Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

• EFS (Arm C, Cohort 1) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ]
• EFS (Arm C, Cohort 2) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ]
• EFS (Arm C, Cohort 3) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ]
• EFS for patients without high allelic ratio FLT3/ITD+ mutations [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ]

• Bortezomib pharmacokinetic plasma concentration-time profiles [ Time Frame: Day 8 of Induction II ]
• OS (Arm C, Cohort 1) [ Time Frame: Up to 11 years ]
• OS (Arm C, Cohort 2) [ Time Frame: Up to 11 years ]
• OS (Arm C, Cohort 3) [ Time Frame: Up to 11 years ]
• OS for patients without high allelic ratio FLT3/ITD+ mutations [ Time Frame: Up to 11 years ]
• Parent-reported questionnaire scores [ Time Frame: At 4 months following start of SCT or intensification II of chemotherapy ]
• Proportion of high risk children without HR FLT3/ITD+ converting from positive MRD at end of Induction I to negative MRD at the end of Induction II [ Time Frame: Up to 8 weeks ]
• Proportion of patients experiencing grade 3 or higher non-hematologic toxicities and infections assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [ Time Frame: Up to 11 years ]
• Relapse rate assessed by bone marrow analysis for leukemic blasts [ Time Frame: Up to 11 years ]
• Serum concentrations of GVHD biomarkers [ Time Frame: Up to day 28 after SCT ]
• Shortening fraction/ejection fraction percentages and change over time [ Time Frame: Baseline to up to 11 years ]
• Systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, time to maximum concentration [Tmax1/2, area under curve [AUC]) [ Time Frame: Up to 4 months ]

• Overall survival
• Remission rate after 1 and 2 courses of therapy
• Proportion of patients dying in each course of therapy
• Course duration
• Length of hospitalization
• Time to blood count recovery
• Relapse rate
• Treatment-related mortality
• Frequency of toxicities, including infectious and cardiac complications

• Course duration [ Time Frame: Up to 6 months ]
• Incidence of treatment-related mortality [ Time Frame: Up to 2 years ]
• Length of hospitalization [ Time Frame: Up to 6 months ]
• Remission rate after 1 course of therapy [ Time Frame: 4 weeks ]
• Remission rate after 2 courses of therapy [ Time Frame: 8 weeks ]
• Time to blood count recovery [ Time Frame: Up to 6 months ]

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 1 of 2 treatment arms or offered treatment on 1 of 2 arms. (Arms A and B are closed to new patient enrollment as of 02/04/2016)

INDUCTION I:

ARM A: 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.

ARM B: 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.

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.

ARM D (unknown FLT3/ITD status prior to study enrollment): Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. 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.

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, cohort 3): 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.

Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 37). 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 (cohort 3): Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 6-28.

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:

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 cohort 3): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (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 in Arm C receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year.

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.

• Leukemia Cutis
• Myeloid Sarcoma
• Untreated Adult Acute Myeloid Leukemia
• Untreated Childhood Myeloid Neoplasm

• Drug: Asparaginase
  Given IM
• Drug: Bortezomib
  Given IV
• Drug: Cytarabine
  Given IT or IV
• Drug: Daunorubicin Hydrochloride
  Given IV
• Drug: Etoposide
  Given IV
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Mitoxantrone Hydrochloride
  Given IV
• Other: Pharmacological Study
  Correlative studies
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies
• Drug: Sorafenib Tosylate
  Given PO

• Experimental: Induction I, Arm A
  Patients receive cytarabine IT on day 1 and ADE chemotherapy comprising cytarabine 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.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction I, 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.
  Interventions:

  • Drug: Bortezomib
  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction I, Arm C
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate PO on days 11-28.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Drug: Sorafenib Tosylate
• Experimental: Induction I, Arm D
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. 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.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
• Experimental: Induction II, 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.
  Interventions:

  • Drug: Cytarabine
  • Other: Laboratory Biomarker Analysis
  • Drug: Mitoxantrone Hydrochloride
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction II, Arm A (LR patients)
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction II, Arm B (HR patients)
  Patients receive MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Bortezomib
  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Drug: Mitoxantrone Hydrochloride
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction II, Arm B (LR patients)
  Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
  Interventions:

  • Drug: Bortezomib
  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Induction II, Arm C

  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.

  Maintenance: Patients receive sorafenib tosylate PO starting on day 40-80 after completion of intensification II or SCT for one year.

  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Drug: Sorafenib Tosylate
• Experimental: 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.
  Interventions:

  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Intensification I, Arm B
  Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8.
  Interventions:

  • Drug: Bortezomib
  • Drug: Cytarabine
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
• Experimental: Intensification I, Arm C
  Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 6-33.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Drug: Sorafenib Tosylate
• Experimental: Intensification II, Arm A (LR)
  Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Intensification II, 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.
  Interventions:

  • Drug: Bortezomib
  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Intensification II, Arm C
  Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 7-34.
  Interventions:

  • Drug: Cytarabine
  • Drug: Daunorubicin Hydrochloride
  • Drug: Etoposide
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Drug: Sorafenib Tosylate
• Experimental: Intensification II, Arms A and B
  Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase IM on days 2 and 9.
  Interventions:

  • Drug: Asparaginase
  • Drug: Cytarabine
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

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