• Toxicity rate (Phase I) [ Designated as safety issue: Yes ]
• Overall survival rate at 2 years (Phase ll) [ Designated as safety issue: No ]

• Toxicity rate (Phase I)
• Overall survival rate at 2 years (Phase ll)

• Pre-irradiation chemotherapy tumor response rate (Phase II) [ Designated as safety issue: No ]
• Progression-free survival (Phase II) [ Designated as safety issue: No ]

• Pre-irradiation chemotherapy tumor response rate (Phase II)
• Progression-free survival (Phase II)

RATIONALE: Drugs used in chemotherapy such as methotrexate and temozolomide use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining methotrexate, temozolomide, and rituximab with radiation therapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of temozolomide when given together with methotrexate and rituximab followed by radiation therapy and to see how well they work in treating patients with primary central nervous system lymphoma.

OBJECTIVES:

• Determine the maximum tolerated dose of temozolomide in combination with methotrexate and rituximab before fractionated whole brain radiotherapy in patients with primary central nervous system lymphoma.
• Compare the 2-year survival rate of patients receiving this chemotherapy regimen before radiotherapy and temozolomide after radiotherapy to that of patients treated on protocol RTOG-9310.
• Compare the tumor response rates of patients treated with this chemotherapy regimen before radiotherapy to that of patients treated on RTOG-9310.
• Determine the progression-free survival of patients treated with this regimen.
• Determine the acute and long-term neurologic toxicity of this regimen in these patients.
• Determine the quality of life of patients treated with this regimen.

OUTLINE: This is a phase I dose-escalation study of temozolomide in combination with methotrexate and rituximab before radiotherapy, followed by a phase II study.

Phase I

• Pre-radiotherapy chemotherapy: Patients receive rituximab IV 3 days prior to the first course of methotrexate. Patients then receive methotrexate IV over 4 hours on weeks 1, 3, 5, 7, and 9 (for a total of 5 doses). Patients also receive oral temozolomide daily for 5 days on weeks 4 and 8.

Cohorts of 3-6 patients receive escalating doses of temozolomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 0 of 3 or 1 of 6 patients experience dose-limiting toxicity.

• Radiotherapy: Patients undergo whole brain radiotherapy daily for 5 days on weeks 11, 12, and 13.
• Post-radiotherapy chemotherapy: Patients receive oral temozolomide once daily on days 1-5 beginning at week 14. Treatment repeats every 28 days for 10 courses in the absence of unacceptable toxicity.

Phase II

• Patients receive treatment as in phase I at the MTD of temozolomide. Treatment continues in the absence of unacceptable toxicity.

Quality of life is assessed at baseline, at weeks 10 and 13, every 2 months during post-radiotherapy temozolomide therapy, at the end of therapy, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 52-64 patients (up to 18 patients for phase I and 46 patients for phase II) will be accrued for this study within 19 months.

• Biological: rituximab
• Drug: methotrexate
• Drug: temozolomide
• Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Cytologically confirmed primary CNS lymphoma

  • Based on positive biopsy, cerebrospinal fluid, or vitreous cytology (in association with measurable intraparenchymal tumor)
  • B-cell type
  • CD20+ disease
  • Cytology must demonstrate lymphoma OR an immunohistochemical diagnosis of malignant lymphocytes with a monoclonal lymphocytic population
• No evidence of systemic lymphoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• AST no greater than 2 times ULN
• Alkaline phosphatase no greater than 2 times ULN
• No active hepatitis B

Renal

• Creatinine clearance at least 50 mL/min
• No renal insufficiency

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No HIV positivity
• No other malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix
• No history of idiopathic sensitivity to any of the drugs in this study
• No active infection
• No known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy to the brain, head, or neck

Surgery

• No prior organ transplantation