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: * To assess the maximum tolerated dose (MTD) of temozolomide (TMZ) in combination with methotrexate (MTX) and rituximab (RTX) when administered prior to twice daily fractionated whole brain radiation therapy (WBRT) in patients with primary central nervous system lymphoma. * To compare the two-year survival rate in patients receiving pre-irradiation chemotherapy, twice daily fractionated whole brain radiation therapy and post-irradiation temozolomide to the reported two-year survival rate of Radiation Therapy Oncology Group (RTOG) trial 93-10. RTOG 9310 does not fall within ClinicalTrials.gov registration/reporting requirements.) * To compare the pre-irradiation chemotherapy tumor response rates to the reported rate from RTOG 93-10. * To report progression-free survival. * To assess acute and long-term neurologic toxicity, and to collect quality of life data for this patient group. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
375 mg/m2, intravenously three days prior to the first cycle of methotrexate
Five cycles of methotrexate (MTX) at 3.5 gm/m2 administered every two weeks on weeks 1, 3, 5, 7, and 9 via intravenous infusion over four hours once per cycle. Calcium leucovorin 25 mg orally or intravenously every six hours initiated exactly 24 hours following the start of the MTX infusion. Methotrexate levels to be monitored daily, and calcium leucovorin discontinued when the MTX level is less than 10 micromolar.
Temozolomide 100 mg/m\^2 by mouth per day for five days on weeks 4 and 8.
Temozolomide 150 mg/m\^2 by mouth per day for five days on weeks 4 and 8.
Temozolomide 200 mg/m\^2 per day by mouth for five days on weeks 4 and 8.
Whole brain irradiation (WBRT) during weeks 11, 12, and 13, five days per week (excluding weekends). A daily dose of 2.4 Gy delivered in two fractions of 1.2 Gy each with a minimum inter-fraction interval of 6 hours, with a total dose to brain and meninges of 36 Gy.
Temozolomide (TMZ) 200 mg/m\^2 by mouth per day for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50 for a total of 10 cycles.
Baptist Cancer Institute - Jacksonville
Jacksonville, Florida, United States
Integrated Community Oncology Network at Southside Cancer Center
Jacksonville, Florida, United States
Baptist Medical Center South
Jacksonville, Florida, United States
Integrated Community Oncology Network
Jacksonville Beach, Florida, United States
Integrated Community Oncology Network - Orange Park
Orange Park, Florida, United States
Number of Phase I Participants Experiencing Toxicity
A dose limiting toxicity (DLT) is defined as any grade 3 or 4 non-hematological toxicity (other than grade 3 nausea/vomiting) or any hematological toxicity resulting in the discontinuation of temozolomide. Toxicity evaluation for this dose escalation includes all toxicities occurring prior to the start of radiation therapy. If the patient did not receive radiation therapy, then toxicity evaluation included all toxicities occurring through week 15. Any grade 5 toxicity would result in immediate suspension of accrual.
Time frame: From start of treatment to 10 weeks if radiation therapy received, to 15 weeks if not.
Phase II: Overall Survival Rate at 2 Years (Including Phase I Patients at Same Dose)
Survival time is defined as time from registration to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. (Please note that this outcome measure is considered the primary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
Phase II: Pre-irradiation Chemotherapy Tumor Response Rate (Including Phase I Patients at Same Dose)
Tumor response was centrally reviewed. Complete response: Disappearance of all enhancing tumor, the patient must be off steroid therapy and neurologically stable or improved; partial response: ≥ 50% decrease in enhancing tumor; progressive disease: ≥ 25% increase in a lesion, progressive or newly emergent meningeal or ocular disease. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: From start of treatment to 10 weeks if RT received, to 15 weeks if not.
Phase II: Progression-free Survival (Including Phase I Patients at Same Dose)
Progression is defined as greater than 25% increase in enhancing tumor or the appearance of new lesions in the brain, eye, or the appearance of a new positive cerebrospinal fluid (CSF) cytology. The patient may be neurologically stable or worse and on stable or increasing doses of corticosteroid. Progression-free survival time is defined as time from registration to the date of progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. (Please note that this outcome measure is considered a secondary endpoint for the Phase II component of the study, but that the patients from Phase I that were treated at the same dose level are included, as indicated in the treatment arm descriptions. )
Time frame: Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years.
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Florida Cancer Center - Palatka
Palatka, Florida, United States
Flagler Cancer Center
Saint Augustine, Florida, United States
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