A Phase III Randomized Trial for Patients with de novo AML using Bortezomib (IND# 58443, NSC# 681239) and Sorafenib (BAY 43-9006, IND#69896, NSC# 724772) for Patients with High Allelic Ratio FLT3/ITD.
This randomized phase II/III trial is studying how well giving bortezomib and sorafenib tosylate together works in treating patients with newly diagnosed acute myeloid leukemia with or without mutations.
Ages Eligible for Study: up to 29 Years Genders Eligible for Study: Both Accepts Healthy Volunteers: No Criteria DISEASE CHARACTERISTICS: Patients must be newly diagnosed with de novo acute myelogenous leukemia and must meet 1 of the following criteria: Patients with previously untreated primary AML who meet the customary criteria for AML with â?¥ 20% bone marrow blasts as set out in the 2008 WHO Myeloid Neoplasm Classification are eligible Patients with cytopenias and bone marrow blasts who do not meet the customary criteria for the diagnosis of AML (patients with less than 20% blasts) are eligible if they have a karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities), or if they have the unequivocal presence of megakaryoblasts, as set out in the 2008 WHO Myeloid Neoplasm Classification Patients with biopsy-proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) are eligible Patients must meet one of the following criteria: Low-risk disease as defined by any of the following: Presence of [inv(16)/t(16;16) or t(8;21)] or presence of NPM or CEBPÎ± mutation, regardless of minimum-residual disease (MRD) status at end of Induction I Standard-risk cytogenetics (neither favorable or unfavorable) with negative MRD ( less than 0.1%) at end of Induction I Patients who do not have MRD data and have non-informative molecular studies (NPM, CEBPÎ±, and cytogenetics) will be classified as having low-risk disease High-risk disease as defined by any of the following: FLT3/ITD+ with high allelic ratio (HR FLT3/ITD+) Unfavorable cytogenetics (monosomy 7, monosomy 5, and del5q) Standard-risk cytogenetics with positive MRD (â?¥ 0.1%) at end of Induction I Patients with juvenile myelomonocytic leukemia (JMML) are not eligible Patients with Philadelphia chromosome positive AML, biphenotypic or bilineal acute leukemia, or acute promyelocytic leukemia are not eligible High-risk patients may have a donor (bone marrow or cord blood) meeting the following criteria available: Matched family donor (MFD)* HLA, A, B, C, DRB1, identical, or 1 antigen or allele mismatched HLA typing must be performed using molecular high-resolution technique All available first-degree family members (parents and siblings) must be HLA typed Use of syngeneic donors will NOT be permitted in this study NOTE: *For MFD SCT, the use of peripheral blood stem cells (PBSC) is not permitted on this study. Alternative donor HLA, A, B, C, DRB1 identical or 1 antigen- or allele-mismatched unrelated donor HLA A, B, DRB1 4 of 6 antigen-matched unrelated donor cord blood unit with an adequate cell dose (nucleated cell dose greater than 3.7x10^7/kg or CD34+ cell dose greater than 2 x 10^5/kg) Mismatched family member donor with at least one haplotype match, or 5 of 6 antigen phenotypic match PATIENT CHARACTERISTICS: Patients with any performance status are eligible Patients with constitutional trisomy 21 are not eligible Patients with any of the following are not eligible: Fanconi anemia Shwachman syndrome Any other known bone marrow failure syndrome Another concurrent malignancy Not pregnant or nursing Negative pregnancy test Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation PRIOR CONCURRENT THERAPY: Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and intrathecal (IT) cytarabine given at diagnosis is allowed Hydroxyurea and ATRA must be discontinued prior to initiation of protocol therapy No concurrent peripheral blood stem cell transplantation Patients who have previously received any other chemotherapy, radiation therapy, or any other antileukemic therapy are not eligible for this protocol Concomitant administration of strong CYP3A4 inducers and inhibitors (including clinically relevant moderate inhibitors) is prohibited on both sorafenib cohorts
This is a multicenter, dose-escalation study of sorafenib tosylate and an open-label randomized study. Patients are stratified according to disease risk (low vs high). Patients are randomized to 1 of 2 treatment arms or offered treatment on a third arm. Induction I: Arm A: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy comprising cytarabine IV over 15-30 minutes on days 1-10; daunorubicin IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5. Arm B: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV on days 1, 4, and 8. Arm C (high-risk [HR] FLT3/ITD+ disease): Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate orally (PO) on days 11-28. Induction II: Patients without HR FLT3/ITD+ disease begin Induction II administration on day 29. Arm A (low-risk [LR] patients): Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A. Arm A (HR patients): Patients receive cytarabine IT on day 1 and MA chemotherapy comprising high-dose cytarabine IV over 1-3 hours on days 1-4, and mitoxantrone IV over 15-30 minutes on days 3-6. Arm B (LR patients): Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B. Arm B (HR patients): Patients receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8. Arm C (patients with HR FLT3/ITD+ disease, cohorts 1 and 2): Patients receive cytarabine IT on day 1, cytarabine IV over 15-30 minutes on days 1-8, daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 1-28. Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 29). Patients with refractory disease are off protocol therapy. Intensification I: Arm A: Patients receive cytarabine IT on day 1 and AE chemotherapy comprising high-dose cytarabine IV over 1-3 hours, and etoposide IV over 1-2 hours on days 1-5. Arm B: Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8. Arm C (cohorts 1 and 2): Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 1-28. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 29. Patients with refractory disease are off protocol therapy. Intensification II: Arm A (LR): Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients). Arm B (LR): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and bortezomib IV on days 1, 4, and 8. Arms A and B (HR and no donor for SCT): Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. Arm C (HR cohorts 1 and 2): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 1-28. Stem cell transplantation (SCT) (HR patients with matched family [MFD] or unrelated donor): Conditioning regimen: Patients receive fludarabine IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. Transplantation: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. Graft-vs-host disease (GVHD) prophylaxis: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. Blood, bone marrow, and tissue samples are collected at baseline and periodically during study for mutation and translocation analysis, cytogenetic/FISH analysis, gene and protein expression, and other studies. Some patients (aged 2 to 18 years) and/or parents may complete questionnaires about health-related quality of life (Pediatric Quality of Life (PedsQL) 4.0 Generic Core Scale, the PedsQL 3.0 Acute Cancer Module, and the PedsQL Multidimensional Fatigue Scale) and parental stress (Pediatric Inventory for Parents (PIP) scale) at baseline and periodically during the study and follow-up. After completion of study therapy, patients are followed up monthly for 6 months, every 2 months for 6 months, every 3 months for 1 year, every 6 months for 1 year, and then yearly for up to 8 years.
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