Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts (ONTIME)
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.
Chronic Myelomonocytic Leukemia
Drug: ON 01910.Na
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Overall survival [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]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.
- 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.
|Study Start Date:||November 2010|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
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).
Drug: ON 01910.Na
The dose of ON 01910.Na will be 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. Infusion bags must be changed every 24 hours and a new infusion bag must be used for each of the subsequent 24 hours until completion of the total 72-hour infusion time.
Other Name: rigosertib
No Intervention: Best supportive care (BSC)
Patients will receive best supportive care (BSC).
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.
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|Study Director:||Francois E. Wilhelm, MD, PhD||Onconova Therapeutics, Inc.|