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

Phase 3

Active, not recruiting

• Conditions: Acute Myeloid Leukemia; Myeloid Sarcoma; Leukemia Cutis; Myeloid Neoplasm
• Interventions: Drug: Asparaginase; Drug: Daunorubicin Hydrochloride; Drug: Cytarabine; Drug: Bortezomib; Other: Laboratory Biomarker Analysis; Drug: Etoposide; Drug: Mitoxantrone Hydrochloride; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Sorafenib Tosylate

• Registration Number: NCT01371981
• Lead Sponsor: National Cancer Institute (NCI)

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 Timeline

• Study First Submitted: 2011-06-10
• Study First Submitted QC: 2011-06-10
• Study First Posted: 2011-06-13
• Study Start: 2011-06-20
• Primary Completion: 2019-03-31
• Results First Submitted: 2020-04-20
• Results First Submitted QC: 2020-06-24
• Results First Posted: 2020-07-07
• Status Verified: 2025-04
• Last Update Submitted: 2025-07-08
• Last Update Posted: 2025-07-09
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 1645

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D	Daunorubicin Hydrochloride	See Detailed Description. May reassigned to Arm C.
Arm B	Pharmacological Study	See Detailed Description
Arm C (Cohort 3)	Laboratory Biomarker Analysis	See Detailed Description. Different dose.
Arm D	Laboratory Biomarker Analysis	See Detailed Description. May reassigned to Arm C.
Arm C (Cohort 1)	Laboratory Biomarker Analysis	See Detailed Description
Arm C (Cohort 1)	Pharmacological Study	See Detailed Description
Arm C (Cohort 1)	Questionnaire Administration	See Detailed Description
Arm C (Cohort 2)	Sorafenib Tosylate	See Detailed Description.
Arm A	Mitoxantrone Hydrochloride	See Detailed Description
Arm A	Pharmacological Study	See Detailed Description
Arm A	Quality-of-Life Assessment	See Detailed Description
Arm A	Questionnaire Administration	See Detailed Description
Arm A	Daunorubicin Hydrochloride	See Detailed Description
Arm A	Laboratory Biomarker Analysis	See Detailed Description
Arm B	Questionnaire Administration	See Detailed Description
Arm B	Daunorubicin Hydrochloride	See Detailed Description
Arm C (Cohort 2)	Laboratory Biomarker Analysis	See Detailed Description.
Arm C (Cohort 2)	Questionnaire Administration	See Detailed Description.
Arm C (Cohort 1)	Quality-of-Life Assessment	See Detailed Description
Arm C (Cohort 2)	Daunorubicin Hydrochloride	See Detailed Description.
Arm C (Cohort 3)	Mitoxantrone Hydrochloride	See Detailed Description. Different dose.
Arm B	Etoposide	See Detailed Description
Arm B	Laboratory Biomarker Analysis	See Detailed Description
Arm B	Quality-of-Life Assessment	See Detailed Description
Arm C (Cohort 1)	Mitoxantrone Hydrochloride	See Detailed Description
Arm C (Cohort 1)	Sorafenib Tosylate	See Detailed Description
Arm C (Cohort 2)	Mitoxantrone Hydrochloride	See Detailed Description.
Arm B	Mitoxantrone Hydrochloride	See Detailed Description
Arm C (Cohort 1)	Daunorubicin Hydrochloride	See Detailed Description
Arm C (Cohort 2)	Quality-of-Life Assessment	See Detailed Description.
Arm C (Cohort 3)	Questionnaire Administration	See Detailed Description. Different dose.
Arm C (Cohort 3)	Sorafenib Tosylate	See Detailed Description. Different dose.
Arm C (Cohort 2)	Pharmacological Study	See Detailed Description.
Arm C (Cohort 3)	Daunorubicin Hydrochloride	See Detailed Description. Different dose.
Arm C (Cohort 3)	Quality-of-Life Assessment	See Detailed Description. Different dose.
Arm C (Cohort 3)	Pharmacological Study	See Detailed Description. Different dose.
Arm D	Etoposide	See Detailed Description. May reassigned to Arm C.
Arm D	Pharmacological Study	See Detailed Description. May reassigned to Arm C.
Arm D	Quality-of-Life Assessment	See Detailed Description. May reassigned to Arm C.
Arm D	Questionnaire Administration	See Detailed Description. May reassigned to Arm C.
Arm A	Asparaginase	See Detailed Description
Arm A	Cytarabine	See Detailed Description
Arm A	Etoposide	See Detailed Description
Arm B	Asparaginase	See Detailed Description
Arm B	Cytarabine	See Detailed Description
Arm B	Bortezomib	See Detailed Description
Arm C (Cohort 1)	Cytarabine	See Detailed Description
Arm C (Cohort 1)	Asparaginase	See Detailed Description
Arm C (Cohort 1)	Etoposide	See Detailed Description
Arm C (Cohort 2)	Asparaginase	See Detailed Description.
Arm C (Cohort 2)	Cytarabine	See Detailed Description.
Arm C (Cohort 2)	Etoposide	See Detailed Description.
Arm C (Cohort 3)	Asparaginase	See Detailed Description. Different dose.
Arm C (Cohort 3)	Cytarabine	See Detailed Description. Different dose.
Arm C (Cohort 3)	Etoposide	See Detailed Description. Different dose.
Arm D	Cytarabine	See Detailed Description. May reassigned to Arm C.

Primary Outcome Measures

Name	Time	Method
EFS for Patients on Arm C, Cohort 3	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.
Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations	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	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	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.

Secondary Outcome Measures

Name	Time	Method
OS for Patients on Arm C, Cohort 1	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.
Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy	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	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.
Sorafenib Steady State Concentration	Up to 30 days	Median and range of sorafenib steady state concentration for Induction I.
OS for Patients on Arm C, Cohort 3	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	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.
Change in Ejection Fraction	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.
Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations	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	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.
Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module	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	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.
Bortezomib Clearance	Day 8 of Induction II	Median and range of bortezomib clearance during Induction II.
Serum Concentrations of GVHD Biomarker	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.
Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module	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.
Change in Shortening Fraction	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.

Trial Locations

Locations (220)

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

USA Health Strada Patient Care Center; 🇺🇸 Mobile, Alabama, United States

Banner Children's at Desert; 🇺🇸 Mesa, Arizona, United States

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

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