The Addition of Temozolomide to Conditioning for Autologous Transplantation in Relapsed & Refractory CNS Lymphoma

Study Overview
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Brief Summary
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The primary purpose of the study will be testing the dosing of temozolomide to find the target dose that a person can tolerate. The other part of the study will be determining how helpful it can be to CNS lymphoma patients by adding temozolomide to the conditioning regimen prior to stem cell transplantation. This research study is designed to test the investigational use of temozolomide as part of a conditioning regimen prior to stem cell transplantation. This drug has not yet been approved by the U.S. Food and Drug Administration (FDA) to be used in the setting of stem cell transplantation in lymphomas of the brain (central nervous system or CNS) but it has been studied and used before in transplantation with reasonable results.

Detailed Description
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Currently there is no standard of care for relapsed or refractory primary central nervous system (CNS) lymphoma. After high-dose methotrexate or radiation therapy, the best approach to relapsed disease is undefined. Common practice is the regimen RBEAM as a conditioning regimen in this patient population prior to transplantation. The RBEAM regimen includes R (rituximab), B (BCNU), E (etoposide), A (Ara-C (cytarabine)) and M (melphalan). In addition, dexamethasone is included in the regimen although not noted in the RBEAM mnemonic. However, the melphalan used in this combination is not thought to have much CNS penetration. Therefore, temozolomide, an alkylating agent known to penetrate the CNS and approved by the FDA for brain tumors will be used and evaluated in this study instead of melphalan. The aim of this study is to determine an effective and safe dose of temozolomide orally administered to patients with relapsed primary CNS lymphoma over the 5 days preceding autologous stem-cell transplantation. The hope is that the conditioning regimen DRBEAT [D (dexamethasone) (R (rituximab), B (BCNU), E (etoposide), A (Ara-C (cytarabine)) and T (temozolomide)] will significantly improve the survival of patients with relapsed CNS lymphoma.

Official Title
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A Phase 2a Study of the Addition of Temozolomide to a Standard Conditioning Regimen for Autologous Stem Cell Transplantation in Relapsed and Refractory Central Nervous System (CNS) Lymphoma

Conditions
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B-Cell Lymphoma Originating in the CNS

Intervention / Treatment
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* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years of age and ≤ 75 years of age Patients must have Central Nervous System (CNS) involvement with a mature B-cell non-Hodgkin's Lymphoma, (WHO criteria) Patients must meet one of the below criteria: Patients who have achieved a complete response (CR) or partial response (PR) after initial therapy for Central Nervous System (CNS) B-cell lymphoma, OR Patients with relapsed or progressed disease following therapy for CNS B-cell lymphoma who has achieved a subsequent CR or PR following salvage chemotherapy, OR Patients who are initially refractory to therapy for CNS B-cell lymphoma but who have achieved a CR or PR following a salvage chemotherapy regimen, OR Patients who have developed CNS relapse from systemic B-cell Non-Hodgkin's lymphoma, and have evidence of chemotherapy sensitive lymphoma. Patients fit for autologous stem cell transplantation Patients able to understand and willing to sign a written informed consent document Exclusion Criteria: Patients whose life expectancy is severely limited by diseases other than malignancy Karnofsky Performance Score <60 Patients who are pregnant or breastfeeding Patients who are HIV seropositive Patients who have an uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month Patients with symptomatic coronary artery disease, uncontrolled congestive heart failure. Left Ventricular Ejection Fraction is not required to be measured, however if it is measured, patient is excluded if ejection fraction is <30% Patients requiring supplementary continuous oxygen. DLCO is not required to be measured, however if it is measured, patient is excluded if DLCO <35%. Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function and histology, and for the degree of portal hypertension. Patients with any of the following liver function abnormalities will be excluded Fulminant liver failure Cirrhosis with evidence of portal hypertension or bridging fibrosis Alcoholic hepatitis Esophageal varices A history of bleeding esophageal varices Hepatic encephalopathy Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time Ascites related to portal hypertension Chronic viral hepatitis with total serum bilirubin >3 mg/dL Symptomatic biliary disease Patients with non-B-cell lymphomas or brain tumors that are not lymphomas are Excluded from the study. Non-B-cell lymphomas include: any T-cell lymphoma, natural killer (NK)-cell lymphomas, and Hodgkin lymphomas Patients for whom an insufficient number of stem cells (<2 X 106/kg) have been collected

Ages Eligible for Study
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Minimum Age: 18 Years
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: DRBEAT Regimen<br> | Drug: Temozolomide<br>* The DRBEAT regimen will be similar to RBEAM. Rituximab and Carmustine will be given Day -6. Etoposide and Cytarabine will be given on Days -5 to -2. Temozolomide will be given via divided doses over five days starting on Day -5 to Day -1. A dose escalation design, known as EWOC (Escalation with overdose control) will be used to determine the target dose of temozolomide for this study. The starting dose given over five days will begin at 250mg/m2 (cumulative total dose of 1250 mg/m2), as previous data indicates this to be a safe dose. Based on the reported Dose Limiting toxicities from the previous patients, the EWOC statistical modeling will be performed to determine the next dose level.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Progression-free Survival and Overall Survival | Efficacy of the DRBEAT Regimen will be assessed by analysis of one-year progression-free survival (PFS), defined as the time interval from maximal response from therapy to tumor regrowth, progression*, or death, (*Progression is defined as meeting the response criteria listed in Table 4: Response Criteria for Primary Central Nervous System Lymphoma according to Abrey LE, Batchelor TT, Ferreri AJM et al.) and Overall survival, defined as the time interval between the date of transplant and the date of death from any cause. | (1) One Year (2) Until date of death from any cause, assessed up to 2 years | 
| Safest Dose of Temozolomide for the DRBEAT Regimen | Safety will be assessed using a dose escalation design for temozolomide's use to determine the target dose and also to evaluate any and all acute treatment related toxicities. During the course of patient follow up and therapy, toxicities will be evaluated, particularly as the investigators will be determining the target dose of temozolomide. One of the major criteria for dose limiting toxicity for the study will be any Grade 3 or 4 nonhematologic toxicity from a list of commonly expected toxicities associated with autologous transplantation and temozolomide. | One Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Refractory, Primary Central Nervous System B-cell Lymphoma, Autologous Stem Cell Transplant, Temozolomide, B-Cell Lymphoma, RBEAM, Conditioning Regimen