Clinical Trial: NCT01371981 - My Cancer Genome

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:

Active, not recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT01371981

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: CDR0000701850
SECONDARY ID: AAML1031
SECONDARY ID: COG-AAML1031
SECONDARY ID: S12-02301
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

Interventions

Drug	Synonyms	Arms
Asparaginase	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	Arm A
Bortezomib	[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade	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-28453	Arm A
Daunorubicin Hydrochloride	Cerubidin, Cerubidine, Cloridrato de Daunorubicina, Daunoblastin, Daunoblastina, Daunoblastine, Daunomycin Hydrochloride, Daunomycin, hydrochloride, Daunorubicin.HCl, Daunorubicini Hydrochloridum, FI-6339, Ondena, RP-13057, Rubidomycin Hydrochloride, Rubilem	Arm A
Etoposide	Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16	Arm A
Mitoxantrone Hydrochloride	CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan	Arm A
Sorafenib Tosylate	BAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenib	Arm C (Cohort 1)

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Arm A	Experimental	See Detailed Description	Asparaginase Cytarabine Daunorubicin Hydrochloride Etoposide Mitoxantrone Hydrochloride
Arm B	Experimental	See Detailed Description	Asparaginase Bortezomib Cytarabine Daunorubicin Hydrochloride Etoposide Mitoxantrone Hydrochloride
Arm C (Cohort 1)	Experimental	See Detailed Description	Asparaginase Cytarabine Daunorubicin Hydrochloride Etoposide Mitoxantrone Hydrochloride Sorafenib Tosylate
Arm C (Cohort 2)	Experimental	See Detailed Description.	Asparaginase Cytarabine Daunorubicin Hydrochloride Etoposide Mitoxantrone Hydrochloride Sorafenib Tosylate
Arm C (Cohort 3)	Experimental	See Detailed Description. Different dose.	Asparaginase Cytarabine Daunorubicin Hydrochloride Etoposide Mitoxantrone Hydrochloride Sorafenib Tosylate
Arm D	Experimental	See Detailed Description. May reassigned to Arm C.	Cytarabine Daunorubicin Hydrochloride Etoposide

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:	Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Time Frame:	Up to 3 years
Safety Issue:
Description:	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

Measure:	Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Time Frame:	Up to 3 years
Safety Issue:
Description:	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

Measure:	OS for Patients on Arm C, Cohort 1
Time Frame:	Up to 3 years
Safety Issue:
Description:	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

Measure:	OS for Patients on Arm C, Cohort 2
Time Frame:	Up to 3 years
Safety Issue:
Description:	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

Measure:	OS for Patients on Arm C, Cohort 3
Time Frame:	Up to 3 years
Safety Issue:
Description:	The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

Measure:	Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
Time Frame:	Up to 3 years
Safety Issue:
Description:	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.

Measure:	Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy
Time Frame:	Up to 2 years
Safety Issue:
Description:	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).

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:	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.

Measure:	Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module
Time Frame:	Up to 14 days
Safety Issue:
Description:	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.

Measure:	Total Scale Score From Parent-reported Cancer Module
Time Frame:	Up to 14 days
Safety Issue:
Description:	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.

Measure:	Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module
Time Frame:	Up to 14 days
Safety Issue:
Description:	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.

Measure:	Bortezomib Clearance
Time Frame:	Day 8 of Induction II
Safety Issue:
Description:	Median and range of bortezomib clearance during Induction II.

Measure:	Sorafenib Steady State Concentration
Time Frame:	Up to 30 days
Safety Issue:
Description:	Median and range of sorafenib steady state concentration for Induction I.

Measure:	Change in Shortening Fraction
Time Frame:	Up to 4 weeks
Safety Issue:
Description:	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.

Measure:	Change in Ejection Fraction
Time Frame:	Up to 4 weeks
Safety Issue:
Description:	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.

Measure:	Serum Concentrations of GVHD Biomarker
Time Frame:	Up to day 28 after SCT
Safety Issue:
Description:	The mean serum concentration of the day 28 GVHD biomarker will be estimated as well as the corresponding 95% confidence interval.

Details

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

Last Updated

August 5, 2021

Clinical Trials /

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