Clinical Trials /

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

NCT01371981

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Completed

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  • Official Title: A Phase III Randomized Trial for Patients With De Novo AML Using Bortezomib and Sorafenib (NSC# 681239, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD

Clinical Trial IDs

  • ORG STUDY ID: NCI-2011-02670
  • SECONDARY ID: NCI-2011-02670
  • SECONDARY ID: AAML1031
  • SECONDARY ID: COG-AAML1031
  • SECONDARY ID: S12-02301
  • SECONDARY ID: CDR0000701850
  • SECONDARY ID: AAML1031
  • SECONDARY ID: AAML1031
  • SECONDARY ID: U10CA180886
  • SECONDARY ID: U10CA098543
  • NCT ID: NCT01371981

Conditions

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

Interventions

DrugSynonymsArms
AsparaginaseASP-1, Asparaginase II, Asparaginase-E.Coli, Colaspase, Elspar, Kidrolase, L-Asnase, L-ASP, L-Asparaginase, L-Asparagine amidohydrolase, Laspar, Lcf-ASP, Leucogen, Leunase, MK-965, Paronal, Re-82-TAD-15, Serasa, SpectrilaIntensification II, Arms A and B
Bortezomib[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, VelcadeInduction I, Arm B
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Induction I, Arm A
Daunorubicin HydrochlorideCerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, RubilemInduction I, Arm A
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Induction I, Arm A
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanInduction II, Arm A (HR patients)
Sorafenib TosylateBAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibInduction I, Arm C

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Induction I, Arm AExperimentalPatients 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.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Induction I, Arm BExperimentalPatients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV on days 1, 4, and 8.
  • Bortezomib
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Induction I, Arm CExperimentalPatients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate PO on days 11-28.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Sorafenib Tosylate
Induction I, Arm DExperimentalPatients 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.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Induction II, Arm A (HR patients)ExperimentalPatients 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.
  • Cytarabine
  • Mitoxantrone Hydrochloride
Induction II, Arm A (LR patients)ExperimentalPatients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Induction II, Arm B (HR patients)ExperimentalPatients receive MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.
  • Bortezomib
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Mitoxantrone Hydrochloride
Induction II, Arm B (LR patients)ExperimentalPatients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
  • Bortezomib
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Induction II, Arm CExperimentalPatients 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.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Sorafenib Tosylate
Intensification I, Arm AExperimentalPatients 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.
  • Cytarabine
  • Etoposide
Intensification I, Arm BExperimentalPatients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8.
  • Bortezomib
  • Cytarabine
  • Etoposide
Intensification I, Arm CExperimentalPatients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 6-33.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Sorafenib Tosylate
Intensification II, Arm A (LR)ExperimentalPatients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Intensification II, Arm B (LR)ExperimentalPatients 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.
  • Bortezomib
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
Intensification II, Arm CExperimentalPatients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 7-34.
  • Cytarabine
  • Daunorubicin Hydrochloride
  • Etoposide
  • Sorafenib Tosylate
Intensification II, Arms A and BExperimentalPatients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase IM on days 2 and 9.
  • Asparaginase
  • Cytarabine

Eligibility Criteria

        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
      
Maximum Eligible Age:29 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:OS for patients without high allelic ratio FLT3/ITD+ mutations
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure:OS (Arm C, Cohort 1)
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure:OS (Arm C, Cohort 2)
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure:OS (Arm C, Cohort 3)
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure:Relapse rate assessed by bone marrow analysis for leukemic blasts
Time Frame:Up to 11 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Parent-reported questionnaire scores
Time Frame:At 4 months following start of SCT or intensification II of chemotherapy
Safety Issue:
Description:
Measure:Bortezomib pharmacokinetic plasma concentration-time profiles
Time Frame:Day 8 of Induction II
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Shortening fraction/ejection fraction percentages and change over time
Time Frame:Baseline to up to 11 years
Safety Issue:
Description:
Measure:Serum concentrations of GVHD biomarkers
Time Frame:Up to day 28 after SCT
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

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