Monoclonal Antibody Plus Chemotherapy in Treating Young Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or 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 monoclonal antibody therapy with combination chemotherapy may kill more cancer cells. PURPOSE: Phase I trial to study the effectiveness of combining gemtuzumab ozogamicin with combination chemotherapy in treating children who have relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome.

Detailed Description
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OBJECTIVES: Determine the safety and maximum tolerated dose of gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes. Determine the efficacy of this regimen in these patients. Correlate the likelihood of leukemic blast cells to undergo apoptosis in vitro with the efficacy of this regimen in these patients. Correlate drug resistance as manifested by dye efflux or multiple drug resistance-1 expression by leukemic blast cells with the efficacy of this regimen in these patients. OUTLINE: This is a dose-escalation, multicenter study of gemtuzumab ozogamicin. Patients are assigned by cohort to 1 of 2 treatment regimens. Regimen A: Patients receive cytarabine IV over 2 hours every 12 hours on days 1-4, mitoxantrone IV over 1 hour on days 3-6, and gemtuzumab ozogamicin IV over 2 hours on day 7. Regimen B: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9, asparaginase intramuscularly on days 2 and 9, and gemtuzumab ozogamicin IV over 2 hours on day 3. Cohorts of 3-6 patients receive de-escalating doses of gemtuzumab ozogamicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose below that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed monthly for 6 months, every 2 months for 6 months, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 52 patients will be accrued for this study within 1.5 years.

Official Title
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A Dose Finding Study of the Safety of Gemtuzumab Ozogamicin Combined With Conventional Chemotherapy for Patients With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: asparaginase
* Drug: cytarabine
* Drug: gemtuzumab ozogamicin
* Drug: mitoxantrone hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of primary acute myeloid leukemia (AML) or myelodysplastic syndromes Relapsed (remission duration less than 1 year) OR Failed induction (failed to achieve an initial complete response) Patients with AML as a second malignant neoplasm allowed provided no other prior therapy for AML M2 or M3 bone marrow aspirate at time of study entry No Fanconi's anemia No known CNS leukemia PATIENT CHARACTERISTICS: Age: 21 and under Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Bilirubin no greater than 1.5 times normal AST or ALT less than 2.5 times upper limit of normal No history of veno-occlusive disease of the liver defined as weight increase of more than 5% over baseline and serum bilirubin greater than 5 mg/dL within 20 days after receipt of chemotherapy Renal: Creatinine no greater than 1.5 times normal OR Creatinine clearance or radioisotope glomerular filtration rate (GFR) at least 70 mL/min OR Equivalent GFR by institutional normal range Cardiovascular: Shortening fraction more than 27% by echocardiogram or normal for institution OR Ejection fraction more than 50% by MUGA Other: Not pregnant or nursing PRIOR CONCURRENT THERAPY: Biologic therapy: At least 180 days since prior hematopoietic stem cell transplantation Chemotherapy: Not specified Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified

Ages Eligible for Study
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Maximum Age: 21 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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: asparaginase|nan|
|Drug: cytarabine|nan|
|Drug: gemtuzumab ozogamicin|nan|
|Drug: mitoxantrone hydrochloride|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival |  | Length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Toxicity will be monitored through study chair notification and end course reports |  | 
| Remission Rate | The remission rate in each arm will be estimated by the proportion of patients who achieved remission among patients who received GMTZ at the MTD level. | Length of study | 
| Prognostic Factor Analysis | The predictive value of the likelihood of leukemia blast cells to undergo apoptosis and drug resistance of leukemia blast cells will be assessed by logistic regression |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, previously treated myelodysplastic syndromes