Clinical trial NCT00049517: Combination Chemotherapy With or Without Monoclonal Antibody Therapy in Treating Patients With AML Leukemia
Official title: A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: acute myeloid leukemia
autologous transplantation
gemtuzumab ozogamicin
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 657
Sex: ALL
Minimum age (years): 16
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving combination chemotherapy before a stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the transplanted stem cells. When the healthy stem cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. If the patient's stem cells are to be transplanted, the patient is also treated with a monoclonal antibody, such as gemtuzumab ozogamicin, to kill any remaining cancer cells or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without gemtuzumab ozogamicin followed by stem cell transplant in treating acute myeloid leukemia.

PURPOSE: This randomized phase III trial is studying combination chemotherapy, gemtuzumab ozogamicin, and stem cell transplant to see how well they work compared to combination chemotherapy and peripheral stem cell transplant alone in treating patients with acute myeloid leukemia.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival (Induction Phase)
timeFrame: 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.
measure: Disease-free Survival (Consolidation Phase)
timeFrame: Assessed during the first 4 months, then at least every three months for 2 years. then every six months until five years after study entry, and every 12 months thereafter.
Secondary outcomes:
measure: Overall Survival (Consolidation Phase)
timeFrame: Assessed during the first 4 months, then at least every three months for 2 years. then every six months until five years after study entry, and every 12 months thereafter.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Aurora
country: United States
facility: Aurora Presbyterian Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose Cancer Center at Penrose Hospital
state: Colorado
city: Denver
country: United States
facility: St. Anthony Central Hospital
state: Colorado
city: Denver
country: United States
facility: Porter Adventist Hospital
state: Colorado
city: Denver
country: United States
facility: Presbyterian - St. Luke's Medical Center
state: Colorado
city: Denver
country: United States
facility: St. Joseph Hospital
state: Colorado
city: Denver
country: United States
facility: Rose Medical Center
state: Colorado
city: Denver
country: United States
facility: CCOP - Colorado Cancer Research Program
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Grand Junction
country: United States
facility: St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
state: Colorado
city: Greeley
country: United States
facility: North Colorado Medical Center
state: Colorado
city: Lone Tree
country: United States
facility: Sky Ridge Medical Center
state: Colorado
city: Longmont
country: United States
facility: Hope Cancer Care Center at Longmont United Hospital
state: Colorado
city: Loveland
country: United States
facility: McKee Medical Center
state: Colorado
city: Pueblo
country: United States
facility: St. Mary - Corwin Regional Medical Center
state: Colorado
city: Thornton
country: United States
facility: North Suburban Medical Center
state: Colorado
city: Wheat Ridge
country: United States
facility: Exempla Lutheran Medical Center
state: Colorado
city: Boca Raton
country: United States
facility: Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - West
state: Florida
city: Boca Raton
country: United States
facility: Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus
state: Florida
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center - Miami
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Hematology and Oncology Associates
state: Illinois
city: Evanston
country: United States
facility: Evanston Northwestern Healthcare - Evanston Hospital
state: Illinois
city: Joliet
country: United States
facility: Midwest Center for Hematology/Oncology
state: Illinois
city: Joliet
country: United States
facility: Joliet Oncology-Hematology Associates, Limited - West
state: Illinois
city: Libertyville
country: United States
facility: North Shore Oncology and Hematology Associates, Limited - Libertyville
state: Illinois
city: Naperville
country: United States
facility: La Grange Oncology Associates - Geneva
state: Illinois
city: Niles
country: United States
facility: Cancer Care and Hematology Specialists of Chicagoland - Niles
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Lutheran General Cancer Care Center
state: Illinois
city: Skokie
country: United States
facility: Hematology Oncology Associates - Skokie
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center at Carle Foundation Hospital
state: Illinois
city: Urbana
country: United States
facility: CCOP - Carle Cancer Center
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Tufts-NEMC Cancer Center
state: Massachusetts
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Bemidji
country: United States
facility: MeritCare Bemidji
state: Minnesota
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy and Unity Cancer Center at Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Mercy and Unity Cancer Center at Unity Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology, PA - Maplewood
state: Minnesota
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
state: Minnesota
city: Robbinsdale
country: United States
facility: Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Cancer Center
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology, PA - Woodbury
state: Minnesota
city: Billings
country: United States
facility: CCOP - Montana Cancer Consortium
state: Montana
city: Billings
country: United States
facility: Hematology-Oncology Centers of the Northern Rockies - Billings
state: Montana
city: Billings
country: United States
facility: Northern Rockies Radiation Oncology Center
state: Montana
city: Billings
country: United States
facility: St. Vincent Healthcare Cancer Care Services
state: Montana
city: Billings
country: United States
facility: Billings Clinic - Downtown
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Cancer Center
state: Montana
city: Butte
country: United States
facility: St. James Healthcare Cancer Care
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic - Main Facility
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Helena
country: United States
facility: St. Peter's Hospital
state: Montana
city: Kalispell
country: United States
facility: Glacier Oncology, PLLC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Medical Oncology at KRMC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Regional Medical Center
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Missoula
country: United States
facility: Guardian Oncology and Center for Wellness
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Specialists at Montana Cancer Center
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
state: Montana
city: Bronx
country: United States
facility: Albert Einstein Cancer Center at Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: Fargo
country: United States
facility: CCOP - MeritCare Hospital
state: North Dakota
city: Fargo
country: United States
facility: MeritCare Broadway
state: North Dakota
city: Canton
country: United States
facility: Mercy Cancer Center at Mercy Medical Center
state: Ohio
city: Canton
country: United States
facility: Aultman Cancer Center at Aultman Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Jewish Hospital Cancer Center
state: Ohio
city: Lima
country: United States
facility: St. Rita's Medical Center
state: Ohio
city: Danville
country: United States
facility: Geisinger Cancer Institute at Geisinger Health
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center - Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers
state: Pennsylvania
city: State College
country: United States
facility: Geisinger Medical Group - Scenery Park
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Eau Claire
country: United States
facility: Marshfield Clinic Cancer Care at Regional Cancer Center
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Marshfield
country: United States
facility: Saint Joseph's Hospital
state: Wisconsin
city: Rhinelander
country: United States
facility: Ministry Medical Group at Saint Mary's Hospital
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Clinic - Weston Center
state: Wisconsin
city: Sheridan
country: United States
facility: Welch Cancer Center at Sheridan Memorial Hospital
state: Wyoming
city: Haifa
country: Israel
facility: Rambam Medical Center
Study officials:
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: Hugo F. Fernandez, MD
role: STUDY_CHAIR
References:
citation: Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1249-59. doi: 10.1056/NEJMoa0904544.
citation: Fernandez HF, Sun Z, Bennett JM, et al.: A single dose of gemtuzumab-ozogamicin (GO) in consolidation prior to autologous transplant for younger patients with newly diagnosed acute myeloid (AML) is safe but has no effect on disease free survival: interim results of Eastern Cooperative Oncology Group study (E1900). [Abstract] Biol Blood Marrow Transplant 14 (2): A-52, 21-2, 2008.
citation: Vance GH, Kim H, Hicks GA, Cherry AM, Higgins R, Hulshizer RL, Tallman MS, Fernandez HF, Dewald GW. Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900). Leuk Res. 2007 May;31(5):605-9. doi: 10.1016/j.leukres.2006.07.026. Epub 2006 Sep 22.
citation: Fernandez HF, Kim HT, Bennett JM, et al.: Gemtuzumab-ozogamicin (GO; mylotarg®) as part of consolidation therapy for AML before autograft: low incidence of hepatic veno-occlusive disease. [Abstract] Biol Blood Marrow Transplant 11 (2 Suppl 1): A-187, 2005.
citation: Gonen M, Sun Z, Figueroa ME, Patel JP, Abdel-Wahab O, Racevskis J, Ketterling RP, Fernandez H, Rowe JM, Tallman MS, Melnick A, Levine RL, Paietta E. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood. 2012 Sep 13;120(11):2297-306. doi: 10.1182/blood-2012-02-414425. Epub 2012 Aug 1.
citation: Fernandez HF, Sun Z, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald G, Ketterling RP, Rowe JM, Lazarus HM, Tallman MS. Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin. Blood. 2011 May 19;117(20):5306-13. doi: 10.1182/blood-2010-09-309229. Epub 2011 Mar 17.
citation: Luskin MR, Gimotty PA, Smith C, Loren AW, Figueroa ME, Harrison J, Sun Z, Tallman MS, Paietta EM, Litzow MR, Melnick AM, Levine RL, Fernandez HF, Luger SM, Carroll M, Master SR, Wertheim GB. A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia. JCI Insight. 2016 Jun 16;1(9):e87323. doi: 10.1172/jci.insight.87323.
citation: Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, Lazarus HM, Levine RL, Litzow MR, Paietta EM, Patel JP, Racevskis J, Rowe JM, Tallman MS, Sun Z, Luger SM. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016 Mar 24;127(12):1551-8. doi: 10.1182/blood-2015-07-657403. Epub 2016 Jan 11.
citation: Walter RB, Othus M, Paietta EM, Racevskis J, Fernandez HF, Lee JW, Sun Z, Tallman MS, Patel J, Gonen M, Abdel-Wahab O, Levine RL, Estey EH. Effect of genetic profiling on prediction of therapeutic resistance and survival in adult acute myeloid leukemia. Leukemia. 2015 Oct;29(10):2104-7. doi: 10.1038/leu.2015.76. Epub 2015 Mar 16. No abstract available.