Methotrexate, Mannitol, Rituximab, and Carboplatin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate the safety and toxicities of a treatment regimen consisting of rituximab
(intravenously [IV]) the day prior to methotrexate (intra-arterially [IA]), and carboplatin
(IA) in conjunction with blood-brain barrier disruption (BBBD) and delayed sodium thiosulfate
(IV).

II. To demonstrate, adding a monoclonal antibody and carboplatin to methotrexate BBBD, that a
45% rate of complete response (CR) within the first 3 months of treatment is achieved, while
excluding a CR rate as low as 30%.

SECONDARY OBJECTIVES:

I. To estimate the response rate (counting all CRs), the two-year overall survival and the
two-year event-free survival, as baselines for subsequent trials.

OUTLINE:

Patients receive rituximab IV over 5 hours on day 1, mannitol IA, methotrexate IA over 10
minutes, and carboplatin IA over 10 minutes on days 2 and 3. Patients then receive sodium
thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats monthly
for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 months, then every 2
months for 2 years, every 6 months for 1 year, and then annually for at least 2 years.

Inclusion Criteria:

- Subjects with histopathologic confirmation of intermediate or high-grade primary
central nervous system lymphoma (PCNSL) as documented by brain biopsy, or cytology
(analysis from cerebral spinal fluid [CSF] or vitrectomy), and cluster of
differentiation 20 (CD20) positive; whenever possible, the tumor should be
characterized by immunophenotype

- Subjects must be =< 90 days from diagnosis of PCNSL in the brain or spine; time from
pathologic diagnosis to initiation of treatment should be specified; subjects with
history of only ocular lymphoma are eligible if < 90 days since documented brain
parenchymal disease (by imaging or by biopsy)

- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance score =< 3
(Karnofsky >= 30)

- Hematocrit >= 25% (may be reached by transfusion)

- White blood cell count >= 2.5 x 10^3/mm^3

- Absolute granulocyte count >= 1.2 x 10^3/mm^3

- Platelets >= 100 x 10^3/mm^3 (or >= lower limit of institutional normal value)

- Calculated creatinine clearance (Cr Cl) >= 50 ml/min; eligible for full dose
methotrexate

- Calculated Cr Cl >= 30 ml/min; eligible for reduced dose methotrexate

- Bilirubin =< 2.0 x upper limit of institutional normal value

- The subject may have had other systemic chemotherapy for PCNSL during the 90 days
since PCNSL diagnosis; prior systemic chemotherapy must have been given at least 4
weeks prior to study entry (6 weeks for nitrosourea agents), with the exceptions of
methotrexate and rituximab which may have been given at least 10 days prior; ocular
lymphoma treatment may have been given any time prior to study entry; if the subject
has undergone treatment for parenchymal disease and the parenchymal disease has
progressed on a stable or increasing dose of steroids, the subject is not eligible for
enrollment

- Sexually active women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
treatment and for the duration of study treatment; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- Subjects with a bone marrow biopsy which shows microscopic, low-level involvement of
lymphoma are eligible

- Subject with seropositivity for hepatitis B or hepatitis C must be cleared by
hepatology service prior to participating in treatment protocol

Exclusion Criteria:

- Prior cranial or spinal radiotherapy

- Subjects with radiographic signs of excessive intra-cranial mass effect with
associated rapid neurologic deterioration, and/or spinal block, are unsafe to undergo
BBBD chemotherapy and are not eligible

- Uncontrolled (over the last 30 days), clinically significant confounding medical
conditions

- Seropositivity for the human immunodeficiency virus

- Systemic lymphoma

- Subjects who have a positive serum human chorionic gonadotropin (hCG), are pregnant or
lactating are ineligible

- Known allergy to any of the study agents

- Subjects who are at significant risk for general anesthesia