Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed Acute Myeloid Leukemia With or Without Mutations
|First Received Date ICMJE||June 10, 2011|
|Last Updated Date||October 21, 2013|
|Start Date ICMJE||June 2011|
|Estimated Primary Completion Date||June 2017 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Event-free survival [ 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.
|Original Primary Outcome Measures ICMJE
||Event-free survival [ Designated as safety issue: No ]|
|Change History||Complete list of historical versions of study NCT01371981 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Bortezomib and Sorafenib Tosylate in Patients With Newly Diagnosed Acute Myeloid Leukemia With or Without Mutations|
|Official Title ICMJE||A Phase III Randomized Trial for Patients With de Novo AML Using Bortezomib and Sorafenib (IND#114480; NSC# 681239, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD|
This randomized phase II/III trial studies how well bortezomib and sorafenib tosylate together works in treating patients with newly diagnosed acute myeloid leukemia with or without mutations. 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 more than one drug (combination chemotherapy) may kill more cancer cells. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.
I. To compare event-free survival (EFS) and overall survival (OS) of patients with de novo acute myeloid leukemia (AML) without high allelic ratio FLT3/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 COG-AAML0531.
IV. To determine the feasibility of administering sorafenib with standard chemotherapy and in a one year maintenance phase in patients with de novo high allelic ratio FLT3/ITD+ AML.
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 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), 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 wild type (WT)1, runt-related transcription factor (RUNX)1, mixed-lineage leukemia (MLL)-partial tandem duplication (PTD), tet methylcytosine dioxygenase (TET)2, c-CBL, KIT, and other novel AML-associated genes in pediatric AML.
XIV. To correlate the expression of CD74 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 FMS-like tyrosine kinase-3 (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 multicenter, dose-escalation study of sorafenib tosylate and an open-label randomized study. Patients are stratified according to disease risk (low vs high). Patients are randomized to 1 of 2 treatment arms or offered treatment on a third arm.
ARM A: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy comprising cytarabine intravenously (IV) over 1-30 minutes on days 1-10; daunorubicin IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5.
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.
ARM C (high-risk [HR] FLT3/ITD+ disease): Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A and sorafenib tosylate orally (PO) on days 11-28.
INDUCTION II: Patients without HR FLT3/ITD+ disease begin Induction II administration on day 29.
ARM A (low-risk [LR] patients): Patients receive cytarabine IT and ADE chemotherapy as in Induction I Arm A.
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.
ARM B (LR patients): Patients receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I Arm B.
ARM B (HR patients): Patients receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8.
ARM C (patients with HR FLT3/ITD+ disease, cohorts 1 and 2): Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 1-28.
Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 29). Patients with refractory disease are off protocol therapy.
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.
ARM B: Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and bortezomib IV on days 1, 4, and 8.
ARM C (cohorts 1 and 2): Patients receive cytarabine IT and AE chemotherapy in Intensification II, Arm A, and sorafenib tosylate PO on daily on days 1-28.
Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 29. Patients with refractory disease are off protocol therapy.
ARM A (LR): Patients receive cytarabine IT on day 1 and MA chemotherapy as in Induction II, Arm A (HR patients).
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.
ARMS A AND B (HR and no donor for SCT): Patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9.
ARM C (HR cohorts 1 and 2): Patients receive cytarabine IT on day 1, MA chemotherapy as in Induction II, Arm A (HR patients), and sorafenib tosylate PO on days 1-28.
STEM CELL TRANPLANTATION (SCT) (HR patients with matched family [MFD] or unrelated donor):
CONDITIONING REGIMEN: Patients receive fludarabine 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.
GRAFT-VS-HOST DISEASE (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 in Arm C receive sorafenib tosylate PO starting on day 40-80 after completion of intensification II or SCT for one year.
Blood, bone marrow, and tissue samples are collected at baseline and periodically during study for mutation and translocation analysis, cytogenetic/FISH analysis, gene and protein expression, and other studies. Some patients (aged 2 to 18 years) and/or parents may complete questionnaires about health-related quality of life (Pediatric Quality of Life (PedsQL) 4.0 Generic Core Scale, the PedsQL 3.0 Acute Cancer Module, and the PedsQL Multidimensional Fatigue Scale) and parental stress (Pediatric Inventory for Parents (PIP) scale) at baseline and periodically during the study and follow-up.
After completion of study therapy, patients are followed up monthly for 6 months, every 2 months for 6 months, every 3 months for 1 year, every 6 months for 1 year, and then yearly for up to 8 years.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||1250|
|Completion Date||Not Provided|
|Estimated Primary Completion Date||June 2017 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||up to 29 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Not Provided|
|Location Countries ICMJE||United States, Australia, Canada, New Zealand, Puerto Rico|
|NCT Number ICMJE||NCT01371981|
|Other Study ID Numbers ICMJE||NCI-2011-02670, NCI-2011-02670, COG-AAML1031, CDR0000701850, AAML1031, AAML1031, U10CA098543|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||National Cancer Institute (NCI)|
|Study Sponsor ICMJE||National Cancer Institute (NCI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Cancer Institute (NCI)|
|Verification Date||October 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP