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

• Sponsor: Eastern Cooperative Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00049517
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 657
• Locations: 99
• Arms: 6
• Actual Duration (Months): 204
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: sargramostim; Drug: busulfan; Drug: cyclophosphamide; Drug: cytarabine; Drug: gemtuzumab ozogamicin (GO); Drug: Daunorubicin; Procedure: Autologous HCT; Procedure: Allogeneic HCT	Phase 3

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

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 657 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial in Adult Acute Myeloid Leukemia: Daunorubicin Dose-Intensification Prior to Risk-Allocated Autologous Stem Cell Transplantation
• Actual Study Start Date: Dec 1, 2002
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Standard Daunorubicin Then Autologous HCT Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Biological: sargramostim; Given IV or as an injection; Other Names: Leukine ; Drug: busulfan; Given IV; Other Names: Myleran ; Drug: cyclophosphamide; Given IV; Other Names: Endoxan Cytoxan Neosar Procytox Revimmune cytophosphane ; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Experimental: High-dose Daunorubicin Then Autologous HCT Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Biological: sargramostim; Given IV or as an injection; Other Names: Leukine ; Drug: busulfan; Given IV; Other Names: Myleran ; Drug: cyclophosphamide; Given IV; Other Names: Endoxan Cytoxan Neosar Procytox Revimmune cytophosphane ; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Experimental: Standard Daunorubicin Then GO/Autologous HCT Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Biological: sargramostim; Given IV or as an injection; Other Names: Leukine ; Drug: busulfan; Given IV; Other Names: Myleran ; Drug: cyclophosphamide; Given IV; Other Names: Endoxan Cytoxan Neosar Procytox Revimmune cytophosphane ; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: gemtuzumab ozogamicin (GO); Given IV; Other Names: Mylotarg ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Experimental: High-dose Daunorubicin Then GO/Autologous HCT Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Biological: sargramostim; Given IV or as an injection; Other Names: Leukine ; Drug: busulfan; Given IV; Other Names: Myleran ; Drug: cyclophosphamide; Given IV; Other Names: Endoxan Cytoxan Neosar Procytox Revimmune cytophosphane ; Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: gemtuzumab ozogamicin (GO); Given IV; Other Names: Mylotarg ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Autologous HCT; Autologous hematopoietic cell transplantation; Other Names: Autologous hematopoietic cell transplantation
Active Comparator: Standard Daunorubicin Then Allogeneic HCT or no Consolidation Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available.	Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Allogeneic HCT; Allogeneic hematopoietic cell transplantation; Other Names: Allogeneic hematopoietic cell transplantation
Experimental: High-dose Daunorubicin Then Allogeneic HCT or no Consolidation Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available.	Drug: cytarabine; Given as a continuous infusion; Other Names: cytosine arabinoside ; Drug: Daunorubicin; Given intravenously daily for 3 days at a dose of either 45 or 90 mg/m2.; Other Names: daunomycin daunomycin cerubidine ; Procedure: Allogeneic HCT; Allogeneic hematopoietic cell transplantation; Other Names: Allogeneic hematopoietic cell transplantation

Outcome Measures

Primary Outcome Measures

1. Overall Survival (Induction Phase) [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.]

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

2. Disease-free Survival (Consolidation Phase) [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.]

   Disease-free survival is defined from the time of the confirmation of a complete remission via biopsy to the relapse of the disease.

Secondary Outcome Measures

1. Overall Survival (Consolidation Phase) [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.]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama	United States	35294
2	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
3	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
4	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
5	St. Anthony Central Hospital	Denver	Colorado	United States	80204
6	Porter Adventist Hospital	Denver	Colorado	United States	80210
7	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
8	St. Joseph Hospital	Denver	Colorado	United States	80218
9	Rose Medical Center	Denver	Colorado	United States	80220
10	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224-2522
11	Swedish Medical Center	Englewood	Colorado	United States	80110
12	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado	United States	81502
13	North Colorado Medical Center	Greeley	Colorado	United States	80631
14	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
15	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80502
16	McKee Medical Center	Loveland	Colorado	United States	80539
17	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
18	North Suburban Medical Center	Thornton	Colorado	United States	80229
19	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
20	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - West	Boca Raton	Florida	United States	33428
21	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus	Boca Raton	Florida	United States	33486
22	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
23	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
24	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
25	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
26	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
27	Evanston Northwestern Healthcare - Evanston Hospital	Evanston	Illinois	United States	60201-1781
28	Midwest Center for Hematology/Oncology	Joliet	Illinois	United States	60432
29	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois	United States	60435
30	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois	United States	60048
31	La Grange Oncology Associates - Geneva	Naperville	Illinois	United States	60563
32	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois	United States	60714
33	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois	United States	60068-1174
34	Hematology Oncology Associates - Skokie	Skokie	Illinois	United States	60076
35	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois	United States	61801
36	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
37	Fort Wayne Medical Oncology and Hematology	Fort Wayne	Indiana	United States	46815
38	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
39	Tufts-NEMC Cancer Center	Boston	Massachusetts	United States	02111
40	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
41	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
42	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
43	MeritCare Bemidji	Bemidji	Minnesota	United States	56601
44	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
45	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
46	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
47	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
48	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
49	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
50	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
51	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
52	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
53	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
54	United Hospital	Saint Paul	Minnesota	United States	55102
55	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
56	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
57	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
58	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59101
59	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
60	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
61	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
62	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
63	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
64	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
65	Great Falls Clinic	Great Falls	Montana	United States	59405
66	St. Peter's Hospital	Helena	Montana	United States	59601
67	Glacier Oncology, PLLC	Kalispell	Montana	United States	59901
68	Kalispell Medical Oncology at KRMC	Kalispell	Montana	United States	59901
69	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
70	Community Medical Center	Missoula	Montana	United States	59801
71	Guardian Oncology and Center for Wellness	Missoula	Montana	United States	59804
72	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana	United States	59807-7877
73	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
74	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
75	NYU Cancer Institute at New York University Medical Center	New York	New York	United States	10016
76	CCOP - MeritCare Hospital	Fargo	North Dakota	United States	58122
77	MeritCare Broadway	Fargo	North Dakota	United States	58122
78	Mercy Cancer Center at Mercy Medical Center	Canton	Ohio	United States	44708
79	Aultman Cancer Center at Aultman Hospital	Canton	Ohio	United States	44710-1799
80	Jewish Hospital Cancer Center	Cincinnati	Ohio	United States	45236
81	St. Rita's Medical Center	Lima	Ohio	United States	45801
82	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
83	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
84	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283
85	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
86	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
87	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
88	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
89	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838
90	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
91	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin	United States	54701
92	Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
93	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
94	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
95	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
96	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
97	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
98	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming	United States	82801
99	Rambam Medical Center	Haifa		Israel	31096

Sponsors and Collaborators

• Eastern Cooperative Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Hugo F. Fernandez, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Eastern Cooperative Oncology Group
• ClinicalTrials.gov Identifier: NCT00049517
• Other Study ID Numbers: CDR0000258113; U10CA021115; E1900
• First Posted: Jan 27, 2003
• Last Update Posted: Nov 17, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eastern Cooperative Oncology Group: acute myeloid leukemia; autologous transplantation; gemtuzumab ozogamicin
• Additional relevant MeSH terms: Leukemia; Cytarabine; Cyclophosphamide; Busulfan; Daunorubicin; Gemtuzumab; Sargramostim

Study Results

Participant Flow

Recruitment Details	From December 2002 through November 2008, a total of 657 patients were enrolled in the study.

Arm/Group Title	Standard Daunorubicin Then Autologous HCT	High-dose Daunorubicin Then Autologous HCT	Standard Daunorubicin Then GO/Autologous HCT	High-dose Daunorubicin Then GO/Autologous HCT	Standard Daunorubicin Then Allogeneic HCT or no Consolidation	High-dose Daunorubicin Then Allogeneic HCT or no Consolidation
Arm/Group Description	Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. The patients undergoing autologous hematopoietic cell transplantation (HCT) received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses (without pharmacokinetic sampling) followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Before initiating consolidation therapy, patients with CR were randomized to a standard or an investigational arm. All patients received 2 cycles of high-dose cytarabine therapy (3 g/m2 given IV over a 3-hour period every 12 hours every other day for a total of 6 doses), followed by sargramostim 250 μg/m2 until recovery of blood counts. patients randomized to the investigational arm received a single dose of Gemtuzumab ozogamicin (GO) at 6 mg/m2 followed by sargramostim 250 μ/m2 until recovery of counts. The patients undergoing autologous HCT received intravenous busulfan 0.8 mg/kg every 6 hours for 16 doses followed by intravenous cyclophosphamide 60 mg/kg daily for 2 days.	Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available.	Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Consolidation/Transplant: Patients without CR did not receive any consolidation treatment. Patients in CR with an unfavorable cytogenetic profile or an initial white blood cell count > 100,000/μL were to proceed to allogeneic HCT if they had a suitable human leukocyte antigen (HLA)-matched sibling donor available.
Period Title: Induction
STARTED	79	90	63	75	188	162
Treated	79	90	63	75	186	160
COMPLETED	79	90	63	75	128	108
NOT COMPLETED	0	0	0	0	60	54
Period Title: Induction
STARTED	79	90	63	75	21	24
Randomized to Autologous HCT +/- GO	59	73	63	75	0	0
COMPLETED	27	40	25	32	15	18
NOT COMPLETED	52	50	38	43	6	6

Baseline Characteristics

Arm/Group Title	Standard Daunorubicin (Induction Therapy)	High Dose Daunorubicin (Induction Therapy)	Total
Arm/Group Description	Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course.	Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine as in arm I. Patients may receive a second course of induction therapy if CR is not achieved after the first course. The second course is administered as in arm I.	Total of all reporting groups
Overall Participants	330	327	657
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47	48	48
Sex: Female, Male (Count of Participants)
Female	158 47.9%	164 50.2%	322 49%
Male	172 52.1%	163 49.8%	335 51%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (Induction Phase)
Description	Overall survival is defined as the time from randomization in the induction phase to death.
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.

Outcome Measure Data

Analysis Population Description

All randomized patients are included in the analysis (intention-to-treat).

Arm/Group Title	Standard Daunorubicin	High-dose Daunorubicin
Arm/Group Description	Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Patients with CR received consolidation treatment thereafter.	Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Patients with CR received consolidation treatment thereafter.
Measure Participants	330	327
Median (95% Confidence Interval) [months]	15.7	23.7

2. Primary Outcome

Title	Disease-free Survival (Consolidation Phase)
Description	Disease-free survival is defined from the time of the confirmation of a complete remission via biopsy to the relapse of the disease.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Only 270 patients who were randomized in the consolidation phase are included in the analysis.

Arm/Group Title	Autologous HCT	Go/Autologous HCT
Arm/Group Description	Patients with CR in the induction phase were randomized to receive autologous HCT or GO/autologous HCT.	Patients with CR in the induction phase were randomized to receive autologous HCT or GO/autologous HCT.
Measure Participants	132	138
Median (95% Confidence Interval) [Months]	15.0	13.6

3. Secondary Outcome

Title	Overall Survival (Consolidation Phase)
Description	Overall survival is defined as the time from randomization in the consolidation phase to death.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Only 270 patients who were randomized in the consolidation phase are included in the analysis.

Arm/Group Title	Autologous HCT	Go/Autologous HCT
Arm/Group Description	Patients with CR in the induction phase were randomized to receive autologous HCT or GO/autologous HCT.	Patients with CR in the induction phase were randomized to receive autologous HCT or GO/autologous HCT.
Measure Participants	132	138
Median (95% Confidence Interval) [Months]	35.5	27.9

Adverse Events

Time Frame	Assessed weekly while on treatment and for 30 days after the end of treatment.
Arm/Group Title	Standard Daunorubicin (Induction Therapy)		High Dose Daunorubicin (Induction Therapy)
Arm/Group Description	Induction: Patients receive standard-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine IV continuously on days 1-7. Patients may receive a second course of induction therapy if complete remission (CR) is not achieved after the first course. Conditioning/Transplant: 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 peripheral blood stem cell (PBSC) transplantation on day 0. Patients receive sargramostim (GM-CSF) or filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 0 and continuing until blood counts recover.		Induction: Patients receive high-dose daunorubicin IV over 10-15 minutes on days 1-3 and cytarabine as in arm I. Patients may receive a second course of induction therapy if CR is not achieved after the first course. The second course is administered as in arm I. Conditioning/Transplant: 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.
All Cause Mortality
	Standard Daunorubicin (Induction Therapy)		High Dose Daunorubicin (Induction Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Daunorubicin (Induction Therapy)		High Dose Daunorubicin (Induction Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	328/328 (100%)		325/325 (100%)
Blood and lymphatic system disorders
Anemia	257/328 (78.4%)		251/325 (77.2%)
Hemolysis	1/328 (0.3%)		0/325 (0%)
Leukopenia	320/328 (97.6%)		323/325 (99.4%)
Lymphopenia	3/328 (0.9%)		4/325 (1.2%)
Neutropenia	319/328 (97.3%)		305/325 (93.8%)
Thrombocytopenia	321/328 (97.9%)		321/325 (98.8%)
Transfusion platelets	199/328 (60.7%)		206/325 (63.4%)
Transfusion: PRBCS	197/328 (60.1%)		191/325 (58.8%)
Hematologic-other	1/328 (0.3%)		0/325 (0%)
Hypertension	5/328 (1.5%)		2/325 (0.6%)
Hypotension	9/328 (2.7%)		12/325 (3.7%)
Thrombosis	4/328 (1.2%)		2/325 (0.6%)
Weight gain	1/328 (0.3%)		0/325 (0%)
DIC	5/328 (1.5%)		2/325 (0.6%)
Bilirubin Increased	13/328 (4%)		15/325 (4.6%)
Hypoalbuminemia	5/328 (1.5%)		3/325 (0.9%)
AST increased	3/328 (0.9%)		4/325 (1.2%)
ALT Increased	10/328 (3%)		5/325 (1.5%)
Febrile neutropenia	121/328 (36.9%)		117/325 (36%)
Hypokalemia	0/328 (0%)		1/325 (0.3%)
CNS hemorrhage	2/328 (0.6%)		1/325 (0.3%)
Petechiae	5/328 (1.5%)		2/325 (0.6%)
Cardiac disorders
Sinus Tachycardia	0/328 (0%)		2/325 (0.6%)
Supraventricular arrhythmias	1/328 (0.3%)		6/325 (1.8%)
Ventricular arrthhmia	1/328 (0.3%)		2/325 (0.6%)
Arrhythmia-other	0/328 (0%)		1/325 (0.3%)
Acute Vascular leak syndrome	0/328 (0%)		1/325 (0.3%)
Cardiac ischemia	0/328 (0%)		1/325 (0.3%)
Cardiac-Left Ventricular Function	0/328 (0%)		4/325 (1.2%)
Cardiac Troponin I	1/328 (0.3%)		0/325 (0%)
Pericardial Effusion/Pericarditis	2/328 (0.6%)		0/325 (0%)
Cardiac-other	1/328 (0.3%)		2/325 (0.6%)
Ear and labyrinth disorders
Stomatitis	9/328 (2.7%)		20/325 (6.2%)
Gastrointestinal disorders
Colitis	6/328 (1.8%)		8/325 (2.5%)
Diarrhea	2/328 (0.6%)		1/325 (0.3%)
Dysphagia	2/328 (0.6%)		4/325 (1.2%)
Nausea	19/328 (5.8%)		16/325 (4.9%)
Typhlitis	6/328 (1.8%)		9/325 (2.8%)
Vomiting	7/328 (2.1%)		8/325 (2.5%)
Constipation	0/328 (0%)		1/325 (0.3%)
Ileus	0/328 (0%)		3/325 (0.9%)
Proctitis	4/328 (1.2%)		0/325 (0%)
Diarrhea w/o prior colostomy	7/328 (2.1%)		12/325 (3.7%)
Diarrhea w/ prior colostomy	1/328 (0.3%)		1/325 (0.3%)
GI-other	1/328 (0.3%)		3/325 (0.9%)
Hematemesis	1/328 (0.3%)		0/325 (0%)
Melena/GI Bleeding	0/328 (0%)		4/325 (1.2%)
Rectal Bleeding	1/328 (0.3%)		1/325 (0.3%)
Abdominal Pain	4/328 (1.2%)		3/325 (0.9%)
Rectal or Perirectal Pain	2/328 (0.6%)		2/325 (0.6%)
General disorders
VOD	1/328 (0.3%)		1/325 (0.3%)
Edema	1/328 (0.3%)		0/325 (0%)
Fatigue	18/328 (5.5%)		19/325 (5.8%)
Fever	22/328 (6.7%)		29/325 (8.9%)
Weight loss	1/328 (0.3%)		3/325 (0.9%)
Epistaxis	8/328 (2.4%)		10/325 (3.1%)
Dyspnea	18/328 (5.5%)		13/325 (4%)
Rigors/chills	0/328 (0%)		1/325 (0.3%)
Constitutional symptoms	1/328 (0.3%)		0/325 (0%)
Chest Pain	1/328 (0.3%)		0/325 (0%)
Pain-other	5/328 (1.5%)		4/325 (1.2%)
Infections and infestations
Wound-infectious	2/328 (0.6%)		1/325 (0.3%)
Infection w/ Gr3-4 neutropenia	154/328 (47%)		168/325 (51.7%)
Catheter-Related Infection	1/328 (0.3%)		4/325 (1.2%)
Infection w/ unknown ANC	1/328 (0.3%)		1/325 (0.3%)
Infection w/o neutropenia	10/328 (3%)		13/325 (4%)
Infection- Other	1/328 (0.3%)		1/325 (0.3%)
Acidosis	0/328 (0%)		1/325 (0.3%)
Injury, poisoning and procedural complications
Operative Injury of Vein/Artery	1/328 (0.3%)		0/325 (0%)
Wound - non-infectious	0/328 (0%)		1/325 (0.3%)
Hemorrhage with Grade 3 or 4 Platelets	30/328 (9.1%)		36/325 (11.1%)
Hemorrhage without Grade 3 or 4 Platelets	0/328 (0%)		1/325 (0.3%)
Hemorrhage Associated with Surgery	1/328 (0.3%)		1/325 (0.3%)
Investigations
PTT	1/328 (0.3%)		0/325 (0%)
SIADH	1/328 (0.3%)		0/325 (0%)
Alkaline phosphatase increased	1/328 (0.3%)		6/325 (1.8%)
Creatinine increased	2/328 (0.6%)		1/325 (0.3%)
Metabolism and nutrition disorders
hyperglycemia	7/328 (2.1%)		4/325 (1.2%)
Dehydration	0/328 (0%)		1/325 (0.3%)
Hypernatremia	0/328 (0%)		1/325 (0.3%)
Hypocalcemia	4/328 (1.2%)		3/325 (0.9%)
Hypokalemia	11/328 (3.4%)		9/325 (2.8%)
Hyponatremia	6/328 (1.8%)		8/325 (2.5%)
Hypophosphatemia	3/328 (0.9%)		4/325 (1.2%)
Tumor Lysis Syndrome	2/328 (0.6%)		2/325 (0.6%)
Musculoskeletal and connective tissue disorders
Bone Marrow Cellularity	0/328 (0%)		1/325 (0.3%)
Arthritis	1/328 (0.3%)		0/325 (0%)
Muscle Weakness	1/328 (0.3%)		0/325 (0%)
Myositis	0/328 (0%)		1/325 (0.3%)
Joint, Muscle, Bone-Other	1/328 (0.3%)		0/325 (0%)
Arthralgia	2/328 (0.6%)		3/325 (0.9%)
Bone, pain	2/328 (0.6%)		2/325 (0.6%)
Myalgia	1/328 (0.3%)		3/325 (0.9%)
Nervous system disorders
Ataxia	0/328 (0%)		1/325 (0.3%)
Dizziness/Lightheadedness	4/328 (1.2%)		0/325 (0%)
Neuropathy-motor	1/328 (0.3%)		0/325 (0%)
Neuropathy-sensory	0/328 (0%)		1/325 (0.3%)
Seizure	1/328 (0.3%)		1/325 (0.3%)
Speech Impairment	1/328 (0.3%)		0/325 (0%)
Syncope	6/328 (1.8%)		0/325 (0%)
Ocular-Other	2/328 (0.6%)		0/325 (0%)
Headache	4/328 (1.2%)		4/325 (1.2%)
Psychiatric disorders
Anorexia	26/328 (7.9%)		32/325 (9.8%)
Confusion	3/328 (0.9%)		5/325 (1.5%)
Depressed Level of consciousness	0/328 (0%)		2/325 (0.6%)
Hallucinations	2/328 (0.6%)		0/325 (0%)
Insomnia	1/328 (0.3%)		0/325 (0%)
Anxiety/Agitation	2/328 (0.6%)		2/325 (0.6%)
Depression	0/328 (0%)		2/325 (0.6%)
Renal and urinary disorders
Hematuria	1/328 (0.3%)		2/325 (0.6%)
Renal Failure	3/328 (0.9%)		3/325 (0.9%)
Reproductive system and breast disorders
Vaginal Bleeding	3/328 (0.9%)		1/325 (0.3%)
Respiratory, thoracic and mediastinal disorders
Hemoptysis	2/328 (0.6%)		3/325 (0.9%)
Pleuritic Pain	0/328 (0%)		2/325 (0.6%)
ARDS	3/328 (0.9%)		1/325 (0.3%)
Cough	1/328 (0.3%)		0/325 (0%)
Dyspnea	18/328 (5.5%)		13/325 (4%)
Hypoxia	12/328 (3.7%)		14/325 (4.3%)
Pleural effusion	2/328 (0.6%)		4/325 (1.2%)
Pneumonitis/pulmonary infiltrates	7/328 (2.1%)		11/325 (3.4%)
Skin and subcutaneous tissue disorders
Pruritus	2/328 (0.6%)		2/325 (0.6%)
Rash	17/328 (5.2%)		16/325 (4.9%)
Hand-Foot Reaction	1/328 (0.3%)		0/325 (0%)
Skin- Other	1/328 (0.3%)		0/325 (0%)
Vascular disorders
Hot flashes	0/328 (0%)		1/325 (0.3%)
Hemorrhage-Other	1/328 (0.3%)		1/325 (0.3%)
Other (Not Including Serious) Adverse Events
	Standard Daunorubicin (Induction Therapy)		High Dose Daunorubicin (Induction Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	319/328 (97.3%)		318/325 (97.8%)
Blood and lymphatic system disorders
Anemia	319/328 (97.3%)		318/325 (97.8%)
Leukopenia	281/328 (85.7%)		267/325 (82.2%)
Neutropenia	243/328 (74.1%)		230/325 (70.8%)
Thrombocytopenia	295/328 (89.9%)		292/325 (89.8%)
General disorders
Nausea	16/328 (4.9%)		18/325 (5.5%)
Fatigue	11/328 (3.4%)		18/325 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.