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Phase III MultiCenter Randomized Controlled Study to Assess Efficacy and Safety of ON 01910.Na 72-Hr Continuous IV Infusion in MDS Patients With Excess Blasts Relapsing After or Refractory to or Intolerant to Azacitidine or Decitabine


Phase 3
18 Years
N/A
Open (Enrolling)
Both
Myelodysplastic Syndromes, MDS, RAEB, Chronic Myelomonocytic Leukemia

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Trial Information

Phase III MultiCenter Randomized Controlled Study to Assess Efficacy and Safety of ON 01910.Na 72-Hr Continuous IV Infusion in MDS Patients With Excess Blasts Relapsing After or Refractory to or Intolerant to Azacitidine or Decitabine


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% - 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival

Outcome Description:

Overall survival (OS) is defined as the time from randomization to death from any cause. All patients will be followed until death or progression, even if they have discontinued treatment for whatever cause. Patients lost to follow-up will be censored at the time last known alive. The OS primary analysis will compare the active ON 01910.Na regimen to BSC once a total number of 223 deaths has been reached.

Outcome Time Frame:

Up to 18 months

Safety Issue:

No

Principal Investigator

Francois E. Wilhelm, MD, PhD

Investigator Role:

Study Director

Investigator Affiliation:

Onconova Therapeutics, Inc.

Authority:

United States: Food and Drug Administration

Study ID:

04-21

NCT ID:

NCT01241500

Start Date:

November 2010

Completion Date:

December 2013

Related Keywords:

  • Myelodysplastic Syndromes
  • MDS
  • RAEB
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic syndromes
  • MDS
  • Leukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute

Name

Location

Albert Einstein College of MedicineBronx, New York  10461
Mayo ClinicRochester, Minnesota  55905
Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
University of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan  48109-0752
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Medical College of WisconsinMilwaukee, Wisconsin  53226
Mary Bird Perkins Cancer CenterBaton Rouge, Louisiana  70809
Rush University Medical CenterChicago, Illinois  60612-3824
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Kansas Medical CenterKansas City, Kansas  66160-7353
Hackensack University Medical CenterHackensack, New Jersey  07601
Overlook HospitalSummit, New Jersey  07902-0220
Yale Cancer CenterNew Haven, Connecticut  06520-8028
Mount Sinai Medical CenterNew York, New York  10029
University of Texas Southwestern Medical Center at DallasDallas, Texas  75235-8897
Stanford Cancer CenterStanford, California  94305-5824
Martin Memorial Cancer CenterStuart, Florida  34995-9010
Integrated Community Oncology NetworkJacksonville Beach, Florida  32250
Innovative Medical Research of South Florida, Inc.Miami, Florida  33138
Cleveland ClinicCleveland, Ohio  44195
University of Chicago Medical CenterChicago, Illinois  60637
University of Texas M. D. Anderson Cancer CenterHouston, Texas  77030
Georgetown University HospitalWashington, District of Columbia  20007
University of California San Diego Moores Cancer CenterLa Jolla, California  
Providence Cancer CenterSouthfield, Michigan  48075
Virginia G. Piper Cancer CenterScottsdale, Arizona  85724
Cardinal Bernardin Cancer CenterMaywood, Illinois  
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
Emory University Winship Cancer InstituteAtlanta, Georgia  30322
University of Oklahoma Health Science CenterOklahoma City, Oklahoma  73104
Johns Hopkins HospitalBaltimore, Maryland  21287
Cancer Care Centers of South TexasSan Antonio, Texas  78229
University of Pennsylvania Health SystemPhiladelphia, Pennsylvania  19104
Weill Cornell Medical CollegeNew York, New York  10021
Cleveland Clinic FloridaWeston, Florida  33331
Woodlands Medical SpecialistsPensacola, Florida  32503
Mount Sinai Comprehensive Cancer CentersMiami Beach, Florida  33140
Edward H. Kaplan MD & AssociatesSkokie, Illinois  60076
North Shore - LIJ Health SystemLake Success, New York  11042
Bon Secours St. Francois Health SystemGreenville, South Carolina  29601
North Shore Medical CenterEvanston, Illinois  60201