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A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation


Phase 3
16 Years
60 Years
Open (Enrolling)
Both
Leukemia

Thank you

Trial Information

A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation


OBJECTIVES:

- To compare the overall survival (OS) between two induction regimens (standard versus
dose intense daunorubicin and cytarabine) in patients with de novo AML.

- To compare disease-free survival (DFS) between two consolidation regimens.

- To compare overall survival between two consolidation regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
induction therapy (standard-dose daunorubicin vs high-dose daunorubicin).

- Induction therapy: Patients are randomized to 1 of 2 induction arms.

- Standard: Patients receive standard-dose daunorubicin IV over 10-15 minutes on
days 1-3 and cytarabine IV continuously on days 1-7.

- High dose: Patients receive high-dose daunorubicin IV over 10-15 minutes on days
1-3 and cytarabine as in arm I.

Patients in both arms may receive a second course of induction therapy if complete remission
(CR) is not achieved after the first course. The second course is administered as in arm I
to all patients. Patients who don't achieve CR after 2 courses of induction therapy are
removed from study.

Patients who achieve CR after induction therapy proceed to post-remission therapy with
EITHER allogeneic transplantation only (on or off study) OR consolidation therapy and
autologous transplantation (on study), according to risk status and donor status.

Patients who are considered at intermediate or high risk for relapse (unfavorable
cytogenetics/high WBC) and have a suitable related donor undergo an allogeneic
transplantation. Patients with intermediate-risk cytogenetics, WBC no greater than
100,000/mm^3, and appropriate donors have the option of undergoing allogeneic
transplantation.

- Allogeneic transplantation: Within 1-3 months after recovery from induction therapy,
patients receive busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV
over 4 hours on days -3 and -2. Allogeneic bone marrow or peripheral blood stem cells
(PBSCs) are infused on day 0. Patients receive graft-vs-host disease (GVHD) prophylaxis
comprising cyclosporine IV over 1-4 hours beginning on day -1 and then orally (when
tolerated) twice daily until day 180. Alternatively, patients may receive tacrolimus IV
over 24 hours beginning on day -1 and then orally twice daily until day 180. Patients
also receive methotrexate IV on days 1, 3, 6, and 11.

Patients who do not meet the criteria for allogeneic transplantation (i.e., are favorable
risk or do not have a matching related donor) or who opt not to undergo allogeneic
transplantation proceed to consolidation therapy followed by randomization to 1 of 2
autologous transplantation arms.

- Consolidation therapy: Beginning 2-8 weeks after recovery from induction therapy,
patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 1, 3, and
5. A second course is administered 3 weeks after blood recovery. Patients receive
filgrastim (G-CSF) subcutaneously (SC) daily for 4 days and then autologous PBSCs are
harvested by leukapheresis.

- Autologous stem cell transplantation: Patients are randomized to 1 of 2 autologous
transplantation arms.

- Arm I: Within 1 month after PBSC collection, patients receive conditioning
comprising busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV over
2 hours on days -3 and -2. Patients then undergo autologous PBSC transplantation
on day 0. Patients receive sargramostim (GM-CSF) or G-CSF IV or SC beginning on
day 0 and continuing until blood counts recover.

- Arm II (closed to accrual as of 10/4/2007): Within 2-4 weeks after PBSC
collection, patients receive gemtuzumab ozogamicin IV over 2 hours on day 1 and
GM-CSF SC or IV beginning on day 10 and continuing until blood counts recover.
Within 2-3 weeks after blood count recovery, patients receive conditioning and
undergo autologous PBSC transplantation as in arm I.

Patients are followed monthly for 1 year, every 2 months for 1 year, and then every 3 months
for up to 7 years.

ACTUAL ACCRUAL: A total of 657 patients were accrued for this study.


Inclusion Criteria:



- Morphologically confirmed acute myeloid leukemia (AML) (greater than 20% blasts in
the peripheral blood or marrow) meeting any of the following criteria:

- Recurrent cytogenetic translocations

- t(8;21)(q22;q22)

- Bone marrow eosinophil abnormalities

- inv(16)(p13;q22)

- t(16;16)(p13;q22)

- 11q23 abnormalities

- Multilineage dysplasia without presence of myelodysplastic syndromes (MDS)

- Minimally differentiated AML

- AML without maturation

- AML with maturation

- AML not otherwise categorized

- Acute myelomonocytic leukemia

- Acute monocytic leukemia

- Acute erythroid leukemia

- Acute megakaryocytic leukemia

- Acute basophilic leukemia

- Patients undergoing allogeneic transplantation must have a sibling donor match
defined as human leukocyte antigen (HLA) match or haplotype match with one locus
mismatch on other haplotype

- Age 16 to 60

- Eastern Cooperative Oncology Group (ECOG) performance status 0-4

- Aspartate aminotransferase (AST) less than 4 times upper limit of normal (ULN)

- Alkaline phosphatase less than 4 times ULN

- Creatinine no greater than 2.0 mg/dL

- Creatinine clearance at least 50 mL/min

- Left ventricular ejection fraction (LVEF) at least 45% by post-induction multigated
acquisition (MUGA) scan

- Negative pregnancy test

- Fertile patients must use effective contraception

- HIV negative

- Prior hydroxyurea allowed

- Prior corticosteroids allowed

Exclusion Criteria:

- Recurrent cytogenetic translocations

- Acute promyelocytic leukemia (PML) with t(15;17)(q22;q21)

- Variant acute PML with t(v;17)

- Multilineage dysplasia with prior MDS

- Acute panmyelosis with myelofibrosis

- Blastic transformation of chronic myelogenous leukemia

- Secondary AML (chemotherapy-induced or evolved from MDS)

- Pregnant or nursing

- Bilirubin greater than 2.0 mg/dL (unless related to Gilbert's syndrome or
hemolysis)

- Significant cardiac disease requiring active therapy (e.g., digoxin, diuretics,
antiarrhythmics, or antianginal medications)

- Prior biologic therapy

- Prior cytotoxic chemotherapy for any malignancy

- Prior radiotherapy for any malignancy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Survival (Induction Phase)

Outcome Description:

Overall survival is defined as the time from randomization in the induction phase to death.

Outcome Time Frame:

Assessed during the first 4 months, then at least every three months for 2 years. then every six months until 5 years after study entry and every 12 months thereafter.

Safety Issue:

No

Principal Investigator

Hugo F. Fernandez, MD

Investigator Role:

Study Chair

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute

Authority:

United States: Federal Government

Study ID:

CDR0000258113

NCT ID:

NCT00049517

Start Date:

December 2002

Completion Date:

October 2016

Related Keywords:

  • Leukemia
  • acute myeloid leukemia
  • autologous transplantation
  • gemtuzumab ozogamicin
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Mayo Clinic ScottsdaleScottsdale, Arizona  85259
Mayo Clinic Cancer CenterRochester, Minnesota  55905
CCOP - Carle Cancer CenterUrbana, Illinois  61801
CCOP - Metro-MinnesotaSaint Louis Park, Minnesota  55416
Aurora Presbyterian HospitalAurora, Colorado  80012
Penrose Cancer Center at Penrose HospitalColorado Springs, Colorado  80933
CCOP - Colorado Cancer Research ProgramDenver, Colorado  80224-2522
Porter Adventist HospitalDenver, Colorado  80210
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
St. Joseph HospitalDenver, Colorado  80218
Rose Medical CenterDenver, Colorado  80220
Swedish Medical CenterEnglewood, Colorado  80110
St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical CenterGrand Junction, Colorado  81502
Sky Ridge Medical CenterLone Tree, Colorado  80124
Hope Cancer Care Center at Longmont United HospitalLongmont, Colorado  80502
St. Mary - Corwin Regional Medical CenterPueblo, Colorado  81004
North Suburban Medical CenterThornton, Colorado  80229
Evanston Northwestern Healthcare - Evanston HospitalEvanston, Illinois  60201-1781
Joliet Oncology-Hematology Associates, Limited - WestJoliet, Illinois  60435
Carle Cancer Center at Carle Foundation HospitalUrbana, Illinois  61801
Tufts-NEMC Cancer CenterBoston, Massachusetts  02111
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
MeritCare BemidjiBemidji, Minnesota  56601
Fairview Ridges HospitalBurnsville, Minnesota  55337
Mercy and Unity Cancer Center at Mercy HospitalCoon Rapids, Minnesota  55433
Fairview Southdale HospitalEdina, Minnesota  55435
Mercy and Unity Cancer Center at Unity HospitalFridley, Minnesota  55432
Minnesota Oncology Hematology, PA - MaplewoodMaplewood, Minnesota  55109
Virginia Piper Cancer Institute at Abbott - Northwestern HospitalMinneapolis, Minnesota  55407
Hubert H. Humphrey Cancer Center at North Memorial Outpatient CenterRobbinsdale, Minnesota  55422-2900
Park Nicollet Cancer CenterSt. Louis Park, Minnesota  55416
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Minnesota Oncology Hematology, PA - WoodburyWoodbury, Minnesota  55125
MeritCare BroadwayFargo, North Dakota  58122
CCOP - MeritCare HospitalFargo, North Dakota  58122
Aultman Cancer Center at Aultman HospitalCanton, Ohio  44710-1799
Mercy Cancer Center at Mercy Medical CenterCanton, Ohio  44708
Jewish Hospital Cancer CenterCincinnati, Ohio  45236
St. Rita's Medical CenterLima, Ohio  45801
Penn State Cancer Institute at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033-0850
Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283
Geisinger Medical Group - Scenery ParkState College, Pennsylvania  16801
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical CenterWilkes-Barre, Pennsylvania  18711
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical CenterLa Crosse, Wisconsin  54601
University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadison, Wisconsin  53792-6164
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
CCOP - Montana Cancer ConsortiumBillings, Montana  59101
Great Falls ClinicGreat Falls, Montana  59405
University of Florida Shands Cancer CenterGainesville, Florida  32610-0232
Winship Cancer Institute of Emory UniversityAtlanta, Georgia  30322
Albert Einstein Cancer Center at Albert Einstein College of MedicineBronx, New York  10461
NYU Cancer Institute at New York University Medical CenterNew York, New York  10016
North Colorado Medical CenterGreeley, Colorado  80631
McKee Medical CenterLoveland, Colorado  80539
Northern Rockies Radiation Oncology CenterBillings, Montana  59101
Hematology-Oncology Centers of the Northern Rockies - BillingsBillings, Montana  59101
St. Peter's HospitalHelena, Montana  59601
Kalispell Regional Medical CenterKalispell, Montana  59901
Glacier Oncology, PLLCKalispell, Montana  59901
Montana Cancer Center at St. Patrick Hospital and Health Sciences CenterMissoula, Montana  59802
Montana Cancer Specialists at Montana Cancer CenterMissoula, Montana  59802
Community Medical CenterMissoula, Montana  59801
Advocate Lutheran General Cancer Care CenterPark Ridge, Illinois  60068-1174
Indiana University Melvin and Bren Simon Cancer CenterIndianapolis, Indiana  46202-5289
Geisinger Cancer Institute at Geisinger HealthDanville, Pennsylvania  17822-0001
Virginia Commonwealth University Massey Cancer CenterRichmond, Virginia  23298-0037
Robert H. Lurie Comprehensive Cancer Center at Northwestern UniversityChicago, Illinois  60611
Fox Chase Cancer Center - PhiladelphiaPhiladelphia, Pennsylvania  19111-2497
Hematology Oncology Associates - SkokieSkokie, Illinois  60076
UPMC Cancer CentersPittsburgh, Pennsylvania  15232
Hematology and Oncology AssociatesChicago, Illinois  60611
Midwest Center for Hematology/OncologyJoliet, Illinois  60432
North Shore Oncology and Hematology Associates, Limited - LibertyvilleLibertyville, Illinois  60048
Fort Wayne Medical Oncology and HematologyFort Wayne, Indiana  46815
Welch Cancer Center at Sheridan Memorial HospitalSheridan, Wyoming  82801
St. Anthony Central HospitalDenver, Colorado  80204-1335
Exempla Lutheran Medical CenterWheat Ridge, Colorado  80033
University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136
La Grange Oncology Associates - GenevaNaperville, Illinois  60563
Cancer Care and Hematology Specialists of Chicagoland - NilesNiles, Illinois  60714
Billings Clinic - DowntownBillings, Montana  59107-7000
Bozeman Deaconess Cancer CenterBozeman, Montana  59715
St. James Healthcare Cancer CareButte, Montana  59701
Great Falls Clinic - Main FacilityGreat Falls, Montana  59405
Kalispell Medical Oncology at KRMCKalispell, Montana  59901
Marshfield Clinic Cancer Care at Regional Cancer CenterEau Claire, Wisconsin  54701
Saint Joseph's HospitalMarshfield, Wisconsin  54449
Ministry Medical Group at Saint Mary's HospitalRhinelander, Wisconsin  54501
Marshfield Clinic - Weston CenterWeston, Wisconsin  54476
Lurleen Wallace Comprehensive Cancer at University of Alabama - BirminghamBirmingham, Alabama  35294
Guardian Oncology and Center for WellnessMissoula, Montana  59804
St. Vincent Healthcare Cancer Care ServicesBillings, Montana  59101
Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main CampusBoca Raton, Florida  33486
Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - WestBoca Raton, Florida  33428