Combination Chemotherapy, Monoclonal Antibody, and Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I/II Study Of Pre-Irradiation Chemotherapy With Methotrexate, Rituximab, And Temozolomide And Post -Irradiation Temozolomide For Primary Central Nervous System Lymphoma

Conditions
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Brain and Central Nervous System Tumors, Lymphoma

Intervention / Treatment
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* Drug: rituximab
* Drug: methotrexate
* Drug: temozolomide 100 mg/m^2
* Drug: temozolomide 150 mg/m^2
* Drug: temozolomide 200 mg/m^2
* Radiation: radiation therapy
* Drug: post-radiation therapy temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Primary central nervous system (CNS) lymphoma [B-cell, Cluster of Differentiation 20 (CD20) antigen positive] based on positive biopsy or cerebrospinal fluid (CSF) or vitreous cytology (in association with measurable intraparenchymal tumor). Cytology must demonstrate lymphoma or have an immunohistochemical diagnosis of malignant lymphocytes with a monoclonal lymphocytic population. Life expectancy ≥ 8 weeks; Zubrod performance status of 0-2; Absolute granulocyte count ≥1500/mm3; platelet count ≥ 100,000/mm3; creatinine clearance ≥ 50, calculated with the Cockcroft-Gault Equation: Cr Clearance = (140-age) x wt (kg)/(Cr[mg/dl]x 72); Bilirubin, serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (AST) ≤ 2 x institutional upper limits of normal; Patients must sign a study-specific informed consent prior to study entry. Age ≥ 18 Exclusion criteria: Evidence of systemic lymphoma; Prior malignancy (excluding in situ carcinoma of the cervix or non-melanomatous skin cancer)unless disease free for at least five years; Prior radiotherapy to the brain or head/neck; Prior chemotherapy; History of idiopathic sensitivity to any of the drugs to be used; Active infectious process; Seropositive for HIV, AIDS, or post-organ transplant; Pregnant women are ineligible as treatment involves unforeseeable risks to the participant and to the embryo or fetus. Active hepatitis B.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Temozolomide 100 mg<br>Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2. | Drug: rituximab<br>* 375 mg/m2, intravenously three days prior to the first cycle of methotrexate<br>Drug: methotrexate<br>* 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.<br>Drug: temozolomide 100 mg/m^2<br>* Temozolomide 100 mg/m^2 by mouth per day for five days on weeks 4 and 8.<br>Radiation: radiation therapy<br>* 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.<br>* Other names: radiotherapy;Drug: post-radiation therapy temozolomide<br>* 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.<br>|
| Experimental: Phase I: Temozolomide 150 mg<br>Rituximab, methotrexate, temozolomide 150 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2. | Drug: rituximab<br>* 375 mg/m2, intravenously three days prior to the first cycle of methotrexate<br>Drug: methotrexate<br>* 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.<br>Drug: temozolomide 150 mg/m^2<br>* Temozolomide 150 mg/m^2 by mouth per day for five days on weeks 4 and 8.<br>Radiation: radiation therapy<br>* 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.<br>* Other names: radiotherapy;Drug: post-radiation therapy temozolomide<br>* 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.<br>|
| Experimental: Phase I: Temozolomide 200 mg<br>Rituximab, methotrexate, temozolomide 200 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2. | Drug: rituximab<br>* 375 mg/m2, intravenously three days prior to the first cycle of methotrexate<br>Drug: methotrexate<br>* 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.<br>Drug: temozolomide 200 mg/m^2<br>* Temozolomide 200 mg/m^2 per day by mouth for five days on weeks 4 and 8.<br>Radiation: radiation therapy<br>* 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.<br>* Other names: radiotherapy;Drug: post-radiation therapy temozolomide<br>* 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.<br>|
| Experimental: Phase II: Temozolomide 100 mg<br>Rituximab, methotrexate, temozolomide 100 mg/m^2, followed by radiation therapy, then post-radiation therapy temozolomide 200 mg/m^2. | Drug: rituximab<br>* 375 mg/m2, intravenously three days prior to the first cycle of methotrexate<br>Drug: methotrexate<br>* 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.<br>Drug: temozolomide 100 mg/m^2<br>* Temozolomide 100 mg/m^2 by mouth per day for five days on weeks 4 and 8.<br>Radiation: radiation therapy<br>* 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.<br>* Other names: radiotherapy;Drug: post-radiation therapy temozolomide<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. ) | Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. ) | 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. ) | Analysis occured after all patients have been on study for 2 years. Maximum follow-up at time of analysis was 8.5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma