S0106 Cytarabine and Daunorubicin w/ or w/o Gemtuzumab Followed By HD Cytarabine and Either Gemtuzumab or Nothing in de Novo AML

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different ways to stop cancer cells from dividing so they stop growing and die. Monoclonal antibodies, such as gemtuzumab ozogamicin, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with gemtuzumab ozogamicin may kill more cancer cells. It is not yet known whether induction therapy using cytarabine and daunorubicin is more effective with or without gemtuzumab ozogamicin or whether postconsolidation therapy using gemtuzumab ozogamicin is more effective than no additional therapy in treating de novo (first occurrence) acute myeloid leukemia. PURPOSE: This randomized phase III trial is comparing two different regimens of chemotherapy and monoclonal antibody therapy to see how well they work in treating patients with previously untreated de novo acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Compare disease-free survival of patients with previously untreated de novo acute myeloid leukemia treated with induction therapy comprising cytarabine and daunorubicin with vs without gemtuzumab ozogamicin followed by consolidation therapy comprising high-dose cytarabine and post-consolidation therapy comprising gemtuzumab ozogamicin vs no additional therapy. Compare the complete remission rate in patients treated with these regimens. Compare the frequency and severity of the toxic effects of these regimens in these patients. Other objectives (if funding allows): Determine the prognostic significance of CD33 expression on the response rate in patients receiving gemtuzumab ozogamicin. Determine the prognostic significance of FLT3 mutations in these patients before treatment with these regimens. Determine the prognostic significance of minimal residual disease in remission specimens from these patients treated with these regimens. Determine the prognostic significance of the flow cytometric detection of minimal residual disease in specimens collected from these patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified during induction therapy according to age (< 35 years vs ≥ 35 years) and during post-consolidation therapy according to preinduction cytogenetic risk group. Induction therapy: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive daunorubicin IV on days 1-3, cytarabine IV continuously on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 4. Patients receive filgrastim (G-CSF) or sargramostim (GM-CSF) IV or subcutaneously once daily beginning on day 15 and continuing until blood counts recover. Arm II: Patients receive daunorubicin, cytarabine, and G-CSF or GM-CSF as in arm I. Patients in both arms undergo bone marrow aspiration and biopsy on day 14 (and on day 19, if applicable) and then proceed to reinduction therapy. Reinduction therapy: Patients receive daunorubicin IV on days 1-3 and cytarabine IV continuously on days 1-7. Patients also receive G-CSF or GM-CSF as in induction therapy. Patients who achieve A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to consolidation therapy. Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1, 3, and 5. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients who maintain A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status after consolidation therapy proceed to post-consolidation therapy. Post-consolidation therapy: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive gemtuzumab ozogamicin IV over 2 hours on day 1. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive no additional therapy. Patients are observed at days 30 and 60 after randomization. Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years. PROJECTED ACCRUAL: A total of 684 patients (342 per treatment arm) will be accrued for this study within 4.5-5 years.

Official Title
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A Phase III Study of the Addition of Gemtuzumab Ozogamicin (Mylotarg®) During Induction Therapy Versus Standard Induction With Daunomycin and Cytosine Arabinoside Followed by Consolidation and Subsequent Randomization to Post-Consolidation Therapy With Gemtuzumab Ozogamicin (Mylotarg®) or No Additional Therapy For Patients Under Age 61 With Previously Untreated De Novo Acute Myeloid Leukemia (AML)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: gemtuzumab ozogamicin
* Other: observation
* Drug: Cytosine arabinoside
* Drug: Daunomycin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Morphologically confirmed acute myeloid leukemia (AML) by bone marrow aspiration and biopsy* within the past 14 days No M3 disease NOTE: *Patients with marked leukocytosis may be registered before the availability of biopsy results if the absolute blast count is ≥ 100,000 cells/µL No blastic transformation of chronic myelogenous leukemia No pre-existing hematologic disorder evolving to AML (e.g., myelodysplasia or secondary leukemia) PATIENT CHARACTERISTICS: Age 18 to 60 Performance status Zubrod 0-3 Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN No known hepatitis B or C infection No known liver disease Renal Not specified Cardiovascular LVEF ≥ 50% by MUGA or echocardiogram No unstable cardiac arrhythmias No unstable angina Other No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior systemic chemotherapy Prior hydroxyurea to control high cell counts allowed No more than 1 prior dose of intrathecal chemotherapy for acute leukemia Concurrent intrathecal chemotherapy allowed during induction therapy Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Post-consolidation GO<br>Patients receive gemtuzumab ozogamicin IV over 2 hours on day 1. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. | Drug: gemtuzumab ozogamicin<br>* Given IV, induction Arm1 6mg/m2 D4; post-consolidation 5mg/m2 3 doses >/= 28 days apart<br>* Other names: mylotarg;|
| Other: Post-consolidation observation<br>Patients receive no additional therapy. Patients are observed at days 30 and 60 after randomization. | Other: observation<br>* No treatment given<br>|
| Active Comparator: Induction 7+3<br>Standard induction regimen of 7 days of Ara-C (cytosine arabinoside) and 3 days of daunomycin | Drug: Cytosine arabinoside<br>* IV; induction Arms1/2 and reinduction 100 mg/m2/d days 1-7; consolidation 3gm/m2 q3hrs D1, 3, 5<br>* Other names: Ara-C;Drug: Daunomycin<br>* IV; induction Arm1 45mg/m2 D1-3; Arm2 and reinduction 60 mg/m2 D1-3;<br>* Other names: daunorubicin;|
| Active Comparator: Induction 7+3+GO<br>Gemtuzumab (GO) added to the standard induction regimen of 7 days of Ara-C and 3 days of daunomycin | Drug: Cytosine arabinoside<br>* IV; induction Arms1/2 and reinduction 100 mg/m2/d days 1-7; consolidation 3gm/m2 q3hrs D1, 3, 5<br>* Other names: Ara-C;Drug: Daunomycin<br>* IV; induction Arm1 45mg/m2 D1-3; Arm2 and reinduction 60 mg/m2 D1-3;<br>* Other names: daunorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Disease-free Survival (DFS) | Measured from data of randomization to post-consolidation therapy until relapse from complete response or death from any cause, with observations censored at the date of last contact for patients last known to be alive without report of relapse. | After completing any treatment, every 6 months for 2 years, than annually for years 3-5 | 
| Complete Remission |  | After induction therapy was completed (1 or 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event | For induction, daily for the first 10 days, then twice weekly until consolidation treatment. Weekly during consolidation treatment. Weekly if randomized to post-consolidation G.O. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated adult acute myeloid leukemia, adult acute eosinophilic leukemia, adult acute basophilic leukemia, 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), 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)