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

Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed Acute Myeloid Leukemia With or Without Mutations
This study is currently recruiting participants.
Verified August 2012 by National Cancer Institute (NCI)

First Received on June 10, 2011.  
Last Updated on August 16, 2012  
History of Changes
Sponsor: Children’s Oncology Group
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01371981
  Purpose

RATIONALE: 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.

PURPOSE: 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.

Condition Intervention Phase
Leukemia Drug: asparaginase
Drug: bortezomib
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: etoposide
Drug: mitoxantrone hydrochloride
Drug: sorafenib tosylate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Trial for Patients With de Novo AML Using Bortezomib (IND# 58443, NSC# 681239) and Sorafenib (BAY 43-9006, IND#69896, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

  • Event-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • 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 ]

Estimated Enrollment: 1250
Study Start Date: June 2011
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)

Arms

Assigned Interventions
Active Comparator: 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.
Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV
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.
Drug: bortezomib

Given IV

Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV
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.
Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV

Drug: sorafenib tosylate

Given orally
Active Comparator: Induction II, Arm A (LR patients)

Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV
Active Comparator: 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.
Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV

Drug: mitoxantrone hydrochloride

Given IV
Experimental: Induction II, Arm B (LR patients)

Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
Drug: bortezomib

Given IV

Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV
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.
Drug: bortezomib

Given IV

Drug: cytarabine

Given IT

Drug: mitoxantrone hydrochloride

Given IV
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.
Drug: cytarabine

Given IT

Drug: daunorubicin hydrochloride

Given IV

Drug: etoposide

Given IV

Drug: sorafenib tosylate

Given orally
Active Comparator: 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.
Drug: cytarabine

Given IT
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.
Drug: bortezomib

Given IV

Drug: cytarabine

Given IT
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.
Drug: cytarabine

Given IT

Drug: sorafenib tosylate

Given orally
Active Comparator: Intensification II, Arm A (LR)

Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).
Drug: cytarabine

Given IT

Drug: mitoxantrone hydrochloride

Given IV
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.
Drug: bortezomib

Given IV

Drug: cytarabine

Given IT

Drug: mitoxantrone hydrochloride

Given IV
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.
Drug: asparaginase

Given IM

Drug: cytarabine

Given IT
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.
Drug: cytarabine

Given IT

Drug: mitoxantrone hydrochloride

Given IV

Drug: sorafenib tosylate

Given orally

 
Show Detailed Description

  Eligibility

Ages Eligible for Study:   up to 29 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • 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 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-proven isolated myeloid sarcoma (myeloblastoma; chloroma, including leukemia cutis) 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) cytogenetic features or NPM or CEBPα mutation regardless of monosomy 7, monosomy 5, or del5q and regardless of MRD at end of Induction I
      • Negative MRD (< 0.1%) at end of Induction I and no high-risk disease features
      • 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 > 0.4 (HR FLT3/ITD+) regardless of low-risk features
      • Presence of monosomy 7, monosomy 5, or del5q, without inv(16)/t(16;16) or t(8;21) cytogenetics or NPM or CEBPα mutations
      • AML without inv(16)/t(16;16), t(8;21), NPM, CEPBα mutations, monosomy 7, monosomy 5, del5q, or HR FLT3/ITD+, but with evidence of residual AML (≥ 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 NOTE: *For MFD SCT, the use of peripheral blood stem cells (PBSC) is not permitted on 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 adequate cell dose (nucleated cell dose > 3.7×10^7/kg or CD34+ cell dose > 2 x 10^5/kg)
      • Mismatched family member donor with at least one haplotype match, or 5 of 6 antigen phenotypic match

PATIENT CHARACTERISTICS:

  • 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 an effective contraceptive method for the duration of their study participation

PRIOR CONCURRENT THERAPY:

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

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT01371981

 
Show 134 Study Locations

Sponsors and Collaborators
Children’s Oncology Group
Investigators
Principal Investigator: Richard Aplenc, MD, MSCE Children’s Hospital of Philadelphia
  More Information

Additional Information:

No publications provided

Responsible Party: Gregory H. Reaman, Children’s Oncology Group – Group Chair Office
ClinicalTrials.gov Identifier: NCT01371981    
History of Changes
Other Study ID Numbers: CDR0000701850, COG-AAML1031
Study First Received: June 10, 2011
Last Updated: August 16, 2012
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):

adult acute minimally differentiated myeloid leukemia (M0)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myeloblastic leukemia without maturation (M1)
adult acute myelomonocytic leukemia (M4)
untreated adult acute myeloid leukemia
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)
childhood acute minimally differentiated myeloid leukemia (M0)
childhood acute myeloblastic leukemia with maturation (M2)
childhood acute myeloblastic leukemia without maturation (M1)
childhood acute myelomonocytic leukemia (M4)
untreated childhood acute myeloid leukemia and other myeloid malignancies
adult acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
childhood acute monoblastic leukemia (M5a)
childhood acute monocytic leukemia (M5b)
adult acute erythroid leukemia (M6)
adult pure erythroid leukemia (M6b)
childhood acute erythroleukemia (M6)
adult acute megakaryoblastic leukemia (M7)
childhood acute megakaryocytic leukemia (M7)

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Etoposide phosphate
Bortezomib
Sorafenib
Asparaginase
Cytarabine
Daunorubicin
Etoposide
Mitoxantrone
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents, Phytogenic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 21, 2012

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