Treating Patients With Recurrent PCNSL With Carboplatin/BBBD and Adding Rituxan To The Treatment Regimen

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as carboplatin, cyclophosphamide, etoposide, etoposide phosphate, and cytarabine, use different ways to stop cancer cells from dividing so they stop growing or die. Osmotic blood-brain barrier disruption uses certain drugs to open the blood vessels around the brain and allow anticancer substances to be delivered directly to the brain tumor. Chemoprotective drugs such as sodium thiosulfate may protect normal cells from the side effects of carboplatin-based chemotherapy. Combining rituximab with chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining rituximab with combination chemotherapy given with osmotic blood-brain barrier disruption plus sodium thiosulfate in treating patients who have refractory or recurrent primary CNS lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of rituximab, carboplatin, cyclophosphamide, etoposide or etoposide phosphate and cytarabine administered in conjunction with osmotic blood-brain barrier disruption and high-dose sodium thiosulfate, in terms of complete response rate, in patients with refractory or recurrent primary CNS lymphoma. Secondary Determine the overall survival and 2-year progression-free survival of patients treated with this regimen. Determine the quality of life and cognitive function of patients treated with this regimen. Determine the neurotoxicity of this regimen in these patients. Determine the percentage of patients with ototoxicity over time after treatment with this regimen. Determine the effect of delayed administration of sodium thiosulfate on granulocyte and erythrocyte counts in these patients. OUTLINE: This is a multicenter study. Patients receive rituximab IV on day 1. On days 2 and 3, patients receive carboplatin intra-arterially over 10 minutes, cyclophosphamide IV over 10 minutes, and etoposide or etoposide phosphate IV over 10 minutes in conjunction with blood-brain barrier disruption. Patients also receive high-dose sodium thiosulfate IV over 15 minutes administered 4 and 8 hours after carboplatin on days 2 and 3 and intraventricular or intrathecal cytarabine on day 14. Beginning 48 hours after the last dose of chemotherapy, patients receive filgrastim (G-CSF)* subcutaneously (SC) daily for 7-10 days or until blood counts recover. Treatment repeats every 4 weeks for up to 12 courses. NOTE: * Alternatively, patients may receive a single dose of pegfilgrastim SC, administered 48 hours after the completion of chemotherapy Patients with intraocular lymphoma also receive methotrexate intravitreally twice weekly until the vitreous is clear of cells by slit lamp exam; once weekly for 1 month; and then monthly for 1 year. Quality of life is assessed at baseline, every 3 months during treatment, within 30 days of final treatment, then every 6 months for 1 year, and then annually thereafter. Patients are followed monthly for 3 months, every 2 months for 8 months, every 3 months for 1 year, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 11-25 patients will be accrued for this study within 7-10 years.

Official Title
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A Phase II Trial Involving Patients With Recurrent PCNSL Treated With Carboplatin/BBBD, by Adding Rituxan (Rituximab), An Anti CD-20 Antibody, To The Treatment Regimen

Conditions
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Brain and Central Nervous System Tumors, Drug/Agent Toxicity by Tissue/Organ, Lymphoma, Thrombocytopenia

Intervention / Treatment
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* Drug: Rituxan
* Drug: Cyclophosphamide
* Drug: Etoposide
* Drug: Etoposide phosphate
* Drug: Carboplatin
* Drug: Sodium thiosulfate
* Drug: Neupogen
* Drug: Neulasta
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Signed informed consent form in accordance with institutional guidelines Histologically or cytologically confirmed primary CNS lymphoma documented by brain biopsy or cerebrospinal fluid or vitrectomy analysis CD20 positive disease Progressive or relapsed disease during or after completion of prior methotrexate-based chemotherapy Aged 18 months to 75 years Performance status ECOG 0-3 OR Karnofsky 30-100% Hematocrit at least 25% (transfusion or epoetin alfa allowed) Absolute granulocyte count at least 1,200/mm^3 Platelet count at least 100,000/mm^3 OR at least lower limit of normal Bilirubin no greater than 2.0 times upper limit of normal Creatinine less than 1.8 mg/dL Calculated Creatinine clearance (CrCl) at least 50 mL/min Adequate cardiac function to tolerate general anesthesia Adequate pulmonary function to tolerate general anesthesia Available for follow-up for 1 year post therapy Fertile patients must use effective contraception for a minimum of 2 months before and during study participation EXCLUSION CRITERIA: Radiographic signs of intra-cranial herniation and/or spinal block HIV positive Systemic lymphoma Positive serum HCG, pregnant or lactating Allergy to study agents Hepatitis B or hepatitis C positive

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 75 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: All subjects<br> | Drug: Rituxan<br>* Total dose: 375mg/m2 infused IV; Every 4 weeks for up to one year.<br>* Other names: Rituximab;Drug: Cyclophosphamide<br>* Dose 330mg/m2 x 2 days infused IV; Every 4 weeks for up to 1 year<br>Drug: Etoposide<br>* Dose 200mg/m2 x 2 days infused IV; Every 4 weeks for up to one year. Etoposide phosphate may be given instead.<br>Drug: Etoposide phosphate<br>* Dose 200mg/m2 infused IV x 2 days; Every 4 weeks for up to one year. Etoposide may be given instead.<br>Drug: Carboplatin<br>* Dose: 200mg/m2 x 2 days infused IA with BBBD; Every 4 weeks for up to one year.<br>Drug: Sodium thiosulfate<br>* Dose: 4 hrs post carboplatin = 20gm/m2; Dose: 8 hrs post carboplatin = 16gm/m2 Infused IV x 2 days<br>* Other names: STS;Drug: Neupogen<br>* 48 hours after chemotherapy, QD x 7-10 days until WBC greater than 5000. Neulasta (Pegfilgrastim) may be given instead.<br>* Other names: filgrastim;Drug: Neulasta<br>* Dose: 6mg, 24-72 hours after chemotherapy. Neupogen may be given instead.<br>* Other names: Pegfilgrastim;Drug: Cytarabine<br>* Dose: 40mg on Day 14 following chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Complete Response Rate to Chemotherapy Regimen Assessed by Radiographic Response at 2 Years. | Per RECIST criteria (v1.1) and assessed by magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Survival Assessed by Clinical and Radiographic Response | Overall survival is measured from entry onto study until death from any cause or until death or progression of disease, respectively. | 5 years | 
| Progression-free Survival Assessed by Clinical and Radiographic Response From First Day of Treatment Until Tumor Progression |  | 5 years | 
| Quality of Life Assessed by EORTC QOL Before Treatment and Then Every 3 Months |  | 5 years | 
| Ototoxicity Assessed by Audiology Hearing Test Done Monthly During Treatment |  | 2 years | 
| Effect of Sodium Thiosulfate (STS) on Granulocytes and Erythrocytes Assessed by Complete Blood Count Lab Values Done Weekly During Treatment |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug/agent toxicity by tissue/organ, thrombocytopenia, intraocular lymphoma, primary central nervous system non-Hodgkin lymphoma, primary central nervous system Hodgkin lymphoma