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

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.

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% - 19% BM blasts)

- CMML (10% - 20% BM blasts) and WBC < 13,000/μL

- RAEB-t (20% - 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