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
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 Description
Primary Outcome:
- Event-free Survival (EFS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
- EFS for Patients on Arm C, Cohort 1
- EFS for Patients on Arm C, Cohort 2
- EFS for Patients on Arm C, Cohort 3
Secondary Outcome:
- Overall Survival (OS) for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
- OS for Patients on Arm C, Cohort 1
- OS for Patients on Arm C, Cohort 2
- OS for Patients on Arm C, Cohort 3
- Relapse Rate for Patients Without High Allelic Ratio FLT3/ITD+ Mutations
- Proportion of Patients Experiencing Grade 3 or Higher Non-hematologic Toxicities and Infections While on Protocol Therapy
- 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
- Total Scale Score From Parent-reported Pediatric Quality of Life Inventory Module
- Total Scale Score From Parent-reported Cancer Module
- Total Scale Score From Parent-reported Multidimensional Fatigue Scale Module
- Bortezomib Clearance
- Sorafenib Steady State Concentration
- Change in Shortening Fraction
- Change in Ejection Fraction
- Serum Concentrations of GVHD Biomarker
PRIMARY OBJECTIVES:
-
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.
- To determine the feasibility of combining bortezomib with standard chemotherapy in
patients with de novo AML.
- To compare the OS and EFS of high-risk patients treated with intensive Induction II with
historical controls from AAML03P1 and AAML0531.
-
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:
-
To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic
ratio FLT3/ITD+ AML.
- 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.
- 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.
- 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.
- To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy
and stem cell transplant (SCT) for AML.
- To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination
regimen.
- To obtain sorafenib and metabolite steady state pharmacokinetics and
pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib.
- To compare the changes in shortening fraction/ejection fraction over time between
patients treated with and without dexrazoxane.
- To refine the use of minimal-residual disease (MRD) detection with 4-color flow
cytometry.
- 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 tumour 1 [WT1] expression).
- To determine the leukemic involvement of the hematopoietic early progenitor cell and its
role in defining response to therapy.
- To define the leukemic stem cell population in patients with AML.
- 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.
- 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.
- To evaluate the changes in protein expression and unfolded protein response (UPR) in
patients with AML.
- To determine the expression level of wild-type FLT3, and correlate with outcome and in
vitro sensitivity to FLT3 inhibition.
- To collect biology specimens at diagnosis, treatment time points, and relapse for
future biology studies
- 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.
View this trial on ClinicalTrials.gov
