Chemotherapy With or Without Gemtuzumab Ozogamicin in Treating Older Patients With Acute Myeloid Leukemia (AML-17)

Gemtuzumab Ozogamicin (GO) Combined With Standard Intensive Chemotherapy Versus Standard Intensive Chemotherapy Alone For Induction/Consolidation In Patients 61-75 Years Old With Previously Untreated AML: A Randomized Phase III Trial (AML-17) Of The EORTC-LG and the GIMEMA-ALWP

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known if combining combination chemotherapy with monoclonal antibody therapy will kill more cancer cells.

PURPOSE: Randomized phase III trial to determine the effectiveness of combination chemotherapy with or without gemtuzumab ozogamicin in treating patients who have acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: mitoxantrone hydrochloride; Drug: cytarabine; Drug: etoposide; Drug: idarubicin; Drug: gemtuzumab ozogamicin

Detailed Description

OBJECTIVES:

• Determine the antileukemic activity of standard induction chemotherapy with or without gemtuzumab ozogamicin in elderly patients with previously untreated acute myeloid leukemia.
• Determine the overall survival of patients treated with these regimens.
• Determine the rate of response, disease-free survival, event-free survival, incidence of relapse, and incidence of death of patients treated with these regimens.
• Determine the rate, type, and grade of toxicity of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to age (61-69 vs 70-75), CD33 positivity (less than 5% vs 5-19% vs 20-80% vs more than 80% vs unknown), initial WBC before hydroxyurea administration if needed (less than 30,000/mm^3 vs at least 30,000/mm^3), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I:

  • Induction (phase I): Patients receive gemtuzumab ozogamicin IV over 2 hours on days 1 and 15.
  • Induction (phase II/MICE regimen): Beginning between days 50 and 53, patients receive mitoxantrone IV over 30 minutes on days 1, 3, and 5; etoposide IV over 1 hour on days 1-3; and cytarabine IV continuously on days 1-7. Bone marrow evaluation is performed on day 29. Patients with partial remission (PR) receive a second course of MICE chemotherapy regimen. Patients with complete remission (CR) after 1 or 2 courses of MICE regimen proceed to consolidation therapy. Patients with progressive disease go off therapy.
  • Consolidation: Beginning within 4 weeks of documentation of CR, patients receive gemtuzumab ozogamicin IV over 2 hours on day 0; idarubicin IV on days 1, 3, and 5; etoposide IV over 1 hour on days 1-3; and cytarabine IV continuously on days 1-5. After at least day 30, patients receive a second consolidation course in the absence of disease progression or unacceptable toxicity.

• Arm II:

  • Induction (MICE regimen): Patients receive mitoxantrone, etoposide, and cytarabine as in arm I induction. Bone marrow evaluation is performed on day 29. Patients with PR receive a second course of MICE chemotherapy regimen. Patients with CR after 1 or 2 courses of MICE regimen proceed to consolidation therapy. Patients with progressive disease go off therapy.
  • Consolidation: Patients receive idarubicin, etoposide, and cytarabine as in arm I consolidation.

Patients are followed monthly for 1 year, every 3 months for 2 years, and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 450 patients (225 per treatment arm) will be accrued for this study within 3.75 years.

• Study Type: Interventional
• Enrollment (Actual): 472
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4010
    • A. oe. Krankenhaus der Barmherzigen Schwestern Kinderabteilung
  • Vienna, Austria, A-1090
    • Allgemeines Krankenhaus - Universitatskliniken
• Belgium
  • Brugge, Belgium, 8000
    • AZ Sint-Jan
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Brussels, Belgium, 1070
    • Hopital Universitaire Erasme
  • Brussels, Belgium, B 1020
    • Centre Hospitalier Universitaire Brugmann
  • Edegem, Belgium, B-2650
    • Universitair Ziekenhuis Antwerpen
  • Haine Saint Paul, Belgium, 7100
    • Hôpital de Jolimont
  • Liege, Belgium, B-4000
    • CHU Liege - Domaine Universitaire du Sart Tilman
  • Verviers, Belgium, B-4800
    • Centre Hospitalier Peltzer-La Tourelle
• France
  • Lyon, France, 69437
    • Hôpital Edouard Herriot
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75181
    • Hotel Dieu de Paris
• Germany
  • Freiburg, Germany, D-79106
    • Klinikum der Albert - Ludwigs - Universitaet Freiburg
  • Heidelberg, Germany, D-69117
    • Ruprecht - Karls - Universitaet Heidelberg
  • Tuebingen, Germany, D-72076
    • Southwest German Cancer Center at Eberhard-Karls-University
• Italy
  • Bari, Italy, 70124
    • Università degli Studi di Bari
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
  • Bolzano, Italy, 39100
    • Azienda Sanitaria di Bolzano
  • Cagliari, Italy, 09121
    • Ospedale Oncologico A. Businco
  • Cagliari, Italy, 090100
    • Ospedale Binaghi
  • Catania, Italy, 95124
    • Ospedale Ferrarotto
  • Catanzaro, Italy, 88100
    • Ospedale Regionale A. Pugliese
  • Cremona, Italy, 26100
    • Azienda Istituti Ospitalieri
  • Ferrara, Italy, 44100
    • Università di Ferrara
  • Gallarate Varese, Italy, 21013
    • Ospedale S. Antonio Abate
  • Genoa, Italy, 16132
    • Ospedale San Martino
  • Messina, Italy
    • Azienda Ospedaliera Papardo
  • Messina, Italy, 98122
    • Universita degli Studi di Messina
  • Mestre, Italy, 30174
    • Ospedale Civile Umberto I
  • Modena, Italy, 41100
    • Azienda Ospedaliera - Universitaria di Modena
  • Naples, Italy, 80131
    • Federico II University Medical School
  • Naples, Italy, 80127
    • Azienda Ospedaliera "A. Cardarelli"
  • Novara, Italy, 28100
    • Azienda Ospedaliera Maggiore Della Carita
  • Orbassano, Italy, 10043
    • Azienda Ospedale S. Luigi at University of Torino
  • Palermo, Italy, 90146
    • Ospedale Cervello
  • Palermo, Italy
    • Ospedale La Maddalena - Palermo
  • Palermo, Italy, 90127
    • Azienda Ospedaliera Policlinico Paolo Giaccone
  • Perugia, Italy, 06122
    • Perugia Regional Cancer Center
  • Pesaro, Italy, I-61100
    • Azienda Ospedale - d "S. Salvatore"
  • Pescara, Italy, 65100
    • Ospedale Civile Pescara
  • Rome, Italy, 00144
    • Ospedale Sant' Eugenio
  • Rome, Italy, 00161
    • Universita Degli Studi "La Sapeinza"
  • Rome, Italy, 00168
    • Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore
  • Rome, Italy, 00155
    • Libero Istituto Universitario Campus Bio-Medico
  • Rome, Italy, 00184
    • H. San Giovanni-Addolorata Hospital
  • Sassari, Italy, 07100
    • Istituto di Ematologia Universita - University di Sassari
  • Verona, Italy, 37134
    • Policlinico G. B. Rossi - Borgo Roma
  • Vicenza, Italy, 36100
    • Ospedale San Bortolo
• Netherlands
  • 's-Hertogenbosch, Netherlands, 5211 NL
    • Jeroen Bosch Ziekenhuis
  • Amsterdam, Netherlands, 1091 HA
    • Onze Lieve Vrouwe Gasthuis
  • Leiden, Netherlands, 2300 CA
    • Leiden University Medical Center
  • Nijmegen, Netherlands, 6500 HB
    • Universitair Medisch Centrum St. Radboud - Nijmegen
  • Veldhoven, Netherlands, 5500 MB
    • Maxima Medisch Centrum - Veldhoven
• Portugal
  • Porto, Portugal, 4200
    • Hospital Escolar San Joao

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 61 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia (AML)

  • Bone marrow blasts at least 20% by bone marrow aspiration or biopsy

  • FAB subtypes M0-M2 and M4-M7

    • No acute promyelocytic leukemia (FAB subtype M3)

• Previously untreated primary or secondary AML, including AML after myelodysplastic syndromes

  • Hydroxyurea and/or corticosteroid therapy for no more than 14 days allowed
• No blast crisis of chronic myelogenous leukemia
• No AML supervening after other myeloproliferative diseases
• No active CNS leukemia

PATIENT CHARACTERISTICS:

Age

• 61 to 75

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC less than 30,000/mm^3 (pretreatment with hydroxyurea for no more than 14 days allowed)

Hepatic

• Bilirubin no greater than 3 times upper limit of normal (ULN)

Renal

• Creatinine no greater than 3 times ULN

Cardiovascular

• No concurrent severe cardiovascular disease
• No arrhythmias requiring chronic treatment
• No congestive heart failure
• No symptomatic ischemic heart disease

Pulmonary

• No severe pulmonary dysfunction (CTC grade 3-4)

Other

• HIV negative
• No other uncontrolled infection
• No other concurrent malignant disease
• No severe concurrent neurological or psychiatric disease
• No prior alcohol abuse
• No psychological, familial, sociological, or geographical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent hematopoietic growth factors (filgrastim [G-CSF] or sargramostim [GM-CSF]) except for life-threatening infection due to neutropenia

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior enrollment in this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARM A; GO + MICE for remission induction followed by GO + mini-ICE for consolidation	Drug: mitoxantrone hydrochloride; Drug: cytarabine; Drug: etoposide; Drug: idarubicin; Drug: gemtuzumab ozogamicin
Active Comparator: ARM B; MICE for remission induction followed by mini-ICE for consolidation	Drug: mitoxantrone hydrochloride; Drug: cytarabine; Drug: etoposide; Drug: idarubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival

Secondary Outcome Measures

Outcome Measure
Event-free survival
Response (complete remission [CR] or complete remission with incomplete recovery of platelet count [CRp]) rate after induction
Disease-free survival after CR/CRp
Incidence of relapse after CR/CRp
Incidence of death without relapse after CR/CRp
Toxicity (highest grade) assessed by International Working Group CTC v2.0

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Investigators: Study Chair: Sergio Amadori, MD, Azienda Ospedallera Universitaria - Policlinico Tor Vergata, Roma

Publications and helpful links

General Publications

• Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lubbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, Marie JP. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013 Dec 10;31(35):4424-30. doi: 10.1200/JCO.2013.49.0771. Epub 2013 Oct 14.

Study record dates

Study Major Dates

• Study Start: September 1, 2002
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: January 24, 2003
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): August 27, 2012
• Last Update Submitted That Met QC Criteria: August 24, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; untreated adult acute myeloid leukemia; adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Etoposide; Cytarabine; Idarubicin; Mitoxantrone; Gemtuzumab
• Other Study ID Numbers: EORTC-06012; AML-17; GIMEMA-AML-17