Combination Chemotherapy With or Without Monoclonal Antibody Therapy in Treating Patients With AML Leukemia

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00049517
• Other study ID #: CDR0000258113
• Secondary ID: U10CA021115E1900
• Status: Completed
• Phase: Phase 3
• Start date: December 19, 2002
• Est. completion date: December 2019

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 657
• Est. completion date: December 2019
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Leukemia

Intervention

Biological:
• sargramostim
Given IV or as an injection

Drug:
• busulfan
Given IV
• cyclophosphamide
Given IV
• cytarabine
Given as a continuous infusion
• gemtuzumab ozogamicin (GO)
Given IV
• Daunorubicin
Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.

Procedure:
• Autologous HCT
Autologous hematopoietic cell transplantation
• Allogeneic HCT
Allogeneic hematopoietic cell transplantation

Locations

Country	Name	City	State
Israel	Rambam Medical Center	Haifa
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Aurora Presbyterian Hospital	Aurora	Colorado
United States	MeritCare Bemidji	Bemidji	Minnesota
United States	Billings Clinic - Downtown	Billings	Montana
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	St. Vincent Healthcare Cancer Care Services	Billings	Montana
United States	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama
United States	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus	Boca Raton	Florida
United States	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - West	Boca Raton	Florida
United States	Tufts-NEMC Cancer Center	Boston	Massachusetts
United States	Bozeman Deaconess Cancer Center	Bozeman	Montana
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	St. James Healthcare Cancer Care	Butte	Montana
United States	Aultman Cancer Center at Aultman Hospital	Canton	Ohio
United States	Mercy Cancer Center at Mercy Medical Center	Canton	Ohio
United States	Hematology and Oncology Associates	Chicago	Illinois
United States	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois
United States	Jewish Hospital Cancer Center	Cincinnati	Ohio
United States	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania
United States	CCOP - Colorado Cancer Research Program	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - St. Luke's Medical Center	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	St. Anthony Central Hospital	Denver	Colorado
United States	St. Joseph Hospital	Denver	Colorado
United States	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Swedish Medical Center	Englewood	Colorado
United States	Evanston Northwestern Healthcare - Evanston Hospital	Evanston	Illinois
United States	CCOP - MeritCare Hospital	Fargo	North Dakota
United States	MeritCare Broadway	Fargo	North Dakota
United States	Fort Wayne Medical Oncology and Hematology	Fort Wayne	Indiana
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado
United States	Great Falls Clinic	Great Falls	Montana
United States	Great Falls Clinic - Main Facility	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	St. Peter's Hospital	Helena	Montana
United States	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois
United States	Midwest Center for Hematology/Oncology	Joliet	Illinois
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Glacier Oncology, PLLC	Kalispell	Montana
United States	Kalispell Medical Oncology at KRMC	Kalispell	Montana
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois
United States	St. Rita's Medical Center	Lima	Ohio
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado
United States	McKee Medical Center	Loveland	Colorado
United States	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin
United States	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Saint Joseph's Hospital	Marshfield	Wisconsin
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota
United States	Community Medical Center	Missoula	Montana
United States	Guardian Oncology and Center for Wellness	Missoula	Montana
United States	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana
United States	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana
United States	La Grange Oncology Associates - Geneva	Naperville	Illinois
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois
United States	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois
United States	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania
United States	UPMC Cancer Centers	Pittsburgh	Pennsylvania
United States	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado
United States	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Cancer Center	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming
United States	Hematology Oncology Associates - Skokie	Skokie	Illinois
United States	Geisinger Medical Group - Scenery Park	State College	Pennsylvania
United States	North Suburban Medical Center	Thornton	Colorado
United States	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois
United States	CCOP - Carle Cancer Center	Urbana	Illinois
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Marshfield Clinic - Weston Center	Weston	Wisconsin
United States	Exempla Lutheran Medical Center	Wheat Ridge	Colorado
United States	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania
United States	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Eastern Cooperative Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Israel, 

References & Publications (6)

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

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

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 impro — View 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: — View 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 biomarker — View 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) clinic — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (Induction Phase)	Overall survival is defined as the time from randomization in the induction phase to death.	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.
Primary	Disease-free Survival (Consolidation Phase)	Disease-free survival is defined from the time of the confirmation of a complete remission via biopsy to the relapse of the disease.	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	Overall Survival (Consolidation Phase)	Overall survival is defined as the time from randomization in the consolidation phase to death.	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.

External Links

•   Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.