A Phase III, Multi-Center, Randomized, Controlled Study to Assess the Efficacy and Safety of ON 01910.Na Administered as a 72-Hour Continuous Intravenous Infusion Every Other Week in Myelodysplastic Syndrome Patients with Excess Blasts Relapsing After, or Refractory to, or Intolerant to Azacitidine or Decitabine

Summary

This will be a Phase III open-label, randomized, controlled, multicenter study (up to 80 centers).
Approximately 270 patients with MDS classified as RAEB-1, RAEB-2, RAEB-t, or CMML who
failed, were intolerant, or progressed after treatment with 5-azacitidine or decitabine
administered during the past 2 years, will be randomized in a 2:1 ratio to the following
2 treatment regimens:

* BSC + ON 01910.Na 1800 mg/24 hr administered as a 72-hr 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 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 IWG progression criteria are met (i.e., 50%
increase of BM blasts or worsening of cytopenias; see Appendix 1) or until death from any
cause, whichever comes first.

Patients who progress to AML while on study should be offered either standard treatment for AML or enrollment in an appropriate investigational study if they are eligible. For all randomized patients who are removed from the study, anti-leukemic treatments with their start and end dates, as well as patient survival time after study removal will be documented at least monthly.


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, for at least 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.

Participant Eligibility

a. ≥18 years of age;
b. Diagnosis of MDS confirmed within 6 weeks prior to study entry according to WHO
criteria (Appendix 2) or FAB classification ;
c. 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 WBC < 13,000/μL
• RAEB-t (20% to 30% BM blasts), meeting the following criteria:
o WBC < 25 x 109/L at study entry
o Stable WBC at least 4 weeks prior to study entry and not requiring intervention
for WBC control with hydroxyurea, chemotherapy, or leukophoresis;
d. At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin
[Hgb] <10 g/dL);
e. Progression (according to 2006 IWG criteria) at any time after initiation
of azacitidine or decitabine treatment during the 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 either or four 4-week cycles or four 6-week cycles of decitabine administered during the 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 either four 4-week or 4 6-week cycles of decitabine administered during the past 2 years;
or
Intolerance to azacitidine or decitabine defined by drug-related ≥Grade 3 liver or renal
toxicity leading to treatment discontinuation during the past 2 years;
f. Has failed to respond to, relapsed following, not eligible, or opted not to participate in
bone marrow transplantation;
g. Off all other treatments for MDS for at least 4 weeks. Filgrastim (G-CSF) and
erythropoietin are allowed before and during the study as clinically indicated;
h. No medical need for induction chemotherapy;
i. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2;
j. Willing to adhere to the prohibitions and restrictions specified in this protocol;
k. Patient (or patient’s legally authorized representative) must signed an informed consent
document indicating that the patient understands the purpose of and procedures required
for the study and is willing to participate in the study.