 01910.Na
• Psychiatric illness or social situation that limits the patient's ability to tolerate and/or comply with study requirements