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

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.

Inclusion Criteria:

1. Patients ≥ 18 years of age and ≤ 75 years of age

2. Patients must have Central Nervous System (CNS) involvement with a mature B-cell
non-Hodgkin's Lymphoma, (WHO criteria)

3. 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.

4. Patients fit for autologous stem cell transplantation

5. Patients able to understand and willing to sign a written informed consent document

Exclusion Criteria:

1. Patients whose life expectancy is severely limited by diseases other than malignancy

2. Karnofsky Performance Score <60

3. Patients who are pregnant or breastfeeding

4. Patients who are HIV seropositive

5. Patients who have an uncontrolled infection (presumed or documented) with progression
after appropriate therapy for greater than one month

6. 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%

7. Patients requiring supplementary continuous oxygen. DLCO is not required to be
measured, however if it is measured, patient is excluded if DLCO <35%.

8. 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

1. Fulminant liver failure

2. Cirrhosis with evidence of portal hypertension or bridging fibrosis

3. Alcoholic hepatitis

4. Esophageal varices

5. A history of bleeding esophageal varices

6. Hepatic encephalopathy

7. Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the
prothrombin time

8. Ascites related to portal hypertension

9. Chronic viral hepatitis with total serum bilirubin >3 mg/dL

10. Symptomatic biliary disease

9. 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

10. Patients for whom an insufficient number of stem cells (<2 X 106/kg) have been
collected