Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in
 treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib
 tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell
 growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells,
 either by killing the cells or by stopping them from dividing. Giving bortezomib and
 sorafenib tosylate together with combination chemotherapy may be an effective treatment for
 acute myeloid leukemia.
PRIMARY OBJECTIVES:

 I. To compare event-free survival (EFS) and overall survival (OS) in patients with de novo
 acute myeloid leukemia (AML) without high allelic ratio fms-like tyrosine kinase
 (FLT3)/internal tandem duplications (ITD)+ mutations who are randomized to standard therapy
 versus bortezomib/standard combination therapy.

 II. To determine the feasibility of combining bortezomib with standard chemotherapy in
 patients with de novo AML.

 III. To compare the OS and EFS of high-risk patients treated with intensive Induction II with
 historical controls from AAML03P1 and AAML0531.

 IV. To determine the feasibility of administering sorafenib (sorafenib tosylate) with
 standard chemotherapy and in a one year maintenance phase in patients with de novo high
 allelic ratio FLT3/ITD+ AML.

 SECONDARY OBJECTIVES:

 I. To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic
 ratio FLT3/ITD+ AML.

 II. To compare the percentage of patients converting from positive minimal residual disease
 (MRD) to negative MRD after Intensive Induction II with historical controls from AAML03P1 and
 AAML0531.

 III. To compare OS, disease-free survival (DFS), cumulative incidence of relapse, and
 treatment-related mortality from end of Intensification I between patients allocated to best
 allogenic donor stem cell transplant (SCT) and comparable patients on AAML0531 who did not
 receive allogenic donor SCT.

 IV. To compare OS, DFS, cumulative incidence of relapse, treatment-related mortality, and
 severe toxicity between patients allocated to matched family donor SCT on AAML1031 and
 AAML0531.

 V. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy
 and stem cell transplant (SCT) for AML.

 VI. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination
 regimen.

 VII. To obtain sorafenib and metabolite steady state pharmacokinetics and
 pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib.

 VIII. To compare the changes in shortening fraction/ejection fraction over time between
 patients treated with and without dexrazoxane.

 IX. To refine the use of minimal-residual disease (MRD) detection with 4-color flow
 cytometry.

 X. To evaluate the prognostic significance of molecular MRD and its contribution to risk
 identification with multidimensional flow cytometry (MDF)-based MRD in patients with
 translocations amenable to quantitative real time (RT)-polymerase chain reaction (PCR) (e.g.,
 t[8;21], inv[16], t[9;11], Wilms tumor 1 [WT1] expression).

 XI. To determine the leukemic involvement of the hematopoietic early progenitor cell and its
 role in defining response to therapy.

 XII. To define the leukemic stem cell population in patients with AML. XIII. To determine the
 prevalence and prognostic significance of molecular abnormalities of WT1, runt-related
 transcription factor (RUNX)1, mixed-lineage leukemia (MLL)-partial tandem duplication (PTD),
 tet methylcytosine dioxygenase 2 (TET2), Cbl proto-oncogene, E3 ubiquitin protein ligase
 (c-CBL), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and other novel
 AML-associated genes in pediatric AML.

 XIV. Correlate the expression of cluster of differentiation (CD)74 antigen as well as
 proteasome beta 5-subunit (PSMB5) gene expression and mutation with response to bortezomib.

 XV. To evaluate the changes in protein expression and unfolded protein response (UPR) in
 patients with AML.

 XVI. To determine the expression level of wild-type FLT3, and correlate with outcome and in
 vitro sensitivity to FLT3 inhibition.

 XVII. To collect biology specimens at diagnosis, treatment time points, and relapse for
 future biology studies XVIII. To create a pediatric-specific algorithm to predict the
 occurrence of grade 2-4 acute graft-versus-host disease (GVHD) prior to its clinical
 manifestations using a combination of pre-transplant clinical variables and serum GVHD
 biomarker concentrations in the first weeks after SCT.

 OUTLINE: This is a dose-escalation study of sorafenib tosylate. Patients are randomized to
 Arm A or B or offered treatment on 1 of 6 arms. (Arms A and B are closed to new patient
 enrollment as of 02/04/2016)

 Arm A:

 INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy
 comprising cytarabine intravenously (IV) over 1-30 minutes on days 1-10; daunorubicin
 hydrochloride IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on
 days 1-5.

 INDUCTION II: Patients with low risk (LR) receive cytarabine IT and ADE chemotherapy as in
 Induction I. Patients with high risk (HR) 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. Patients who achieve complete remission (CR) proceed to Intensification
 I (beginning on day 37). Patients with refractory disease are off protocol therapy.

 INTENSIFICATION I: 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. Patients
 who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on
 day 34. Patients with refractory disease are off protocol therapy.

 INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1 and MA chemotherapy as in
 Induction II. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3
 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.

 STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

 CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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.

 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.

 Arm B:

 INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A.
 Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, and 8.

 INDUCTION II: Patients with LR receive cytarabine IT, ADE chemotherapy, and bortezomib as in
 Induction I. Patients with HR receive cytarabine IT and MA chemotherapy as in Induction II,
 Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.

 INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A,
 Intensification II, and bortezomib IV on days 1, 4, and 8. Patients who achieve CR proceed to
 Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with
 refractory disease are off protocol therapy.

 INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1, MA chemotherapy as in
 Arm A, Induction II (HR patients), and bortezomib IV on days 1, 4, and 8. Patients with HR
 and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and
 asparaginase intramuscularly (IM) on days 2 and 9.

 STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

 CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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.

 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.

 ARM C (COHORT 1):

 INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on
 days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV
 over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36.

 INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A,
 Intensification II, and sorafenib tosylate PO on daily on days 6-28.

 INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A,
 Induction II (HR patients), and sorafenib tosylate PO on days 7-34.

 STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

 CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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.

 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.

 MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion
 of intensification II or SCT for one year.

 ARM C (COHORT 2):

 INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and
 sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including in Induction I and
 concurrently with chemotherapy).

 INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on
 days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV
 over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36.

 INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A,
 Intensification II, and sorafenib tosylate PO on daily on days 6-28.

 INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A,
 Induction II (HR patients), and sorafenib tosylate PO on days 7-34.

 STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

 CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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.

 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.

 MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion
 of intensification II or SCT for one year.

 ARM C (COHORT 3):

 INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and
 sorafenib tosylate PO on days 11-28.

 INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on
 days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV
 over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36.

 INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A,
 Intensification II, and sorafenib tosylate PO on daily on days 6-28.

 INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A,
 Induction II (HR patients), and sorafenib tosylate PO on days 7-34.

 STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):

 CONDITIONING REGIMEN: Patients receive fludarabine phosphate 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.

 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.

 MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion
 of intensification II or SCT for one year.

 ARM D:

 INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive
 cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be
 HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm
 C.

 After completion of study therapy, patients are followed up monthly for 6 months, every 2
 months for 6 months, every 4 months for 1 year, every 6 months for 1 year, and then yearly
 thereafter.
Inclusion Criteria:

 -  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 World Health Organization (WHO)
 Myeloid Neoplasm Classification are eligible

 -  Attempts to obtain bone marrow either by aspirate or biopsy must be made unless
 clinically prohibitive; in cases where it is clinically prohibitive, peripheral
 blood with an excess of 20% blasts and in which adequate flow cytometric and
 cytogenetics/fluorescent in situ hybridization (FISH) testing is feasible can be
 substituted for the marrow exam at diagnosis

 -  Patients with < 20% bone marrow 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

 -  The unequivocal presence of megakaryoblasts, or

 -  Biopsy proven isolated myeloid sarcoma (myeloblastoma; chloroma, including
 leukemia cutis)

 -  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; patients who have previously
 received any other chemotherapy, radiation therapy or any other antileukemic therapy
 are not eligible for this protocol

 Exclusion Criteria:

 -  Patients with any of the following constitutional conditions are not eligible:

 -  Fanconi anemia

 -  Shwachman syndrome

 -  Any other known bone marrow failure syndrome

 -  Patients with constitutional trisomy 21 or with constitutional mosaicism of
 trisomy 21 Note: enrollment may occur pending results of clinically indicated
 studies to exclude these conditions

 -  Patients with any of the following oncologic diagnoses are not eligible:

 -  Any concurrent malignancy

 -  Juvenile myelomonocytic leukemia (JMML)

 -  Philadelphia chromosome positive AML

 -  Biphenotypic or bilineal acute leukemia

 -  Acute promyelocytic leukemia

 -  Acute myeloid leukemia arising from myelodysplasia

 -  Therapy-related myeloid neoplasms Note: enrollment may occur pending results of
 clinically indicated studies to exclude these conditions

 -  Pregnancy and breast feeding

 -  Female patients who are pregnant are ineligible

 -  Lactating females are not eligible unless they have agreed not to breastfeed their
 infants

 -  Female patients of childbearing potential are not eligible unless a negative pregnancy
 test result has been obtained

 -  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