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
I. To compare event-free survival (EFS) and overall survival (OS) of patients with de novo
acute myeloid leukemia (AML) with or 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 combining sorafenib with standard chemotherapy 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 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 COG-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 AAML103P1 and
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
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
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 RT-PCR (e.g., t(8;21), inv(16), t(9;11), WT1
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 WT1, RUNX1,
MLL-PTD, TET2, c-CBL, KIT, and other novel AML-associated genes in pediatric AML.
XIV. To correlate the expression of CD74 antigen as well as 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 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.
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 IV over 15-30 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
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 15-30 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
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
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.
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
From the time on study to induction failure, relapse or death, up to 11 years
Children's Oncology Group
United States: Food and Drug Administration
|Baylor College of Medicine||Houston, Texas 77030|
|Johns Hopkins University||Baltimore, Maryland 21205|
|Cleveland Clinic Foundation||Cleveland, Ohio 44195|
|Roswell Park Cancer Institute||Buffalo, New York 14263|
|Children's Hospital of Philadelphia||Philadelphia, Pennsylvania 19104|
|University of Iowa Hospitals and Clinics||Iowa City, Iowa 52242|
|University of Mississippi Medical Center||Jackson, Mississippi 39216-4505|
|Washington University School of Medicine||Saint Louis, Missouri 63110|
|Medical University of South Carolina||Charleston, South Carolina 29425-0721|
|Rhode Island Hospital||Providence, Rhode Island 02903|
|Medical City Dallas Hospital||Dallas, Texas 75230|
|Midwest Children's Cancer Center||Milwaukee, Wisconsin 53226|
|Sinai Hospital of Baltimore||Baltimore, Maryland 21225|
|Bronson Methodist Hospital||Kalamazoo, Michigan 49007|
|Geisinger Medical Center||Danville, Pennsylvania 17822-0001|
|Loyola University Medical Center||Maywood, Illinois 60153|
|Morristown Memorial Hospital||Morristown, New Jersey 07962-1956|
|Loma Linda University Medical Center||Loma Linda, California 92354|
|Baptist Hospital of Miami||Miami, Florida 33176-2197|
|Newark Beth Israel Medical Center||Newark, New Jersey 07112|
|New York Medical College||Valhalla, New York 10595|
|Cedars-Sinai Medical Center||Los Angeles, California 90048|
|University of Arkansas for Medical Sciences||Little Rock, Arkansas 72205|
|Eastern Maine Medical Center||Bangor, Maine 04401|
|University of Nebraska Medical Center||Omaha, Nebraska 68198-3330|
|Hackensack University Medical Center||Hackensack, New Jersey 07601|
|Children's Hospital Los Angeles||Los Angeles, California 90027-0700|
|Broward General Medical Center||Fort Lauderdale, Florida 33316|
|All Children's Hospital||St. Petersburg, Florida 33701|
|Advocate Hope Children's Hospital||Oak Lawn, Illinois 60453|
|Ochsner Clinic Foundation||New Orleans, Louisiana 70121|
|Carolinas Medical Center||Charlotte, North Carolina 28232-2861|
|University of Oklahoma Health Sciences Center||Oklahoma City, Oklahoma 73104|
|Legacy Emanuel Hospital and Health Center||Portland, Oregon 97227|
|Driscoll Children's Hospital||Corpus Christi, Texas 78466|
|Scott and White Memorial Hospital||Temple, Texas 76508|
|Inova Fairfax Hospital||Falls Church, Virginia 22042-3300|
|Southern California Permanente Medical Group||Downey, California 90242|
|Children's Hospital Central California||Madera, California 93638-8762|
|Kosair Children's Hospital||Louisville, Kentucky 40202-3830|
|Children's Hospital Medical Center of Akron||Akron, Ohio 44308|
|University of Wisconsin Hospital and Clinics||Madison, Wisconsin 53792-0001|
|Overlook Hospital||Summit, New Jersey 07902-0220|
|Winthrop University Hospital||Mineola, New York 11501|
|Mount Sinai Medical Center||New York, New York 10029|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Methodist Children's Hospital of South Texas||San Antonio, Texas 78229-3993|
|Primary Children's Medical Center||Salt Lake City, Utah 84113-1100|
|Montefiore Medical Center||Bronx, New York 10467-2490|
|Children's Hospitals and Clinics of Minnesota - Minneapolis||Minneapolis, Minnesota 55404|
|University of New Mexico Cancer Center||Albuquerque, New Mexico 87131-5636|
|Nationwide Children's Hospital||Columbus, Ohio 43205-2696|
|Children's Hospital of Pittsburgh of UPMC||Pittsburgh, Pennsylvania 15213|
|Dell Children's Medical Center of Central Texas||Austin, Texas 78723|
|Children's Hospital and Research Center at Oakland||Oakland, California 94609-1809|
|Mary Bridge Children's Hospital and Health Center||Tacoma, Washington 98415-0299|
|Lehigh Valley Hospital - Muhlenberg||Bethlehem, Pennsylvania 18017|
|Presbyterian Hospital||Charlotte, North Carolina 28233-3549|
|Lee Memorial Health System||Fort Myers, Florida 33902|
|University of Alabama at Birmingham||Birmingham, Alabama 35294-3300|
|Children's Hospital of Alabama||Birmingham, Alabama 35233|
|Connecticut Children's Medical Center||Hartford, Connecticut 06106|
|Vanderbilt University||Nashville, Tennessee 37232-6305|
|University of North Carolina||Chapel Hill, North Carolina 27599|
|Duke University Medical Center||Durham, North Carolina 27710|
|University of Rochester||Rochester, New York 14642|
|Nemours Children's Clinic - Pensacola||Pensacola, Florida 32504|
|Helen DeVos Children's Hospital at Spectrum Health||Grand Rapids, Michigan 49503|
|Yale University||New Haven, Connecticut 06520|
|Mercy Children's Hospital||Toledo, Ohio 43608|
|Legacy Emanuel Children's Hospital||Portland, Oregon 97227|
|BI-LO Charities Children's Cancer Center||Greenville, South Carolina 29605|
|Dartmouth Hitchcock Medical Center||Lebanon, New Hampshire 03756|
|University Of Vermont||Burlington,, Vermont 05403|
|Albany Medical Center||Albany, New York 12208|
|University of Texas Southwestern Medical Center||Dallas, Texas|
|University of Kentucky||Lexington, Kentucky 40536-0098|
|UC Davis Comprehensive Cancer Center||Sacramento, California 95817|
|Oregon Health and Science University||Portland, Oregon 97201|
|Tulane University Health Sciences Center||New Orleans, Louisiana 70112|
|Virginia Commonwealth University||Richmond, Virginia|
|Florida Hospital||Orlando, Florida 32803|
|Memorial Health University Medical Center||Savannah, Georgia 31404|
|Seattle Children's Hospital||Seattle, Washington 98105|
|Wake Forest University Health Sciences||Winston-Salem, North Carolina 27157|
|Childrens Memorial Hospital||Chicago, Illinois 60614|
|Kaiser Permanente-Oakland||Oakland, California 94611|
|M D Anderson Cancer Center- Orlando||Orlando, Florida 32806|
|University of Hawaii||Honolulu, Hawaii 96813|
|Saint Luke's Mountain States Tumor Institute||Boise, Idaho 83712|
|Saint Vincent Hospital and Health Services||Indianapolis, Indiana 46260|
|Saint John Hospital and Medical Center||Detroit, Michigan 48236|
|Michigan State University - Breslin Cancer Center||East Lansing, Michigan 48824-1313|
|Saint John's Mercy Medical Center||Saint Louis, Missouri 63141|
|Nevada Cancer Research Foundation CCOP||Las Vegas, Nevada 89106|
|Saint Barnabas Medical Center||Livingston, New Jersey 07039|
|New York University Langone Medical Center||New York, New York 10016|
|Columbia University Medical Center||New York, New York 10032|
|State University of New York Upstate Medical University||Syracuse, New York 13210|
|Mission Hospitals Inc||Asheville, North Carolina 28801|
|Saint Vincent Hospital||Green Bay, Wisconsin 54301|
|University of Maryland Greenebaum Cancer Center||Baltimore, Maryland 21201|
|University of South Alabama||Mobile, Alabama 36693|
|University of Illinois||Chicago, Illinois 60612|
|Cook Children's Medical Center||Fort Worth, Texas 76104|
|Memorial Healthcare System - Joe DiMaggio Children's Hospital||Hollywood, Florida 33021|
|West Virginia University Charleston||Charleston, West Virginia 25304|
|The Children's Medical Center of Dayton||Dayton, Ohio 45404|
|Advocate Lutheran General Hospital||Park Ridge, Illinois 60068|
|University of Miami Miller School of Medicine-Sylvester Cancer Center||Miami, Florida 33136|
|University of Minnesota Medical Center-Fairview||Minneapolis, Minnesota 55455|
|Children's Oncology Group||Arcadia, California 91006-3776|
|C S Mott Children's Hospital||Ann Arbor, Michigan 48109|
|Southern Illinois University||Springfield, Illinois 62702|
|Riley Hospital for Children||Indianapolis, Indiana 46202|
|UMDNJ - Robert Wood Johnson University Hospital||New Brunswick, New Jersey 08903|
|Phoenix Childrens Hospital||Phoenix, Arizona 85016|
|Miller Children's Hospital||Long Beach, California 90806|
|Childrens Hospital of Orange County||Orange, California 92868-3874|
|Alfred I duPont Hospital for Children||Wilmington, Delaware 19803|
|Nemours Children's Clinic - Jacksonville||Jacksonville, Florida 32207-8426|
|Nemours Childrens Clinic - Orlando||Orlando, Florida 32806|
|Saint Joseph Children's Hospital of Tampa||Tampa, Florida 33607|
|Children's Healthcare of Atlanta - Egleston||Atlanta, Georgia 30322|
|The Childrens Mercy Hospital||Kansas City, Missouri 64108|
|Rainbow Babies and Childrens Hospital||Cleveland, Ohio 44106|
|Penn State Hershey Children's Hospital||Hershey, Pennsylvania 17033|
|Palmetto Health Richland||Columbia, South Carolina 29203|
|East Tennessee Childrens Hospital||Knoxville, Tennessee 37916|
|Children's Hospital and Medical Center of Omaha||Omaha, Nebraska 68114|
|Saint Joseph's Regional Medical Center||Paterson, New Jersey 07503|
|Childrens Hospital-King's Daughters||Norfolk, Virginia 23507|
|Georgia Health Sciences University||Augusta, Georgia 30912|
|Sanford Medical Center-Fargo||Fargo, North Dakota 58122|
|Children's Hospital Colorado||Aurora, Colorado 80045|
|Floating Hospital for Children at Tufts Medical Center||Boston, Massachusetts 02111|
|University of California San Francisco Medical Center-Parnassus||San Francisco, California 94143|
|Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center||Denver, Colorado 80218|
|Raymond Blank Children's Hospital||Des Moines, Iowa 50309|
|Children's Hospital-Main Campus||New Orleans, Louisiana 70118|
|The Toledo Hospital/Toledo Children's Hospital||Toledo, Ohio 43606|
|Sanford USD Medical Center - Sioux Falls||Sioux Falls, South Dakota 57117-5134|
|T C Thompson Children's Hospital||Chattanooga, Tennessee 37403|
|Providence Sacred Heart Medical Center and Children's Hospital||Spokane, Washington 99204|