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

Trial Purpose and Description

Trial Purpose

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.

Participation Guidelines

Eligibility Criteria

Inclusion criteria:

Male and female patientswho meet all of the following criteria are eligiblefor enrollment in the trial:

a.   18 years of age;

b.   Diagnosis ofMDS confirmed within 6 weeks prior to study entry according to WHO

criteria or FAB classification

c.   MDS classified as follows, according to WHO criteriaand FAB classification:

•    RAEB-1 (5% to 9% BM blasts)

•    RAEB-2 (10% to 20% BM blasts)

•    CMML (I 0% to 20% BM blasts) and WBC < 13.000/JlL

•    RAEB-t (21% to 30% BM blasts), meeting the followingcriteria:

o    WBC < 25 x 1 09/L at study entry

o    Stable WBC at least 4 weeks prior to study entry and not requiringintervention for WBC controlwith hydroxyurea, chemotherapy, or leukophoresis;

d.   At least one cytopenia(ANC < 1800/J.LLor platelet count< I00,000/ LL or hemoglobin

[Hgb] <10 g/dL);

e.   Progression (according to 2006 IWG criteria) at any time after initiation of azacitidine or decitabinetreatment during the past 2 years;

or

Failure to achieve completeor partial responseor hematological improvement (according to 2006 IWG) after at least six 4-week cycles of azacitidine or four 6-week cycles of decitabine administered during the past 2 years;

or

Relapse after initial complete or partialresponse or hematological improvement (according to 2006 IWG criteria) observed after at leastsix 4-week cyclesof azacitidine or four 6-week cycles of decitabineadministered during the past 2 years;

or

Intolerance to azacitidine or decitabine definedby drug-related Grade 3liver or renal toxicity leading to treatmentdiscontinuation 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 treatmentsfor MDS for at least 4 weeks.  Filgrastim (G-CSF)and

erythropoietin are allowed before and during the study as clinicallyindicated;

h.   No medical need for induction chemotherapy;

1.   Eastern Cooperative Oncology Group (ECOG) performance status of O, 1 or 2

j.     Willing to adhere to the prohibitions and restrictions specifiedin this protocol;

k.   Patient (or patient's legallyauthorized representative) must signed an informed consent document indicating that the patientunderstands the purposeof and procedures required for the study and is willing to participate in the study.

Exclusion criteria:

Patients with any of the following will not be enrolled in the study:

a.   Anemia due to factors other than MDS (including hemolysisor gastrointestinal [GI]

bleeding) unless stabilized for I weekafter RBC transfusion;

b.  Any active malignancy within the past year, exceptbasal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast;

c.   Uncontrolled intercurrent illnessincluding, but not limited to, symptomatic congestive heart failure, unstable anginapectoris, or cardiacarrhythmia;

d.  Active infection not adequately responding to appropriate therapy;

e.   Total bilirubin 2:1.5 mg/dL not related to hemolysisor Gilbert's disease;

f.    Alanine transaminase (ALT)/aspartate transaminase (AST)2:2.5 x upper limit of normal

(ULN)

g.   Serum creatinine 2:2.0 mg/dL;

h.  Ascites requiring active medicalmanagement including paracentesis, or hyponatremia

(defined as serum sodium value of <130 mEq/L);

1.   Female patients who are pregnant or lactating;

j.     Patientswho are 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;

k.   Female patients with reproductive potential who do not have a negative urine beta-human

chorionic gonadotropin  (J3HCG) pregnancy test at screening;

I.    Major surgery withoutfull recovery or major surgerywithin 3 weeks of ON 0191O.Na treatment start;

m. Uncontrolled hypertension (defined as a systolicpressure 2:160 mmHg and/or a diastolic

pressure 2: II 0 mmHg);

n.  New onset seizures(within 3 monthsprior to the first dose of ON 0191O.Na) or poorly controlled seizures;

o.   Any other concurrent investigational agent or chemotherapy, radiotherapy, or

immunotherapy;

p.   Prior treatment with low-dosecytarabine during the past 2 years;

q.   Investigational therapywithin 4 weeks of startingON 0 I 9 I O.Na;

Dates:

March 2012

Last Updated:

Study HIC#:

1108008919

Clinicaltrials.gov ID: Yale7332836