Chemotherapy With or Without Gemtuzumab Ozogamicin in Treating Older Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: etoposide
* Drug: gemtuzumab ozogamicin
* Drug: idarubicin
* Drug: mitoxantrone hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 61 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  |  | 
| Event-free survival |  |  | 
| Toxicity (highest grade) assessed by International Working Group CTC v2.0 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), untreated adult acute myeloid leukemia, secondary acute myeloid leukemia, 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)