Rituximab and Combination Chemotherapy in Treating Patients With Primary Central Nervous System Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as methotrexate, leucovorin, vincristine, procarbazine, dexamethasone, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with primary central nervous system (CNS) lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the complete response rate. Secondary Determine the progression-free survival of these patients. Determine the proportion of progression-free and overall survival in these patients. Determine rituximab cerebrospinal fluid pharmacokinetics (only in patients requiring intrathecal chemotherapy). OUTLINE: This is a multicenter study. Patients receive rituximab IV 3 times weekly in weeks 1-4; high-dose methotrexate IV over 2 hours in weeks 1, 3, 5, and 9; oral or IV leucovorin calcium every 6 hours for 12 doses beginning 24 hours after the start of methotrexate in weeks 1, 3, 5, and 9; vincristine IV in weeks 1, 3, 5, 7, and 9; oral procarbazine hydrochloride daily on days 1-7 in weeks 1, 5, and 9; oral dexamethasone daily in weeks 1-6; and cytarabine IV over 2 hours twice weekly in weeks 11 and 14. Patients with positive cerebrospinal fluid also receive methotrexate intrathecally and oral leucovorin calcium every 12 hours for 8 doses beginning 24 hours after the start of methotrexate in weeks 2, 4, 6, 8, and 10. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 43 patients will be accrued for this study.

Official Title
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Phase II Study of Rituximab Given in Conjunction With Standard Chemotherapy in Primary Central Nervous System (CNS) Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: Rituximab
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Leucovorin
* Drug: Methotrexate
* Drug: Procarbazine
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed non-Hodgkin's lymphoma by brain biopsy Patients with inconclusive biopsy or patients who are not candidates for biopsy must have typical CT scan or MRI of the brain AND meet ≥ 1 of the following criteria: Positive cerebrospinal fluid cytology for lymphoma OR a monoclonal lymphoid population as defined by cell surface markers or immunoglobulin gene rearrangement studies Biopsy-proven involvement of the vitreous or uvea if cells are apparent in the posterior chamber or vitreous by ophthalmological examination Bideminsionally measurable disease, defined as contrast-enhancing tumor ≥ 1 cm by pretreatment MRI/CT scan Meningeal or vitreous involvement constitutes evaluable but not measurable disease If an excisional, rather than a needle biopsy was done, measurable disease must be present on a postoperative scan (not a PET-CT scan) ECOG performance status 0-3 Absolute granulocyte count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ upper limit of normal (ULN) SGOT ≤ 2.0 times ULN Creatinine clearance ≥ 50 mL/min Negative pregnancy test Fertile patients must use effective contraception Exclusion criteria: Pregnant or nursing HIV-1 positivity Other malignancy within the past 5 years except basal cell skin cancer or any carcinoma in situ Pre-existing immunodeficiency Hepatitis B surface antigen positivity Systemic lymphoma (as determined by pre-registration CT scans and physical examination) Prior chemotherapy or radiotherapy for primary central nervous system lymphoma Prior organ or bone marrow transplantation

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab + standard chemotherapy<br>Rituximab + high dose methotrexate, leucovorin, vincristine, procarbazine, dexamethasone, and cytarabine. Patients with meningeal involvement will receive additional methotrexate and leucovorin. | Biological: Rituximab<br>* Rituximab is administered intravenously. The initial rate is 50 mg/hr for the first hour. If no toxicity is seen, the rate may be escalated gradually in 50 mg/hour increments at 30-minute intervals to a maximum of 300 mg/hr. If the first dose is well tolerated, the initial rate for subsequent dose is 100 mg/hr, increased gradually in 100 mg/hr increments at 30-minute intervals, not to exceed 400 mg/hr.<br>* Other names: Rituxan;Drug: Cytarabine<br>* 3 g/m2/day in 500 cc D5W IV over 2 hrs. x 2 doses 24hrs. apart, Weeks 11, 14<br>* Other names: Arabinosylcytosine;Drug: Dexamethasone<br>* 16mg (week 1) PO daily Weeks 1, 2, 3, 4, 5, 6 Taper by 4 mg/wk, weeks 2, 3, by 2 mg/wk week 4, 5, 6<br>* Other names: dexamethasone acetate;Drug: Leucovorin<br>* 25 mg PO/IV every 6 hrs. x 12 doses, Weeks 1, 3, 5, 7, 9 For patients with meningeal involvement additionally 10 mg PO every 12 hrs. x 8 doses, Weeks 2, 4, 6, 8, 10<br>* Other names: leucovorin calcium;Drug: Methotrexate<br>* 3.5 g/m2In 500 cc D5W + 25 mEq NaHCO3 IV over 2 hours, Weeks 1, 3, 5, 7, 9 For patients with meningeal involvement additionally: 12 mg Intrathecally, in preservative-free sterile .9NS Weeks 2, 4, 6, 8, 10 Via Ommaya or lumbar puncture<br>* Other names: MTX;Drug: Procarbazine<br>* 100 mg/m2 PO daily x 7 days Weeks 1, 5, 9<br>* Other names: Procarbazine hydrochloride;Drug: Vincristine<br>* 1.4 mg/m2 IV push, Weeks 1, 3, 5, 7, 9 2m2 (2.8 mg) dose cap<br>* Other names: VCR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate - Locally Reviewed | Assessed by the ECOG-ACRIN data manager based upon local review of images and data sent by the local sites. Treatment response was determined by calculating the sum of the maximal cross section in 2 separate axes using enhancing lesion(s) on CT or MRI imaging. The same imaging modality was to be used throughout assessment. Complete response was defined as the disappearance of all contrast enhancing tumor size on CT or MRI, patient was off all glucocorticoids, and resolution of all meningeal and vitreous involvement if present. Response must have lasted at least 4 weeks. | For the primary endpoint, complete response will be based on disease status at three weeks post the end of therapy (week 17). | 

 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