Trial Information

Prospective Phase II Study of a High Dose, Short Course Regimen (R-CODOX-M/IVAC) Including CNS Penetration and Intensive IT Prophylaxis in HIV-Associated Burkitt's and Atypical Burkitt's Lymphoma

OBJECTIVES:

Primary

- Determine the efficacy of rituximab, cyclophosphamide, vincristine, doxorubicin
hydrochloride, and high-dose methotrexate (R-CODOX-M ) alone or alternating with
rituximab and ifosfamide, etoposide phosphate, and high-dose cytarabine (IVAC) and
intrathecal CNS prophylaxis in patients with newly diagnosed, previously untreated,
HIV-associated Burkitt's lymphoma or atypical Burkitt's lymphoma.

- Determine the safety of this regimen in these patients.

Secondary

- Evaluate downstream effectors of apoptosis as mechanisms of chemotherapy resistance and
prognosis and perform exploratory analysis of their relationship to treatment effect.

- Evaluate multi-drug resistance gene expression as a mechanism of chemotherapy
resistance and prognosis and perform exploratory analysis of their relationship to
treatment effect.

- Confirm the use of flow cytometry in the identification of occult leptomeningeal
disease and determine whether abnormal flow cytometry is predictive when CNS cytology
is negative for malignant cells.

- Determine the biologic and prognostic significance of Epstein-Barr virus (EBV)-positive
Burkitt's lymphoma in the highly active antiretroviral therapy era and perform
exploratory analysis of their relationship to treatment effect.

- Compare genotyping in patients with HIV-associated Burkitt's lymphoma with that of
patients who are HIV-negative and determine whether they are uniform in their genetic
profile or whether some cases are more like diffuse large B-cell lymphoma.

- Determine if EBV detection in cerebrospinal fluid at diagnosis is predictive of
leptomeningeal disease.

OUTLINE: This is a prospective, multicenter study. Patients are stratified according to risk
category (low-risk vs high-risk). Patients with low-risk disease receive 3 courses of
R-CODOX-M chemotherapy as described below. Patients with high-risk disease receive 4
alternating courses of R-CODOX-M/IVAC chemotherapy as described below in an A/B/A/B
sequence.* Courses repeat every 21-28 days in the absence of disease progression or
unacceptable toxicity.

NOTE: *In patients presenting with anasarca, pleural effusion, or ascites, methotrexate can
pool causing difficulties with clearance; in this case, treatment may be given in a reverse
sequence: B/A/B/A.

- Regimen A (R-CODOX-M chemotherapy): Patients receive rituximab** IV and doxorubicin
hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on
days 1 and 2, pegfilgrastim subcutaneously (SC) on day 3, vincristine IV on days 1 and
8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV
beginning 24 hours after the start of methotrexate and continuing every 6 hours until
the methotrexate level is less than 50 nmol/L. Patients receive CNS prophylaxis
comprising methotrexate intrathecally (IT), cytarabine IT, and hydrocortisone IT on day
1. Patients with high-risk disease receive an additional dose of cytarabine IT on day
3. Patients also receive filgrastim (G-CSF) SC once daily on days 3-9. Once the
methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily
beginning on approximately day 18 and continuing until blood counts recover.

- Regimen B (rituximab and IVAC chemotherapy): Patients receive rituximab** IV on day 1,
ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and
high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS
prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also
receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC
beginning on day 6 and continuing until blood counts recover.

Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not
receive CNS prophylaxis as above. Instead, these patients receive a combination of
sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and
then every 14 days as tolerated until completion of systemic chemotherapy.

NOTE: **Rituximab may be given up to 3 days before a chemotherapy course and anytime during
the course for 3 (low-risk disease) or 4 (high-risk disease) total doses.

Patients undergo blood and cerebrospinal fluid collection and tumor biopsies periodically
during study treatment for correlative studies of prognostic biomarkers predictive of
survival (e.g., c-flip protein expression; p53 mutations [by immunohistochemistry (IHC)];
multidrug resistance gene expression [by IHC]; and Epstein-Barr virus in tumor DNA or
cerebrospinal fluid [by polymerase chain reaction]); genotyping of Burkitt's lymphoma; and
flow cytometry as a tool (by staining) for detecting occult positivity of leptomeningeal
disease in Burkitt's lymphoma.

After completion of study treatment, patients are followed every 4 months for at least 2
years.

PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.