RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known if chemotherapy is more effective with or without monoclonal antibody therapy for acute myelogenous leukemia. PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without monoclonal antibody therapy in treating patients who have refractory or relapsed acute myelogenous leukemia.

Condition	Treatment or Intervention	Phase
adult acute differentiated monocytic leukemia (M5b) adult acute myeloblastic leukemia without maturation (M1) adult acute minimally differentiated myeloid leukemia (M0) adult acute poorly differentiated monocytic leukemia (M5a) recurrent adult acute myeloid leukemia adult acute erythroleukemia (M6) adult acute myelomonocytic leukemia (M4) adult acute myeloblastic leukemia with maturation (M2) secondary acute myeloid leukemia adult acute megakaryocytic leukemia (M7)	Drug: cytarabine  Drug: etoposide  Drug: mitoxantrone  Drug: monoclonal antibody HuG1-M195	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the efficacy, safety, pharmacokinetics, and immunogenicity of mitoxantrone, etoposide, and cytarabine (MEC) with or without monoclonal antibody HuG1-M195 in patients with refractory or relapsed acute myelogenous leukemia.

PROTOCOL OUTLINE: This is a randomized, multicenter study. Patients are stratified by age (under 50 vs 50 and over) and duration of previous complete remission (CR) (0-6 vs 7-12 months). All patients receive induction chemotherapy comprised of cytarabine IV over 2 hours, mitoxantrone IV over a maximum of 20 minutes, and etoposide IV over 1-2 hours on days 1-6. On day 5 of induction, patients are randomized to one of two treatment arms: Arm I: Patients receive day 6 of induction chemotherapy. Patients then receive monoclonal antibody HuG1-M195 (MOAB HuM195) IV over 4 hours on days 6-9 or 7-10. Treatment with MOAB HuM195 repeats every 2 weeks for 2 courses (courses 1 and 2) in the absence of disease progression or unacceptable toxicity. During course 1, MOAB HuM195 begins 30 minutes to 24 hours postchemotherapy. Patients who do not achieve CR by day 70 of induction and show evidence of bone marrow progression (regimen failure (RF)) are taken off study. Patients without RF are assigned to one of two consolidation groups based on response: Group A (CR): Patients receive consolidation chemotherapy comprised of mitoxantrone IV over a maximum of 20 minutes on days 1 and 2, and cytarabine IV over 2 hours and etoposide IV over 1-2 hours on days 1-4. Patients with New York Heart Association class II heart disease preconsolidation receive no mitoxantrone during consolidation. Patients receive MOAB HuM195 IV over 4 hours on days 4-7 or 5-8. Treatment with MOAB HuM195 repeats every 2 weeks for 2 additional courses (courses 3 and 4). During course 3, MOAB HuM195 begins 30 minutes to 24 hours postchemotherapy. Group B (partial remission (PR), hematologic improvement (HI), or stable disease (SD)): Patients receive MOAB HuM195 as in group A but no consolidation chemotherapy. Patients without RF after treatment on group A or B receive maintenance MOAB HuM195 IV over 4 hours on days 1-4. Treatment repeats every month for 8 additional courses (courses 5-12). Arm II: Patients receive day 6 of induction chemotherapy. Patients receive no MOAB HuM195 during the entire study. Patients without RF at day 70 of induction are assigned to one of two consolidation groups based on response: Group C (CR): Patients receive consolidation chemotherapy as in group A. Group D (PR, HI, or SD): Patients receive no further treatment. Patients may be eligible to receive MOAB HuM195 on PDL Study 195-302. Patients are followed every 3 months for 1 year, and then every 6 months thereafter.

PROJECTED ACCRUAL: A maximum of 200 patients (100 per arm) will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven acute myelogenous leukemia (AML) that may have been primary AML, secondary AML, or preceded by hematologic disorder; All FAB subtypes except M3
• Must meet one of the following three criteria: First relapse within 1 year after documentation of a previous complete remission (CR) achieved by chemotherapy; Refractory to prior chemotherapy comprised of a minimum of 1 induction course, including cytarabine at a minimum of 500 mg/m2 (e.g., 100 mg/m2/day for 5 days) plus an anthracycline; No high dose cytarabine (no cumulative dose greater than 3 g/m2); First relapse from a previous CR with subsequent autologous bone marrow transplantation (BMT), only if all of the following criteria are met: First BMT At least 100 days but less than 1 year posttransplantation; At least 25% cellularity of the bone marrow; Previous BMT included full hematopoietic recovery, defined by all of the following: Hemoglobin at least 10 g/dL (without transfusion); Platelet count at least 100,000/mm3 (without transfusion); Absolute neutrophil count at least 1,500/mm3
• No transplantation candidates
• Bone marrow blasts (leukemic cells) greater than 10%
• No chronic myelogenous leukemia in blast crisis
• No active CNS leukemia

--Prior/Concurrent Therapy--

• Biologic therapy: See Disease Characteristics; At least 30 days since prior experimental biologic therapy (e.g., interleukin-2); No concurrent biologic therapy, including bone marrow transplantation
• Chemotherapy: See Disease Characteristics; For first relapse AML with recent or prior chemotherapy: Prior hydroxyurea given as a short course (up to 48 hours) allowed, if needed, to reduce the peripheral leukocyte count; Hydroxyurea must be discontinued prior to study; For refractory AML with recent or prior chemotherapy: Greater than 2 weeks since prior chemotherapy except hydroxyurea given as above; No other concurrent chemotherapy
• Endocrine therapy: Not specified
• Radiotherapy: No concurrent radiotherapy
• Surgery: Not specified
• Other: No other concurrent experimental therapy; Concurrent therapy for other preexisting diseases allowed

--Patient Characteristics--

• Age: 18 and over
• Performance status: Karnofsky 50-100%
• Life expectancy: Not specified
• Hematopoietic: See Disease Characteristics
• Hepatic: Bilirubin less than 2.0 mg/dL (unless related to Gilbert's disease or due to leukemic infiltration); SGOT or SGPT no greater than 4 times upper limit of normal (unless related to AML)
• Renal: Creatinine less than 2.0 mg/dL (unless related to AML)
• Cardiovascular: Left ventricular function normal; No unstable cardiac arrhythmias, unstable angina pectoris, or myocardial infarction within the past 6 months; No New York Heart Association class III or IV heart disease; No electrocardiogram evidence of active ischemia
• Other: Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception during and for 1 month after study; HIV negative; No other active malignancy requiring therapy; No active serious infection that is uncontrolled by antimicrobial therapy; Medically stable; No significant organ dysfunction

California
      Beckman Research Institute, City of Hope, Los Angeles,  California,  91010,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Sidney Kimmel Cancer Center, San Diego,  California,  92121,  United States
      St. Joseph Hospital - Orange, Orange,  California,  92613-5600,  United States
      Sutter Cancer Center, Sacramento,  California,  95816,  United States
      University of California Davis Cancer Center, Sacramento,  California,  95817,  United States
      USC/Norris Comprehensive Cancer Center, Los Angeles,  California,  90033-0800,  United States
District of Columbia
      Washington Cancer Institute, Washington,  District of Columbia,  20010,  United States
Georgia
      Emory Clinic, Atlanta,  Georgia,  30322,  United States
Illinois
      Loyola University Medical Center, Maywood,  Illinois,  60153,  United States
      University of Illinois at Chicago, Chicago,  Illinois,  60612,  United States
Iowa
      University of Iowa Hospitals and Clinics, Iowa City,  Iowa,  52242,  United States
Louisiana
      Louisiana State University School of Medicine, Shreveport,  Louisiana,  71130-3932,  United States
Maryland
      Johns Hopkins Oncology Center, Baltimore,  Maryland,  21231,  United States
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
      Dana-Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States
      Massachusetts General Hospital Cancer Center, Boston,  Massachusetts,  02114,  United States
      New England Medical Center Hospital, Boston,  Massachusetts,  02111,  United States
Michigan
      West Michigan Cancer Center, Kalamazoo,  Michigan,  49007,  United States
Mississippi
      North Mississippi Hematology and Oncology Associates, Ltd., Tupelo,  Mississippi,  38801,  United States
Missouri
      Washington University Barnard Cancer Center, Saint Louis,  Missouri,  63110,  United States
Nevada
      Nevada Cancer Center, Las Vegas,  Nevada,  89106,  United States
New Jersey
      Cancer Institute of New Jersey, New Brunswick,  New Jersey,  08901,  United States
New York
      Albert Einstein Comprehensive Cancer Center, Bronx,  New York,  10461,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
      New York Medical College, Valhalla,  New York,  10595,  United States
      New York Presbyterian Hospital - Cornell Campus, New York,  New York,  10021,  United States
      North Shore University Hospital, Manhasset,  New York,  11030,  United States
      Roswell Park Cancer Institute, Buffalo,  New York,  14263-0001,  United States
North Carolina
      Duke Comprehensive Cancer Center, Durham,  North Carolina,  27710,  United States
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
Ohio
      Akron General Medical Center, Akron,  Ohio,  44302,  United States
      Cleveland Clinic Taussig Cancer Center, Cleveland,  Ohio,  44195,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Pennsylvania
      Milton S. Hershey Medical Center, Hershey,  Pennsylvania,  17033,  United States
      University of Pennsylvania Cancer Center, Philadelphia,  Pennsylvania,  19104,  United States
      University of Pittsburgh Medical Center, Pittsburgh,  Pennsylvania,  15213,  United States
Tennessee
      Vanderbilt University Medical Center, Nashville,  Tennessee,  37232-2516,  United States
      West Clinic, P.C., Memphis,  Tennessee,  38117,  United States
Wisconsin
      Medical College of Wisconsin, Milwaukee,  Wisconsin,  53226,  United States
Belgium
      Algemeen Ziekenhuis Middelheim, Antwerp,  2020,  Belgium
      Institut Jules Bordet, Brussels,  1000,  Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium
Canada, Alberta
      Cross Cancer Institute, Edmonton,  Alberta,  T6G 1Z2,  Canada
Canada, Manitoba
      Health Sciences Centre, Winnipeg,  Manitoba,  R3A 1R9,  Canada
Canada, Nova Scotia
      Queen Elizabeth II Health Science Center, Halifax,  Nova Scotia,  B3H 2Y9,  Canada
Canada, Ontario
      Princess Margaret Hospital, Toronto,  Ontario,  M5G 2M9,  Canada
France
      Centre Hospitalier Regional et Universitaire d'Angers, Angers,  49033,  France
      CHRU de Nancy - Hopitaux de Brabois, Vandoeuvre-les-Nancy,  54511,  France
Germany
      Klinikum der J.W. Goethe Universitaet, Frankfurt,  D-60590,  Germany
      Klinikum Rechts Der Isar/Technische Universitaet Muenchen, Munich,  D-81675,  Germany
      Universitaetsklinikum Benjamin Franklin, Berlin,  D-12200,  Germany
      University of Rostock, Rostock,  18057,  Germany
      Westfaelische Wilhelms-Universitaet, Munster,  DOH-4-8149,  Germany
Netherlands
      Academisch Medisch Centrum, Amsterdam,  1105 AZ,  Netherlands
United Kingdom, England
      Addenbrooke's NHS Trust, Cambridge,  England,  CB2 2QQ,  United Kingdom
      Christie Hospital N.H.S. Trust, Manchester,  England,  M20 4BX,  United Kingdom
      Leeds Teaching Hospital Trust, Leeds,  England,  LS1 3EX,  United Kingdom
      Royal Free Hospital, Hampstead, London,  England,  NW3 2QG,  United Kingdom

Study chairs or principal investigators

Daniel Levitt,  Study Chair,  Protein Design Labs   

Study ID Numbers:  CDR0000068061; PDL-195-301; NCI-G00-1819; MSKCC-00029; UCLA-9910050
Record last reviewed:  April 2004
Last Updated:  October 13, 2004
Record first received:  July 5, 2000
ClinicalTrials.gov Identifier:  NCT00006045
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08