Doxorubicin Hydrochloride Liposome and Rituximab With Combination Chemotherapy in Treating Patients With Newly Diagnosed Burkitt's Lymphoma or Burkitt-Like Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome, 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 rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving rituximab together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving doxorubicin hydrochloride liposome and rituximab together with combination chemotherapy works in treating patients with newly diagnosed Burkitt's lymphoma or Burkitt-like lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the overall response rate (complete remission, complete remission undetermined, and partial remission) in HIV-negative or HIV-positive patients with newly diagnosed Burkitt's or Burkitt-like lymphoma treated with doxorubicin hydrochloride liposome and rituximab as part of the Magrath regimen. Secondary Determine the complete remission rate in patients treated with this regimen. Determine progression-free and overall survival at 2 years in patients treated with this regimen. Determine the safety of adding rituximab to the standard Magrath regimen in these patients. Determine the safety of using doxorubicin hydrochloride liposome in place of doxorubicin hydrochloride in these patients. Determine correlative levels of rituximab and doxorubicin hydrochloride liposome in cerebrospinal fluid and peripheral blood. OUTLINE: This is a multicenter study. Patients are stratified according to risk category (low risk vs high risk). Patients are assigned to 1 of 2 treatment regimens according to stratum. Regimen A (low-risk disease with no CNS involvement): Patients receive R-CODOX-M chemotherapy comprising rituximab IV over 2-4 hours on days 0 and 8; doxorubicin hydrochloride liposome IV over 30 minutes on day 1; vincristine IV on days 1 and 8; cyclophosphamide IV over 1 hour on days 1-5; and high-dose methotrexate (MTX) IV over 24 hours on day 10. Patients also receive leucovorin calcium IV beginning 36 hours after the start of MTX infusion and continuing every 6 hours until blood levels of MTX are safe. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily on days 4-8 in courses 1 and 3 and on days 6 and 7 in course 2. Beginning on day 12, daily G-CSF dosing resumes until blood counts recover. Patients receive CNS prophylaxis comprising cytarabine intrathecally (IT) on day 1 and MTX IT on day 3. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Regimen B (high-risk disease with or without CNS involvement): Patients receive R-CODOX-M chemotherapy with leucovorin calcium and G-CSF support as in regimen A for courses 1 and 3 and R-IVAC chemotherapy with leucovorin calcium and G-CSF support (as below) for courses 2 and 4. R-IVAC chemotherapy comprises high-dose ifosfamide IV over 3 hours and etoposide IV over 1 hour on days 1-5; cytarabine IV over 3 hours twice daily on days 2 and 3; and rituximab IV over 2-4 hours on day 0 and on day 6 or 7. Patients also receive leucovorin calcium orally every 6 hours on day 6 and G-CSF SC once daily beginning on day 6 or 7 and continuing until blood counts recover. Patients without CNS involvement receive CNS prophylaxis comprising cytarabine IT on days 1 and 3 and MTX IT on day 15 in courses 1 and 3 and MTX IT alone on day 5 in courses 2 and 4. Patients with proven CNS involvement at diagnosis receive cytarabine IT on days 1, 3, and 5 in course 1, on days 7 and 9 in course 2, and on days 1 and 3 in course 3. These patients also receive MTX IT on days 15 and 17 in course 1, on day 5 in courses 2 and 4, and on day 15 in course 3. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. The first 10 patients enrolled on the study undergo cerebrospinal fluid and blood collection during courses 1 and 3 for correlative biological marker and pharmacological studies. After completion of study treatment, patients are followed at 30 days and then periodically for up to 3 years. PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

Official Title
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A Multicenter Phase II Study Incorporating DOXIL® and Rituximab Into the Magrath Regimen for HIV-Negative and HIV-Positive Patients With Newly Diagnosed Burkitt's and Burkitt-like Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Regimen A
* Drug: Regimen B


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed Burkitt's or Burkitt-like non-Hodgkin's lymphoma meeting 1 of the following risk criteria: Low-risk disease meeting all of the following criteria: Normal lactate dehydrogenase level ECOG performance status 0-1 Ann Arbor stage I or II No tumor mass over 10 cm in greatest diameter High-risk disease, defined as disease not meeting low-risk criteria Newly diagnosed disease PATIENT CHARACTERISTICS: ECOG performance status 0-2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Hemoglobin ≥ 8.0 g/dL Absolute neutrophil count ≥ 500/mm³ Platelet count ≥ 100,000/mm³ (50,000/mm³ if bone marrow involvement is documented) AST and ALT ≤ 3 times upper limit of normal (ULN) Alkaline phosphatase ≤ 3 times ULN Bilirubin ≤ 1.5 times ULN (3 times ULN if liver metastases are present) Creatinine clearance > 50 mL/min Creatinine ≤ 2.0 mg/dL LVEF ≥ 45% by MUGA scan or echocardiogram No New York Heart Association class II-IV heart failure No clinically significant pericardial disease No myocardial infarction within the past 6 months No uncontrolled angina No severe uncontrolled ventricular arrhythmias No ECG evidence of acute ischemia or active conduction system abnormalities Investigator must document any baseline ECG abnormality as not medically relevant No other malignancy within the past year except for basal cell carcinoma of the skin or in situ carcinoma of the cervix No other serious medical or psychiatric illness that would preclude study compliance PRIOR CONCURRENT THERAPY: Prior treatment with 1 course of any combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and/or prednisone* (CHOP)-like therapy allowed, provided the following doses are not exceeded: Rituximab 750 mg/m² Cyclophosphamide 1,000 mg/m² Doxorubicin hydrochloride 50 mg/m² Vincristine 2 mg/m² No other investigational drugs within the past 14 days No other concurrent systemic, cytotoxic, investigational, or chemotherapy agents NOTE: *No maximum dose restriction on steroids

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alternating doxil/Magrath regimen & rituximab/Magrath regimen<br>Patients are stratified between high risk and low risk disease status. Low risk patients receive 3 cycles of rituximab (500 mg/m2) R-CODOX-M chemotherapy IV over 2-4 hours with intrathecal chemotherapy (Regimen A). High risk patients receive 1 cycle of R-CODOX-M chemotherapy IV followed by R-IVAC chemotherapy over 30 minutes(Regimen B); regimens A and B are then repeated. | Drug: Regimen A<br>* Cyclophosphamide (800 mg/m2 IV over 1 hour)+ vincristine (1.5 mg/m2 IV PUSH)+ doxorubicin (40 mg/m2 IV)+ high-dose methotrexate (2,700 mg/m2 IV over 23 hours)+ rituximab (500 mg/m2 IV)(R-CODOX-M) regimen<br>* Other names: Amethopterin;Drug: Regimen B<br>* Rituximab (500 mg/m2 IV once)+ Ifosfamide (1500 mg/m2 IV daily over 3 hours)+ Etoposide (60 mg/m2 IV daily over 1 hour), and Cytarabine (2 grams/m2 IV over 3 hours for 4 doses)<br>* Other names: cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) of Patients With Burkitt's and Burkitt-like Lymphoma/Leukemia Treated With Modified Magrath Regimen | Response Rate is defined as combined number of patients with Complete Remission (CR) Complete Remission undetermined (Cru) and Partial Remission (PR) for patients with Burkitt's and Burkitt-like Lymphoma/Leukemia. Response will be measured by CT scans following treatment completion and assessed using Response Criteria for Non-Hodgkin's Lymphoma where: CR=complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms. CRu=same as above but allowing for 75% decrease in lymph node masses and indeterminate or normal bone marrow. PR=50% decrease in SPD of the six largest dominant nodes or nodal masses with no increase in size or other nodes, liver, spleen and no new sites of disease. | After two cycles of treatment and at completion of treatment (4 cycles for high risk and 3 cycles for low risk) up to approximately 20 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) of Patients With Burkitt's and Burkitt-like Lymphoma/Leukemia Treated With Modified Magrath Regimen | Overall Survival (OS) of patients with Burkitt's and Burkitt-like Lymphoma/Leukemia treated with modified Magrath regimen. OS is defined from the first dose of study drug to the time of death for any reason. | At 2 years from treatment initiation Median follow up 34 months (range 15-45) | 
| Safety of Patients With Burkitt's and Burkitt-like Lymphoma/Leukemia Treated With Modified Magrath Regimen (Addition of Rituximab, Subsitution of Adriamycin for Doxil and Using Lower Dose of Methotrexate) | Adverse events (AE) graded as either 3 or 4 and determined to be at least possibly related to study treatment will be collected in patients Burkitt's and Burkitt-like Lymphoma/Leukemia treated with modified Magrath regimen to assess the safety and toxicity profile of the addition of rituximab, subsitution of adriamycin for doxil and lower dose of methotrexate. AEs will be assessed as follows at the following time points: At the end of each cycle or monthly whichever is less frequent and 30 days post last dose of study treatment for a maximum of 3 cycles for regimen A and 4 cycles for regimen B and up to 12 months. In general AEs will be assessed according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v 3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | After each cycle or monthly (whichever is less frequent), 30 days post last dose. Treatment duration was at a median of 13 weeks (range 11-20) for high-risk patients and 10 weeks (range 9-12) for low-risk patients. | 
| Progression Free Survival (PFS) of Patients With Burkitt's and Burkitt-like Lymphoma/Leukemia Treated With Modified Magrath Regimen | Progression Free Survival (PFS) will be defined from the first dose of study drug to the first documentation of progressive disease or death for any reason. Patients that are lost to follow-up before progression will be censored at the point of last documentation of not experiencing the event. | At 2 years from treatment initiation. Median follow up 34 months (range 15-45) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I adult Burkitt lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, contiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult Burkitt lymphoma, AIDS-related peripheral/systemic lymphoma