Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed Acute Myeloid Leukemia With or Without Mutations

• Overall survival [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Remission rate after 1 and 2 courses of therapy [ Time Frame: At 4 weeks and 8 weeks ] [ Designated as safety issue: No ]
• Proportion of patients dying in each course of therapy [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Time to blood count recovery [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Relapse rate assessed by bone marrow analsysis for leukemic blasts [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Incidence of treatment-related mortality [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
• Incidence of 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 ] [ Designated as safety issue: Yes ]

• Overall survival [ Designated as safety issue: No ]
• Remission rate after 1 and 2 courses of therapy [ Designated as safety issue: No ]
• Proportion of patients dying in each course of therapy [ Designated as safety issue: Yes ]
• Course duration [ Designated as safety issue: No ]
• Length of hospitalization [ Designated as safety issue: No ]
• Time to blood count recovery [ Designated as safety issue: No ]
• Relapse rate [ Designated as safety issue: No ]
• Treatment-related mortality [ Designated as safety issue: Yes ]
• Frequency of toxicities, including infectious and cardiac complications [ Designated as safety issue: Yes ]

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. 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 more than one drug (combination chemotherapy) may kill more cancer cells. 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) of patients with de novo acute myeloid leukemia (AML) with or without high allelic ratio FLT3/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 COG-AAML0531.

IV. To determine the feasibility of combining sorafenib with standard chemotherapy in patients with de novo high allelic ratio FLT3/ITD+ AML.

SECONDRY 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 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 COG-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 AAML103P1 and AAML0531.

V. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and 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 RT-PCR (e.g., t(8;21), inv(16), t(9;11), 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, RUNX1, MLL-PTD, TET2, c-CBL, KIT, and other novel AML-associated genes in pediatric AML.

XIV. To correlate the expression of CD74 antigen as well as 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.

OUTLINE: 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 TRANPLANTATION (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.

• Adult Acute Erythroid Leukemia (M6)
• Adult Acute Megakaryoblastic Leukemia (M7)
• Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
• Adult Acute Monoblastic Leukemia (M5a)
• Adult Acute Monocytic Leukemia (M5b)
• Adult Acute Myeloblastic Leukemia With Maturation (M2)
• Adult Acute Myeloblastic Leukemia Without Maturation (M1)
• Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
• Adult Acute Myeloid Leukemia With Del(5q)
• Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
• Adult Acute Myelomonocytic Leukemia (M4)
• Adult Pure Erythroid Leukemia (M6b)
• Childhood Acute Erythroleukemia (M6)
• Childhood Acute Megakaryocytic Leukemia (M7)
• Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
• Childhood Acute Monoblastic Leukemia (M5a)
• Childhood Acute Monocytic Leukemia (M5b)
• Childhood Acute Myeloblastic Leukemia With Maturation (M2)
• Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
• Childhood Acute Myelomonocytic Leukemia (M4)
• Untreated Adult Acute Myeloid Leukemia
• Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

• Drug: asparaginase
  Given IM
  Other Names:

  • ASNase
  • Colaspase
  • Crasnitin
  • Elspar
  • L-ASP
• Drug: daunorubicin hydrochloride
  Given IV
  Other Names:

  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
• Drug: mitoxantrone hydrochloride
  Given IV
  Other Names:

  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
• Drug: sorafenib tosylate
  Given orally
  Other Names:

  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
• Drug: cytarabine
  Given IT or IV
  Other Names:

  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
• Drug: etoposide
  Given IV
  Other Names:

  • EPEG
  • VP-16
  • VP-16-213
• Drug: bortezomib
  Given IV
  Other Names:

  • LDP 341
  • MLN341
  • VELCADE

• Experimental: 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.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
• 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: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
  • Drug: bortezomib
• Experimental: Induction I, Arm C
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate orally (PO) on days 11-28.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: sorafenib tosylate
  • Drug: cytarabine
  • Drug: etoposide
• Experimental: Induction II, Arm A (LR patients)
  Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
• 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: mitoxantrone hydrochloride
  • Drug: cytarabine
• Experimental: Induction II, Arm B (LR patients)
  Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
  • Drug: bortezomib
• 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: daunorubicin hydrochloride
  • Drug: mitoxantrone hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
  • Drug: bortezomib
• Experimental: Induction II, Arm C
  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.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: sorafenib tosylate
  • Drug: cytarabine
  • Drug: etoposide
• 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
• 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: cytarabine
  • Drug: etoposide
  • Drug: bortezomib
• 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 1-28.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: sorafenib tosylate
  • Drug: cytarabine
  • Drug: etoposide
• 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: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
• 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: daunorubicin hydrochloride
  • Drug: cytarabine
  • Drug: etoposide
  • Drug: bortezomib
• 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 intramuscularly (IM) on days 2 and 9.
  Interventions:

  • Drug: asparaginase
  • Drug: cytarabine
• 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 1-28.
  Interventions:

  • Drug: daunorubicin hydrochloride
  • Drug: sorafenib tosylate
  • Drug: cytarabine
  • Drug: etoposide

Inclusion Criteria:

• 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 ≥ 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 diagnosisof AML (patients with < 20% blasts) are eligible if they have a karyotypic abnormality characteristic ofde novo AML (t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22) or 11q23 abnormalities), or ifthey have the unequivocal presence of megakaryoblasts, as set out in the 2008 WHO Myeloid NeoplasmClassification
  • Patients with biopsy-proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemiacutis) 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 orCEBPα mutation, regardless of minimum-residual disease (MRD) status at end of Induction I
    • Standard-risk cytogenetics (neitherfavorable or unfavorable) with negative MRD (< 0.1%) at end of Induction I
    • Patients who do not have MRD data and have non-informative molecular studies (NPM, CEBPα,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+)
    • Unfavorablecytogenetics (monosomy 7, monosomy 5, and del5q)
    • Standard-risk cytogenetics with positive MRD(≥ 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

  • 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 adequatecell dose (nucleated cell dose > 3.7x10^7/kg or CD34+ cell dose > 2 x 10^5/kg)
    • Mismatched family member donor with at least one haplotype match, or 5 of 6 antigenphenotypic match
• 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 aneffective contraceptive method for the duration of their study participation

• Prior therapy with hydroxyurea, all-trans retinoic acid (ATRA), corticosteroids (any route), and intrathecal (IT) cytarabinegiven at diagnosis is allowed

  • Hydroxyurea and ATRA must be discontinued prior to initiation of protocoltherapy
• No concurrent peripheral blood stem cell transplantation
• Patients who have previously received any other chemotherapy, radiation therapy, or any otherantileukemic therapy are not eligible for this protocol
• Concomitant administration of strong CYP3A4 inducers and inhibitors (including clinicallyrelevant moderate inhibitors) is prohibited on both sorafenib cohorts