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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01371981
Recruitment Status : Active, not recruiting
First Posted : June 13, 2011
Results First Posted : July 7, 2020
Last Update Posted : July 28, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE June 10, 2011
First Posted Date  ICMJE June 13, 2011
Results First Submitted Date  ICMJE April 20, 2020
Results First Posted Date  ICMJE July 7, 2020
Last Update Posted Date July 28, 2022
Actual Study Start Date  ICMJE June 20, 2011
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
  • Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
  • EFS for Patients on Arm C, Cohort 1 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
  • EFS for Patients on Arm C, Cohort 2 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
  • EFS for Patients on Arm C, Cohort 3 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2011)
Event-free survival
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 24, 2020)
  • Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • OS for Patients on Arm C, Cohort 1 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • OS for Patients on Arm C, Cohort 2 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • OS for Patients on Arm C, Cohort 3 [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.
  • Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations [ Time Frame: Up to 3 years ]
    Cumulative incidence estimates 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events.
  • Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy [ Time Frame: Up to 2 years ]
    The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
  • 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 ]
    The 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 will be estimated as well as the corresponding 95% confidence interval determined using a binomial exact method.
  • Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module [ Time Frame: Up to 14 days ]
    Results represent the total scale scores from the parent report of the PedsQL™ 4.0 Generic Core Scales for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
  • Total Scale Score From Parent-reported Cancer Module [ Time Frame: Up to 14 days ]
    Results represent the total scale scores from the parent report of the PedsQL™ 3.0 Cancer Module for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
  • Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module [ Time Frame: Up to 14 days ]
    Results represent the total scale scores from the parent report of the PedsQL™ Multidimensional Fatigue Scale for timepoint 1 (up to 14 days from start of therapy). Items are reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Therefore, a higher number is a better outcome. The total score is the sum of all the items divided by the number of items answered on all the scales. "Scores on a scale" is used for a unit of measure.
  • Bortezomib Clearance [ Time Frame: Day 8 of Induction II ]
    Median and range of bortezomib clearance during Induction II.
  • Sorafenib Steady State Concentration [ Time Frame: Up to 30 days ]
    Median and range of sorafenib steady state concentration for Induction I.
  • Change in Shortening Fraction [ Time Frame: Up to 4 weeks ]
    Mean percentage change in shortening fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C.
  • Change in Ejection Fraction [ Time Frame: Up to 4 weeks ]
    The mean percentage change in ejection fraction from baseline to the end of Induction I will be determined for eligible patients enrolled on Arms A, B and C.
  • Serum Concentrations of GVHD Biomarker [ Time Frame: Up to day 28 after SCT ]
    The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2011)
  • 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
Current Other Pre-specified Outcome Measures
 (submitted: June 24, 2020)
  • Course Duration [ Time Frame: Up to 6 months ]
    Descriptive statistics will be used to summarize length of hospitalization time.
  • Incidence of Treatment-related Mortality [ Time Frame: Up to 2 years ]
    Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
  • Length of Hospitalization [ Time Frame: Up to 6 months ]
    Descriptive statistics will be used to summarize length of hospitalization time.
  • Remission Rate After 1 Course of Therapy [ Time Frame: 4 weeks ]
    The proportion of patients achieving remission after 1 course of therapy will be estimated along with a corresponding 95% confidence interval.
  • Remission Rate After 2 Courses of Therapy [ Time Frame: 8 weeks ]
    The proportion of patients achieving remission after 2 courses of therapy will be estimated along with a corresponding 95% confidence interval.
  • Time to Blood Count Recovery [ Time Frame: Up to 6 months ]
    Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Official Title  ICMJE 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
Brief Summary 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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Leukemia Cutis
  • Myeloid Neoplasm
  • Myeloid Sarcoma
Intervention  ICMJE
  • Drug: Asparaginase
    Given IM
    Other Names:
    • ASP-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
    • Spectrila
  • Drug: Bortezomib
    Given IV
    Other Names:
    • [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid
    • LDP 341
    • MLN341
    • PS-341
    • PS341
    • Velcade
  • Drug: Cytarabine
    Given IT or IV
    Other Names:
    • .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-28453
  • Drug: Daunorubicin Hydrochloride
    Given IV
    Other Names:
    • Cerubidin
    • Cerubidine
    • Cloridrato de Daunorubicina
    • Daunoblastin
    • Daunoblastina
    • Daunoblastine
    • Daunomycin Hydrochloride
    • Daunomycin, hydrochloride
    • Daunorubicin.HCl
    • Daunorubicini Hydrochloridum
    • FI-6339
    • Ondena
    • RP-13057
    • Rubidomycin Hydrochloride
    • Rubilem
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16
    • VP 16-213
    • VP-16
    • VP-16-213
    • VP16
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mitoxantrone Hydrochloride
    Given IV
    Other Names:
    • CL 232315
    • DHAD
    • DHAQ
    • Dihydroxyanthracenedione Dihydrochloride
    • Mitoxantrone Dihydrochloride
    • Mitoxantroni Hydrochloridum
    • Mitozantrone Hydrochloride
    • Mitroxone
    • Neotalem
    • Novantrone
    • Onkotrone
    • Pralifan
  • 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
    Other Names:
    • BAY 43-9006 Tosylate
    • BAY 54-9085
    • Nexavar
    • sorafenib
Study Arms  ICMJE
  • Experimental: Arm A
    See Detailed Description
    Interventions:
    • Drug: Asparaginase
    • 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: Arm B
    See Detailed Description
    Interventions:
    • Drug: Asparaginase
    • 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: Arm C (Cohort 1)
    See Detailed Description
    Interventions:
    • Drug: Asparaginase
    • 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
    • Drug: Sorafenib Tosylate
  • Experimental: Arm C (Cohort 2)
    See Detailed Description.
    Interventions:
    • Drug: Asparaginase
    • 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
    • Drug: Sorafenib Tosylate
  • Experimental: Arm C (Cohort 3)
    See Detailed Description. Different dose.
    Interventions:
    • Drug: Asparaginase
    • 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
    • Drug: Sorafenib Tosylate
  • Experimental: Arm D
    See Detailed Description. May reassigned to Arm C.
    Interventions:
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 24, 2020)
1645
Original Estimated Enrollment  ICMJE
 (submitted: June 10, 2011)
1250
Estimated Study Completion Date  ICMJE September 30, 2027
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 29 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01371981
Other Study ID Numbers  ICMJE NCI-2011-02670
NCI-2011-02670 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000701850
AAML1031
COG-AAML1031
S12-02301
AAML1031 ( Other Identifier: Children's Oncology Group )
AAML1031 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party National Cancer Institute (NCI)
Original Responsible Party Gregory H. Reaman, Children's Oncology Group - Group Chair Office
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Richard Aplenc Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP