Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01371981




Trial ID
NCT01371981
Ethics application status
Date submitted
10/06/2011
Date registered
10/06/2011
Date last updated
24/05/2018

Titles & IDs
Public title
Bortezomib and Sorafenib Tosylate in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Scientific 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
Secondary ID [1] 0 0
NCI-2011-02670
Secondary ID [2] 0 0
NCI-2011-02670
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Leukemia Cutis 0 0
Myeloid Neoplasm 0 0
Myeloid Sarcoma 0 0
Untreated Adult Acute Myeloid Leukemia 0 0
Untreated Childhood Myeloid Neoplasm 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Asparaginase
Treatment: Drugs - Bortezomib
Treatment: Drugs - Cytarabine
Treatment: Drugs - Daunorubicin Hydrochloride
Treatment: Drugs - Etoposide
Other interventions - Laboratory Biomarker Analysis
Treatment: Drugs - Mitoxantrone Hydrochloride
Other interventions - Pharmacological Study
Other interventions - Quality-of-Life Assessment
Other interventions - Questionnaire Administration
Treatment: Drugs - Sorafenib Tosylate

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.

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.

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.

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.

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.

Experimental: Induction II, Arm A (LR patients) - Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.

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.

Experimental: Induction II, Arm B (LR patients) - Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.

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.

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.

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.

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.

Experimental: Intensification II, Arm A (LR) - Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).

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.

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.

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.


Treatment: Drugs: Asparaginase
Given IM

Treatment: Drugs: Bortezomib
Given IV

Treatment: Drugs: Cytarabine
Given IT or IV

Treatment: Drugs: Daunorubicin Hydrochloride
Given IV

Treatment: Drugs: Etoposide
Given IV

Other interventions: Laboratory Biomarker Analysis
Correlative studies

Treatment: Drugs: Mitoxantrone Hydrochloride
Given IV

Other interventions: Pharmacological Study
Correlative studies

Other interventions: Quality-of-Life Assessment
Ancillary studies

Other interventions: Questionnaire Administration
Ancillary studies

Treatment: Drugs: Sorafenib Tosylate
Given PO

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
EFS for patients without high allelic ratio FLT3/ITD+ mutations
Timepoint [1] 0 0
From the time on study to induction failure, relapse or death, up to 11 years
Primary outcome [2] 0 0
EFS (Arm C, Cohort 1)
Timepoint [2] 0 0
From the time on study to induction failure, relapse or death, up to 11 years
Primary outcome [3] 0 0
EFS (Arm C, Cohort 2)
Timepoint [3] 0 0
From the time on study to induction failure, relapse or death, up to 11 years
Primary outcome [4] 0 0
EFS (Arm C, Cohort 3)
Timepoint [4] 0 0
From the time on study to induction failure, relapse or death, up to 11 years
Secondary outcome [1] 0 0
OS for patients without high allelic ratio FLT3/ITD+ mutations
Timepoint [1] 0 0
Up to 11 years
Secondary outcome [2] 0 0
OS (Arm C, Cohort 1)
Timepoint [2] 0 0
Up to 11 years
Secondary outcome [3] 0 0
OS (Arm C, Cohort 2)
Timepoint [3] 0 0
Up to 11 years
Secondary outcome [4] 0 0
OS (Arm C, Cohort 3)
Timepoint [4] 0 0
Up to 11 years
Secondary outcome [5] 0 0
Relapse rate assessed by bone marrow analysis for leukemic blasts
Timepoint [5] 0 0
Up to 11 years
Secondary outcome [6] 0 0
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)
Timepoint [6] 0 0
Up to 11 years
Secondary outcome [7] 0 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
Timepoint [7] 0 0
Up to 8 weeks
Secondary outcome [8] 0 0
Parent-reported questionnaire scores
Timepoint [8] 0 0
At 4 months following start of SCT or intensification II of chemotherapy
Secondary outcome [9] 0 0
Bortezomib pharmacokinetic plasma concentration-time profiles
Timepoint [9] 0 0
Day 8 of Induction II
Secondary outcome [10] 0 0
Systemic exposure of sorafenib tosylate and N-oxide metabolite for each course of induction and intensification (CL, Vd, time to maximum concentration [Tmax1/2, area under curve [AUC])
Timepoint [10] 0 0
Up to 4 months
Secondary outcome [11] 0 0
Shortening fraction/ejection fraction percentages and change over time
Timepoint [11] 0 0
Baseline to up to 11 years
Secondary outcome [12] 0 0
Serum concentrations of GVHD biomarkers
Timepoint [12] 0 0
Up to day 28 after SCT

Eligibility
Key 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
Minimum age
No limit
Maximum age
29 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [5] 0 0
Royal Children's Hospital-Brisbane - Herston
Recruitment hospital [6] 0 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [7] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [8] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
2310 - Hunter Regional Mail Centre
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4029 - Herston
Recruitment postcode(s) [5] 0 0
4101 - South Brisbane
Recruitment postcode(s) [6] 0 0
3052 - Parkville
Recruitment postcode(s) [7] 0 0
6008 - Perth
Recruitment outside Australia
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Alabama
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Arizona
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Arkansas
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California
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Colorado
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Connecticut
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Delaware
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District of Columbia
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Pennsylvania
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Rhode Island
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South Carolina
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Tennessee
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Texas
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Utah
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Vermont
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Alberta
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British Columbia
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Manitoba
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Newfoundland and Labrador
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Nova Scotia
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Ontario
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Quebec
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New Zealand
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Auckland
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Christchurch
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Puerto Rico
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San Juan

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01371981
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Richard Aplenc
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries