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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-Dia

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Conditions:		Leukemia
Purpose:		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.
Study Summary:		OBJECTIVES: Primary - 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. Secondary - 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. Tertiary - 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.
Criteria:		DISEASE CHARACTERISTICS: - Newly diagnosed acute myeloid leukemia (AML) - Considered candidates for intensive chemotherapy based on examination of peripheral blood or bone marrow aspirate specimens or touch preparations of the bone marrow biopsy obtained within the past 2 weeks - Bone marrow aspirate is required for enrollment, however, if there is discordance between percentage of myeloblasts on the differential of the peripheral blood or aspirate, the peripheral blood criteria are sufficient for diagnosis - Patients with secondary AML (defined as AML that has developed in a person with a history of antecedent blood count abnormalities, myelodysplastic syndromes [MDS], or a myeloproliferative disorder [excluding chronic myeloid leukemia], or a history of prior chemotherapy or radiotherapy for a disease other than AML) are eligible - Patients with acute promyelocytic leukemia (APL) confirmed either by the presence of t(15;17)(q22;q21) or PML/RAR transcripts will be excluded - No blastic transformation of chronic myelogenous leukemia - No documented CNS involvement - Concurrent registration on ECOG-E3903 (Ancillary Laboratory Protocol for the Collecting of Diagnostic Samples from Patients With Leukemia or Related Hematologic Disorders Being Considered for ECOG Treatment Clinical Trials) required (except for patients participating at CTSU institutions; these patients are exempt from this requirement) - Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts (>10^9/L) from peripheral blood - Diagnostic bone marrow and peripheral blood specimens must be submitted for immunophenotyping and selected molecular testing - Peripheral blood stem cell donor meeting 1 of the following criteria: - HLA-identical sibling (6/6) - Low-resolution HLA typing (A,B,DR) allowed - Matched unrelated donor (10/10) - High-resolution class I and II typing (A,B,C,DRB1 and DQ) should be matched at all 10 loci PATIENT CHARACTERISTICS: - ECOG performance status (PS) 0-3 (ECOG PS 0-2 if ≥ 70 years of age) - AST and ALT ≤ grade 1 - Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ grade 1) - Serum creatinine ≤ 1 mg/dL (≤ grade 1) - Cardiac ejection fraction ≥ 45% by MUGA or 2-D ECHO - Fertile patients must use effective contraception - No concurrent active malignancy requiring treatment (other than MDS) - No active, uncontrolled infection - No known HIV infection PRIOR CONCURRENT THERAPY: - See Disease Characteristics - No prior chemotherapy for AML (except for hydroxyurea for increased blast count or leukapheresis for leukocytes) - No prior treatment with azacitidine, decitabine, or low-dose cytarabine
NCT ID:		NCT01041703
Primary Contact:		Principal Investigator James M. Foran, MD, FRCPC Mayo Clinic
Backup Contact:		N/A
Location Contact:		Newark, Delaware 19713 United States Clinical Trial Office - CCOP - Christiana Care Health Services Phone: 302-623-4450 Site Status: Recruiting

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