AAML1031, A Phase III Randomized Trial for Patients with de novo AML using Bortezomib and Sorafenib (IND#114480; NSC# 681239, NSC# 724772) for Patients with High Allelic Ratio FLT3/ITD
AAML1031 will utilize a 4 course chemotherapy backbone. Patients with low risk disease will receive cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/daunorubicin/etoposide (ADE 8+3+5), cytarabine/etoposide (AE), and cytarabine/mitoxantrone (ARAC/Mitox). Patients with high risk disease will receive 3 courses of chemotherapy: cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/mitoxantrone (ARAC/Mitox), and cytarabine/etoposide (AE), prior to best allogenic donor stem cell transplant (SCT). High risk patients without an appropriate allogenic donor will receive high dose cytarabine/L-asparaginase (HD ARAC/LASP) as a fourth chemotherapy course. Patients with HR FLT3/ITD+ will receive 3 courses of chemotherapy, cytarabine/daunorubicin/etoposide (ADE 10+3+5), cytarabine/daunorubicin/etoposide (ADE 8+3+5), cytarabine/etoposide (AE) in combination with sorafenib, followed by best allogenic donor SCT. Patients with HR FLT3/ITD+ who do not have an appropriate allogenic donor will receive sorafenib with ARAC/Mitox as a fourth course of chemotherapy. Bortezomib evaluation will involve random allocation to treatment with standard pediatric AML therapy only (Arm A), or standard AML therapy with bortezomib (Arm B). Sorafenib evaluation will occur in 2 Parts. Part 1 will determine a tolerable dose of sorafenib in combination with standard AML chemotherapy in an initial group of patients with HR FLT3/ITD+ mutations (Cohort 1-Arm C).
Once sorafenib dose determination is concluded, patients with HR FLT3/ITD+ will be allocated to sorafenib plus standard chemotherapy for additional feasibility and efficacy determination (Cohort 2-Arm C). Risk stratification of patients in AAML1031 will utilize cytogenetics, molecular markers and multidimensional flow cytometry to allocate patients into high risk (HR) and low risk (LR) groups. This study will assess health related quality of life (HRQOL) and parental stress at multiple time points during and after therapy, for longitudinal assessment of QOL and parental stress. AAML1031 will also incorporate correlative studies aimed at contributing to the enhancement of future AML treatment parameters and assessment. These correlative studies include evaluation of the in vitro levels of wild type FLT3 in response to sorafenib, analyzing chromosomal abnormalities, complex karyotypes; molecular abnormalities of WT1, RUNX1, MLLPTD and other novel AML associated genes, and leukemic involvement of early progenitor cells.
In addition, bortezomib and sorafenib pharmacokinetic studies will be performed on a subset of patients.
Please see page 10 of the protocol for the Experimental Design Schema.
-- Age: Patients must be less than 30 years of age at the time of study enrollment.
-- Diagnosis: Patients must be newly diagnosed with de novo acute myelogenous leukemia.
-- Patients with previously untreated primary AML who meet the customary criteria for AML with >= 20% bone marrow blasts as set out in the 2008 WHO Myeloid Neoplasm Classification.
-- Patients with cytopenias and bone marrow blasts who do not meet the customary criteria for the diagnosis of AML (patients with < 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 proved isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) are eligible regardless of the results
-- Patients with any performance status are eligible for enrollment.
-- Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and IT cytarabine given at diagnosis is allowed. Hydroxyurea and ATRA must be discontinued prior to initiation of protocol therapy.
-- All patients and/or their parents or legal guardians must sign a written informed consent.
-- All institutional, FDA, and NCI requirements for human studies must be met.