S0535, Gemtuzumab and Combination Chemotherapy in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination chemotherapy may be more effective in treating promyelocytic leukemia. PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

Detailed Description
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OBJECTIVES: To assess the event-free survival and death during the first six weeks in patients with previously untreated, high-risk acute promyelocytic leukemia treated with a combined regimen of tretinoin, arsenic trioxide, and gemtuzumab ozogamicin. To estimate the frequency and severity of toxicities of this regimen in this group of patients. To investigate the molecular response rate utilizing this regimen in high-risk patients. OUTLINE: Induction chemotherapy: Patients receive oral tretinoin twice daily beginning on day 1 until CR (up to 90 days), gemtuzumab ozogamicin IV over 2 hours on day 1, and arsenic trioxide IV over 2 hours 5 days a week beginning on day 10 until CR (up to 60 days) in the absence of disease progression or unacceptable toxicity. Patients achieving A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to consolidation therapy after maintaining B1 peripheral blood status for ≥ 7 days. Consolidation therapy: Beginning between 2-8 weeks after documentation of complete response (CR), patients receive consolidation therapy. Consolidation courses 1 and 2: Patients receive arsenic trioxide IV over 2 hours 5 days a week for 5 weeks. Treatment repeats every 7 weeks for up to 2 courses. Patients remaining in A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status continue with consolidation courses 3 and 4. Consolidation courses 3 and 4: Within 4 weeks of completing consolidation course 2, patients receive oral tretinoin twice daily on days 1-7 and daunomycin IV bolus or over 1 hour on days 1-3. Within 2-8 weeks after recovery to B1 peripheral blood status, patients receive consolidation course 4 as in course 3. Patients who remain in B1 peripheral blood and C1 extramedullary disease status continue on consolidation courses 5 and 6. Consolidation courses 5 and 6: Beginning between 2-8 weeks after recovery to B1 peripheral blood status, patients receive gemtuzumab IV over 2 hours on day 1. Between 2-8 weeks after recovery to B1 peripheral blood status, patients receive consolidation course 6 as in course 5. Patients who remain in A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease status proceed to maintenance therapy. Maintenance therapy: Beginning 2-8 weeks after recovery of blood counts, patients receive oral tretinoin twice daily on days 1-7 every other week for 1 year, oral mercaptopurine once daily for 1 year, and oral methotrexate once weekly for 1 year. Patients undergo bone marrow aspirates and biopsies periodically during study. Samples are analyzed for cytogenetics by fluorescence in situ hybridization (FISH) and for PML-RARα by polymerase chain reaction (PCR). After completion of study treatment, patients are evaluated at 3, 6, 9, 12, 18, 24, and 36 months.

Official Title
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S0535, A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab Ozogamicin in Patients With Previously Untreated High-Risk Acute Promyelocytic Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: arsenic trioxide
* Drug: gemtuzumab ozogamicin
* Drug: mercaptopurine
* Drug: methotrexate
* Drug: tretinoin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Morphologically confirmed acute promyelocytic leukemia (APL) based on bone marrow examination APL-RARα-negative by RT-PCR are not eligible High-risk disease, defined as WBC > 100,000/mm^3 Bone marrow specimens must be made available for cytogenetic studies PATIENT CHARACTERISTICS: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prolonged QTc > 0.47 sec 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 stage II cancer from which the patients is currently in complete remission PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy for acute leukemia At least 3 days since prior tretinoin (ATRA) allowed Prior hydroxyurea, corticosteroids, or leukapheresis to control high cell counts allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Induction: ATRA 45mg/m2 PO D1-CR Gemtuzumab Ozogamicin 9 mg/m2 IV D1 Arsenic Trioxide 0.15 mg/kg/d IV 5days/wk D10-CR Consolidation 1 and 2: Arsenic Trioxide 0.15 mg/kg/d IV 5days/wk x 5 weeks, repeat after 2 weeks rest Consolidation 2 and 3: ATRA 45 mg/m2 PO D1-7 Daunomycin 50 mg/m2/d IV D1-3 Consolidation 5 and 6: GO 9mg/m2 IV D1 Maintenance: ATRA 45 mg/m2/d PO D1-7 every 14 days 6-MP 60 mg/m2/d PO daily for 1 year Methotrexate 20 mg/m2 PO once/wk for 1 year | Drug: arsenic trioxide<br> <br> Drug: gemtuzumab ozogamicin<br> <br> Drug: mercaptopurine<br> <br> Drug: methotrexate<br> <br> Drug: tretinoin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Continuous Complete Remission at 3 Years | Binary variable: yes if the patient achieves complete remission and remains in continuous complete remission until at least 3 years after entering the study; otherwise no. | 3 years | 
| Mortality Rate at 6 Weeks |  | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Toxicities | Adverse events that were possibly, probably or definitely related to study drug are reported. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute promyelocytic leukemia (M3), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), untreated adult acute myeloid leukemia