Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
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| ClinicalTrials.gov Identifier: NCT01371981 |
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Recruitment Status :
Active, not recruiting
First Posted : June 13, 2011
Results First Posted : July 7, 2020
Last Update Posted : April 5, 2021
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia Leukemia Cutis Myeloid Neoplasm Myeloid Sarcoma | 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 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 1645 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (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 |
| Actual Study Start Date : | June 20, 2011 |
| Actual Primary Completion Date : | March 31, 2019 |
| Estimated Study Completion Date : | September 30, 2027 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Familial acute myeloid leukemia with mutated CEBPA
Cytogenetically normal acute myeloid leukemia
Core binding factor acute myeloid leukemia
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A
See Detailed Description
|
Drug: Asparaginase
Given IM
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: Arm B
See Detailed Description
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Drug: Asparaginase
Given IM
Other Names:
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: Arm C (Cohort 1)
See Detailed Description
|
Drug: Asparaginase
Given IM
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 Drug: Sorafenib Tosylate Given PO
Other Names:
|
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Experimental: Arm C (Cohort 2)
See Detailed Description.
|
Drug: Asparaginase
Given IM
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 Drug: Sorafenib Tosylate Given PO
Other Names:
|
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Experimental: Arm C (Cohort 3)
See Detailed Description. Different dose.
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Drug: Asparaginase
Given IM
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 Drug: Sorafenib Tosylate Given PO
Other Names:
|
|
Experimental: Arm D
See Detailed Description. May reassigned to 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 Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- 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.
Secondary Outcome Measures :
- 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.
Other Outcome Measures:
- 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.
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| Ages Eligible for Study: | up to 29 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients must be newly diagnosed with de novo acute myelogenous leukemia
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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
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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:
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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
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01371981
Locations
Show 220 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Richard Aplenc | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by National Cancer Institute (NCI):
Documents provided by National Cancer Institute (NCI):
Study Protocol and Statistical Analysis Plan [PDF] April 24, 2017
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01371981 |
| Other Study ID Numbers: |
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 ) |
| First Posted: | June 13, 2011 Key Record Dates |
| Results First Posted: | July 7, 2020 |
| Last Update Posted: | April 5, 2021 |
| Last Verified: | January 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
Additional relevant MeSH terms:
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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Sarcoma, Myeloid Neoplasms by Histologic Type Neoplasms Sarcoma Neoplasms, Connective and Soft Tissue Cytarabine Etoposide Podophyllotoxin Daunorubicin Mitoxantrone Bortezomib Etoposide phosphate |
Sorafenib Asparaginase Antineoplastic Agents, Phytogenic Antineoplastic Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antimetabolites Antiviral Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |