Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
RATIONALE: Drugs used in chemotherapy, such as clofarabine, daunorubicin hydrochloride, cytarabine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which chemotherapy regimen is more effective in treating acute myeloid leukemia.
PURPOSE: This randomized phase III trial is studying clofarabine to see how well it works compared with daunorubicin hydrochloride and cytarabine when followed by decitabine or observation in treating older patients with newly diagnosed acute myeloid leukemia.
Drug: daunorubicin hydrochloride
|Study Design:||Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age >/= 60 Years)|
- Overall survival [ Designated as safety issue: No ]
- 30-day mortality rate [ Designated as safety issue: No ]
- Induction complete response rates [ Designated as safety issue: No ]
- Effect of decitabine as maintenance therapy vs observation on disease-free survival [ Designated as safety issue: No ]
- Impact of consolidation therapy with non-myeloablative conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donor on overall survival in select patients [ Designated as safety issue: No ]
- Quality of life [ Designated as safety issue: No ]
|Study Start Date:||January 2011|
|Estimated Primary Completion Date:||February 2019 (Final data collection date for primary outcome measure)|
Active Comparator: Arm I (induction therapy)
Patients receive standard therapy comprising daunorubicin hydrochloride IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7.
Given IVDrug: daunorubicin hydrochloride
Experimental: Arm II (induction therapy)
Patients receive clofarabine IV over 1 hour on days 1-5.
Active Comparator: Arm I (consolidation therapy)
Patients receive cytarabine IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.
Experimental: Arm II (consolidation therapy)
Patients receive clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4-6 weeks for 2 courses.
No Intervention: Arm I (maintenance therapy)
Patients undergo observation.
Experimental: Arm II (maintenance therapy)
Patients receive decitabine IV over 1 hour on days 1-3. Treatment repeats every 4 weeks for 12 months the absence of unacceptable toxicity.
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- To compare the overall survival of older patients with newly diagnosed acute myeloid leukemia (AML) treated with clofarabine as induction therapy and consolidation therapy vs standard daunorubicin hydrochloride and cytarabine.
- To evaluate complete remission (CR) rates, duration of remission, and toxicity/treatment-related mortality of patients treated with these regimens.
- To evaluate the feasibility of consolidation therapy with reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation from HLA-identical donors, in terms of the incidence of successful engraftment, acute and chronic graft-vs-host disease, and transplant-related mortality in select patients age 60-69 years who achieve a response to induction therapy.
- To determine the impact of reduced-intensity conditioning and allogeneic stem cell transplantation on overall survival of select patients.
- To compare the duration of remission and disease-free survival of patients in CR following completion of consolidation therapy who are subsequently randomized to receive decitabine as maintenance therapy vs observation.
- To perform expression and methylation profiling in patients treated with decitabine as maintenance therapy and to correlate their integrated epigenetic signatures with response to decitabine.
- To examine the epigenetic profiles of remission marrow in patients randomized to receive decitabine as maintenance therapy vs observation to determine whether epigenetic signatures of apparently morphologically normal bone marrow is predictive of relapse or response to decitabine.
- To explore the possible association of response to clofarabine with nucleoside transporters hENT1, hCNT3, and ABC-transporter P-glycoprotein.
- To assess the intensity of expression of CXCR4 on diagnostic leukemia cells and to correlate this parameter with other established prognostic factors.
- To assess the entire spectrum of somatic mutations and affected pathways at diagnosis of AML and elucidate the association between gene mutation and outcome.
- To compare health-related quality of life (QOL) (physical, functional, leukemia-specific well-being) and fatigue in patients treated with clofarabine vs standard induction therapy.
- To measure the change in health-related QOL that occurs over time.
- To comprehensively assess patient function at the time of study enrollment.
- To determine if components of a comprehensive geriatric assessment or QOL scale predict ability to complete treatment for AML.
- To describe the impact of transplantation on QOL in patients with AML over 60 years of age.
OUTLINE: This is a multicenter study. Patients are stratified according to age (60-69 years vs ≥ 70 years), disease type (secondary vs de novo), therapy-related AML (yes vs no), and antecedent hematologic disorder (yes vs no).
Induction therapy: Patients are randomized to 1 of 2 treatment arms.
- Arm I (standard therapy): Patients receive daunorubicin hydrochloride IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 14.
- Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Patients with residual disease or those who do not achieve an aplastic bone marrow on day 12-14 (i.e., < 5% blasts and < 20% cellularity or markedly/moderately hypocellular) may receive a second course of induction therapy beginning no sooner than day 21 and no later than day 56.
Patients who achieve a complete remission (CR) or CR incomplete (CRi) after induction therapy proceed to consolidation therapy. Patients who are 60-69 years of age who achieve a "morphologic leukemia-free state" after induction therapy and who have an HLA-identical donor proceed to allogeneic stem cell transplantation. Patients undergoing second induction who do not achieve CR by day 56 of the start of re-induction are taken off protocol.
Consolidation therapy: Beginning within 60 days after documentation of CR or CRi, patients receive consolidation therapy in the same arm they were randomized to for induction therapy.
- Arm I (standard therapy): Patients receive cytarabine IV over 1 hour once or twice daily on days 1-6. Treatment repeats every 4-6 weeks for 2 courses.
- Arm II: Patients receive clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4-6 weeks for 2 courses.
Patients who remain in CR after completion of consolidation therapy proceed to maintenance therapy.
Maintenance therapy: Beginning within 60 days after completion of consolidation therapy, patients receive maintenance therapy and are randomized to 1 of 2 arms.
- Arm I: Patients undergo observation monthly for 12 months.
- Arm II: Patients receive decitabine IV over 1 hour on days 1-3. Treatment repeats every 4 weeks for 12 months the absence of unacceptable toxicity.
Allogeneic stem cell transplantation with reduced-intensity conditioning regimen: Patients begin reduced-intensity conditioning 30-90 days after the initiation of induction therapy.
- Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 2 hours every 6 hours on days -4 and -3 (for a total of 8 doses), and anti-thymocyte globulin IV over 4-6 hours on days -4 to -2.
- Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.
Patients complete quality-of-life questionnaires periodically, including health-related quality of life, physical and functional well-being, and fatigue questionnaires.
Peripheral blood, bone marrow, and karyotype samples are collected periodically for cytogenetic analysis and other correlative laboratory studies.
After completion of study treatment, patients are followed up periodically for ≥ 5 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01041703
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|Principal Investigator:||James M. Foran, MD, FRCPC||Mayo Clinic|