Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
This study is currently recruiting participants.
(see Contacts and Locations)
Verified July 2016 by National Cancer Institute (NCI)
Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01371981
First received: June 10, 2011
Last updated: September 26, 2016
Last verified: July 2016
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Purpose
This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.
| Condition | Intervention | Phase |
|---|---|---|
|
Leukemia Cutis Myeloid Sarcoma Untreated Adult Acute Myeloid Leukemia Untreated Childhood Myeloid Neoplasm |
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 Drug: Sorafenib Tosylate |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
Resource links provided by NLM:
Genetics Home Reference related topics:
core binding factor acute myeloid leukemia
cytogenetically normal acute myeloid leukemia
familial acute myeloid leukemia with mutated CEBPA
Drug Information available for:
Cytarabine
Asparaginase
Daunorubicin
Daunorubicin hydrochloride
Etoposide
Mitoxantrone
Mitoxantrone hydrochloride
Etoposide phosphate
Bortezomib
Sorafenib
Daunorubicin citrate
Sorafenib tosylate
Genetic and Rare Diseases Information Center resources:
Myeloid Leukemia
Acute Myeloid Leukemia
Acute Non Lymphoblastic Leukemia
Malignant Mesenchymal Tumor
Soft Tissue Sarcoma
Myeloid Sarcoma
U.S. FDA Resources
Further study details as provided by National Cancer Institute (NCI):
Primary Outcome Measures:
- EFS [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate EFS.
- EFS (Arm C, Cohort 1) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate EFS.
- EFS (Arm C, Cohort 2) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate EFS.
- EFS (Arm C, Cohort 3) [ Time Frame: From the time on study to induction failure, relapse or death, up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate EFS.
Secondary Outcome Measures:
- Bortezomib pharmacokinetic plasma concentration-time profiles [ Time Frame: Day 8 of induction II ] [ Designated as safety issue: No ]Analyzed using descriptive statistics and will be graphically displayed by age group. PK data will be analyzed using methods such as nonlinear mixed effects modeling to estimate bortezomib clearance (Cl) and volume of distribution (Vd) with associated 95% confidence intervals in each age group (2-11 years and 12-16 years of age).
- Change in parent-reported outcomes over time in recipients of SCT or chemotherapy [ Time Frame: Baseline to up to 11 years ] [ Designated as safety issue: No ]Summary measures at each time point as well as the overall trajectory over time in HRQOL and PIP will be described. A mixed linear regression model with repeated measures incorporating covariates as appropriate will be performed.
- Course duration [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
- Incidence of treatment-related mortality [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]Cumulative incidence estimates that account for competing events will be used to estimate treatment-related mortality.
- Length of hospitalization [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]Descriptive statistics will be used to summarize length of hospitalization time.
- OS [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate OS.
- OS (Arm C, Cohort 1) [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate OS.
- OS (Arm C, Cohort 2) [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate OS.
- OS (Arm C, Cohort 3) [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]The Kaplan-Meier method will be used to estimate OS.
- Parent-reported questionnaire scores [ Time Frame: At 4 months following start of SCT or intensification II of chemotherapy ] [ Designated as safety issue: No ]Questionnaires include the Generic Core Scale, Acute Cancer Module, and Multidimensional Fatigue Module summary and dimension scores of HRQOL and Pediatric Inventory for Parents (PIP). Mean values and their 95% confidence intervals (CI) will be presented.
- 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 11 years ] [ Designated as safety issue: No ]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 confidence interval. In addition, this proportion will be compared with the proportion for high risk children without HR FLT3/ITD+ treated on AAML03P1 and AAML0531.
- Proportion of patients dying in each course of therapy [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]
- Proportion of patients experiencing grade 3 or higher non-hematologic toxicities and infections assessed by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) [ Time Frame: Up to 11 years ] [ Designated as safety issue: Yes ]The proportion of patients experiencing grade 3 or higher non-hematologic toxicities and infections will be estimated.
- Relapse rate assessed by bone marrow analysis for leukemic blasts [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]Cumulative incidence estimates that account for competing events will be used to estimate relapse rate.
- Remission rate after 1 course of therapy [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
- Remission rate after 2 courses of therapy [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
- Serum concentrations of GVHD biomarkers [ Time Frame: Up to day 28 after SCT ] [ Designated as safety issue: No ]Logistic regression modeling will be used to assign individual weights to each individual biomarker and clinical variable to maximize sensitivity and specificity of a mathematical algorithm for the prediction of grade 2-4 GVHD occurring on or before day 56 post-SCT. It will be tested whether algorithms using the day 7, 14, or 28 biomarker panel, or a combination of the biomarker panels at these different time points are most useful for the prediction of GVHD. The different algorithms will be compared on the basis of maximal specificity and sensitivity using the Akaike information criterion.
- Shortening fraction/ejection fraction percentages and change over time [ Time Frame: Baseline to up to 11 years ] [ Designated as safety issue: No ]Analyzed by repeated measures analysis of variance accounting for dexrazoxane exposure and other clinically relevant covariates, including age, gender, body mass index, risk group, and treatment arm.
- Systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, time to maximum concentration [Tmax]½, area under curve [AUC]) [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]Descriptive statistics will be used to summarize the systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, Tmax½, AUC). If sufficient data is available, comparison to steady state pharmacokinetic data from ADVL0413 will be performed using Wilcoxon sign rank test. For plasma inhibitory assay (PIA)-PK correlations, a random effects linear regression model will be used to describe the relationship between PIA and PK levels for each of the trough plasma samples collected for each patient.
- Time to blood count recovery [ Time Frame: Up to 11 years ] [ Designated as safety issue: No ]Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery.
| Estimated Enrollment: | 1750 |
| Study Start Date: | June 2011 |
| Estimated Primary Completion Date: | June 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Induction I, Arm A
Patients receive cytarabine IT on day 1 and ADE chemotherapy comprising cytarabine IV over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
Experimental: Induction I, Arm C
Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate PO on days 11-28.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
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:
|
|
Experimental: Induction I, Arm D
Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
|
|
Experimental: 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 or IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
Experimental: Induction II, Arm A (LR patients)
Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
Experimental: Induction II, Arm C
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. Maintenance: Patients receive sorafenib tosylate PO starting on day 40-80 after completion of intensification II or SCT for one year. |
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
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:
|
|
Experimental: 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 or IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
|
|
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 6-33.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
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:
|
|
Experimental: 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 or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
|
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 7-34.
|
Drug: Cytarabine
Given IT or IV
Other Names:
Drug: Daunorubicin Hydrochloride
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
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:
|
|
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 IM on days 2 and 9.
|
Drug: Asparaginase
Given IM
Other Names:
Drug: Cytarabine
Given IT or IV
Other Names:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment
Other: Questionnaire Administration
Ancillary studies
|
Show Detailed Description
Eligibility| Ages Eligible for Study: | up to 29 Years (Child, Adult) |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01371981
Show 218 Study Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01371981
Show 218 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Richard Aplenc | Children's Oncology Group |
More Information
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01371981 History of Changes |
| Other Study ID Numbers: | NCI-2011-02670 NCI-2011-02670 COG-AAML1031 CDR0000701850 AAML1031 AAML1031 U10CA180886 U10CA098543 |
| Study First Received: | June 10, 2011 |
| Last Updated: | September 26, 2016 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Sarcoma, Myeloid Neoplasms by Histologic Type Neoplasms Sarcoma Neoplasms, Connective and Soft Tissue Sorafenib Etoposide phosphate Bortezomib Etoposide Cytarabine Mitoxantrone Daunorubicin |
Asparaginase Podophyllotoxin Niacinamide Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Vitamin B Complex Vitamins Micronutrients Growth Substances Physiological Effects of Drugs Antineoplastic Agents, Phytogenic Topoisomerase II Inhibitors Topoisomerase Inhibitors |
ClinicalTrials.gov processed this record on September 28, 2016