Intensive Chemotherapy and Rituximab in the Treatment of Burkitt Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to learn more about how well a chemotherapy regime including rituximab works in treating patients with Burkitt or atypical Burkitt lymphoma.

Detailed Description
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Patients will be placed into one of two groups, low risk and high risk. Low risk disease is defined as one area of disease measuring less than 10cm and a normal blood test called LDH (lactate hydrogenase). Patients not fitting the low risk criteria are considered high risk. If the patient has low risk disease their treatment cycle consist of three cycles of A. If the patient has high risk disease they will receive Cycle A followed by cycle B which will then repeat. Cycle A consists of the drugs: rituximab, cyclophosphamide, oncovin, doxorubicin and methotrexate (R-CODOX-M). The treatment cycle is approximately 14 days. A spinal tap is performed on day 1 and day 3 of the cycle and the patient will be hospitalized until between day 11 and day 13. After the patient's blood counts return to normal(usually around day 21),the next round of treatment will occur. Cycle B consists of the drugs: rituximab, ifosfamide, VP-16 and ara-c (IVAC). The treatment cycle is approximately 5 days. A spinal tap is performed on day 4 and once blood counts return to normal the patient will start cycle A again. After the patient has finished the treatments, they will be re-evaluated with CT scans and PET scans to determine whether or not they are in remission. Every three months for two years, blood tests and CT and PET scans will be performed. Follow up after that will be every 6 months for two years.

Official Title
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Phase II Study of Intensive Chemotherapy and Rituximab in Burkitt Lymphoma

Conditions
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Burkitt Lymphoma, Non-Hodgkins Lymphoma, Atypical Burkitt Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Methotrexate
* Drug: Leucovorin
* Drug: Ifosfamide
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Mesna


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented Burkitt or atypical Burkitt according to World Health Organization (WHO) criteria. Pathology must be reviewed at the Brigham and Women's Hospital (BWH). Measurable or evaluable disease: Disease reproducibly measurable in two perpendicular dimensions on exam, computed tomography (CT), radiograph, or magnetic resonance imaging (MRI). Disease present on bone marrow biopsy will be considered as evaluable disease. The following may not be used as the sole site of measurable or evaluable disease: *ascites, *pleural effusion, *bone lesion or *central nervous system (CNS) disease. Age > 18 Laboratory data (within 2 weeks of study registration): ANC > 1500/ul; platelet > 100,000/ul; creatinine < 1.5 X normal; creatinine clearance > 60 ml/min; bilirubin < 1.5 X normal; AST and ALT < 2.5 X normal; alkaline phosphates < 3 X normal; HIV negative; cardiac ejection fraction > 50%. Exclusion Criteria: Previous chemotherapy or radiation therapy. Steroids of less than 72 hours duration for impending oncologic emergency are allowed. Uncontrolled bacterial, fungal, or viral infection. Concomitant malignancy excluding carcinoma in situ of the cervix and basal cell carcinoma of the skin. Serious comorbid disease. Clinically significant pulmonary symptomatology. In patients with a history of symptomatic pulmonary disease, pulmonary function tests (PFTs) should document an forced expiratory volume at 1 second (FeV1), forced vital capacity (FVC), and total lung capacity (TLC) of > 60% predicted and carbon monoxide diffusing capacity of the lung (DLCO) of > 50% predicted. No clinically significant cardiac symptomatology. The cardiac ejection fraction must be > 50%. Pregnancy. All males and females with reproductive potential must consent to use an effective form of contraception while on study. Major surgery within the previous 2 weeks.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Risk<br>Low-risk patients receive 3 cycles of regimen A. Regimen A: Rituximab (375 mg/m^2) on Days 1 and 3. Cyclophosphamide (800 mg/m^2) on days 1 and 2. Vincristine (1.4 mg/m^2) on days 1 and 10. Doxorubicin (50 mg/m^2) on Day 1. Methotrexate (3000 mg/m^2) on Day 10. Intrathecal Cytarabine (50mg) will be given on Day 1 and intrathecal methotrexate (12mg) will be given on Days 1 and 10. Leucovorin on days 11 and 12. Rituximab is given on Days 1 and 3 in cycle 1, and on Day 1 of all other cycles. | Drug: Rituximab<br>* Low Risk: Intravenously on Day 3 of the first cycle (One cycle is 14 days) then day 1 for next 2 cycles (Regimen A) High Risk: Regimen A followed by a 5-day cycle where rituximan is given on day 1<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Low Risk/High Risk: Intravenously on day 1 and day 2 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Low Risk/High Risk: Given on day 1 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Adriamycin, Rubex;Drug: Vincristine<br>* Low Risk/High Risk: Given intravenously on day 1 and day 10 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Oncovin, vincristine sulfate;Drug: Methotrexate<br>* Low Risk: Given on day 10 of a 14-day cycle for 3 cycles (regimen A) High Risk: Regimen A followed by methotrexate on day 3 and day 5 of a 5-day cycle<br>* Other names: Rheumatrex, Trexall;Drug: Leucovorin<br>* Low Risk/High Risk: Given on days 11, 12 and 13 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Folinic acid;Drug: Cytarabine<br>* Low Risk: Given on days 1, 3, 5 and 10 of a 14-day cycle for 3 cycles (regimen A) High Risk: After regimen A, cytarabine given on days 1 and 2 of a 5-day cycle<br>* Other names: Cytosar, Tarabine PFS;|
| Experimental: High Risk<br>High-risk patients receive 4 alternating cycles of regimens A and B (A-B-A-B). Regimen A (as described earlier). Regimen B: Rituximab (375mg/m^2) on Day 1. Ifosfamide (1500mg/m^2) on Days 1-5. Mesna (275 mg/m^2) on Days 1-5. Etoposide (60mg/mg^2) on Days 1-5. Cytarabine (2 gm/m^2) twice a day on Days 1 and 2. Intrathecal methotrexate (12mg) on Day 5, and intrathecal methotrexate (50mg) on Day 3 (also on Day 1 for patients with central nervous system involvement). | Drug: Rituximab<br>* Low Risk: Intravenously on Day 3 of the first cycle (One cycle is 14 days) then day 1 for next 2 cycles (Regimen A) High Risk: Regimen A followed by a 5-day cycle where rituximan is given on day 1<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Low Risk/High Risk: Intravenously on day 1 and day 2 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Low Risk/High Risk: Given on day 1 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Adriamycin, Rubex;Drug: Vincristine<br>* Low Risk/High Risk: Given intravenously on day 1 and day 10 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Oncovin, vincristine sulfate;Drug: Methotrexate<br>* Low Risk: Given on day 10 of a 14-day cycle for 3 cycles (regimen A) High Risk: Regimen A followed by methotrexate on day 3 and day 5 of a 5-day cycle<br>* Other names: Rheumatrex, Trexall;Drug: Leucovorin<br>* Low Risk/High Risk: Given on days 11, 12 and 13 of a 14-day cycle for 3 cycles (regimen A)<br>* Other names: Folinic acid;Drug: Ifosfamide<br>* High Risk: After Regimen A, Ifosomide given on days 1-5 of a 5 day cycle<br>* Other names: Ifex;Drug: Etoposide<br>* High Risk: After Regimen A, etoposide given days 1-5 of a 5-day cycle<br>* Other names: Vepesid;Drug: Cytarabine<br>* Low Risk: Given on days 1, 3, 5 and 10 of a 14-day cycle for 3 cycles (regimen A) High Risk: After regimen A, cytarabine given on days 1 and 2 of a 5-day cycle<br>* Other names: Cytosar, Tarabine PFS;Drug: Mesna<br>* High Risk: After regimen A, mesna is given on days 1-5 of a 5-day cycle<br>* Other names: Mesnex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates (CR and PR) in Adults With Burkitt/Atypical Burkitt | Complete Response (CR): Disappearance of all measurable or evaluable disease confirmed. Partial Response (PR): Reduction of 50% or greater in the sum of the products of the perpendicular diameters of all measurable. Of 8 High Risk participants, 7 met the primary response outcome. 1 High Risk participant did not meet protocol defined primary outcome response and died two months following enrollment. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Participants are followed after completion of protocol therapy until disease progression to determine disease free survival. | Until disease progression up to 120 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Burkitt Lymphoma, atypical Burkitt lymphoma, Non-Hodgkin's Lymphoma, rituximab