Study of Voraxaze in Patients With Central Nervous System Lymphoma

Inclusion Criteria:

- Histologically documented B-cell non-Hodgkin‟s lymphoma involving the brain, spinal
cord, and/or leptomeningeal space.

°Patients in whom the type of lymphoma could not be determined or is unknown (e.g.,
not enough tissue for further analysis) are assumed to have a B cell lymphoma and are
eligible

- Patients with parenchymal lesions must have unequivocal evidence of disease
progression on imaging (MRI of the brain/spine or CT head) 28 days prior to study
registration. For patients with leptomeningeal disease only, CSF cytology must
document lymphoma cells and/or imaging findings must be consistent with CSF disease 28
days prior to study registration (at the discretion of the investigator).

- Patients who have already received one or two doses of methotrexate for treatment of
primary CNS lymphoma are eligible for enrollment.

- Patients must not have evidence of systemic non-Hodgkin lymphoma requiring active
treatment.

- Men and woman must be at least 18 years of age on the day of consenting to the study.

- Patients must have a Karnofsky Performance Status (KPS) ≥ 50 (See Appendix 2).

- Patients must be willing and able to comply with scheduled visits, treatment plan, and
laboratory tests.

- Patients must have adequate bone marrow and organ function shown by:

- Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L;

- Platelets ≥ 100 x 10^9/L and no platelet transfusion within the past 28 days
prior to study registration;

- Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cells (RBC) transfusion within the
past 28 days prior to study registration;

- International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper
limit of normal;

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the
upper limit of normal;

- Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3
times the upper limit of normal with direct bilirubin within the normal range in
patients with well documented Gilbert Syndrome;

- CrCl ≥ 60 mL/min using the Cockcroft-Gault equation. Men: CrCl (min/mL) =
(140-age) X (actual weight in kg) / 72 X serum creatinine (mg/dL) Women: CrCl
(mL/min) = (140-age) X (actual weight in kg) X 0.85 / 72 X serum creatinine
(mg/dL)

- Women of reproductive potential must agree to use highly effective methods of birth
control during the period of therapy and for 30 days after the last dose of the study
drug. Men who are sexually active must agree to use highly effective contraception
during the period of therapy and for 3 months after the last dose.

- Female subjects of childbearing potential must have a negative plasma pregnancy test
upon study entry.

- Patients must be able to tolerate MRI/CT scans.

- Patients must be able to tolerate lumbar puncture and/or Ommaya taps.

- Participants must have recovered to grade 1 toxicity from prior therapy. NOTE: Prior
autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent
patients from enrollment into the trial.

NOTE: Patients who have initiated and received up to two doses of MTX treatment will not be
excluded from study as long as all pretreatment assessments have been completed within 28
days of trial initiation.

Exclusion Criteria:

- Patient with SCNSL requiring treatment for extra-CNS disease are excluded.

- Patient with ocular manifestation of systemic lymphoma are excluded.

- Patient concurrently using other approved or investigational antineoplastic agents.

- Patient has received chemotherapy, monoclonal antibodies or targeted anticancer
therapy ≤ 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosoureas
or mitomycin-C prior to starting the study drug, or the patient has not recovered from
the side effects of such therapy.

- Patient has received external beam radiation therapy to the CNS within 28 days of the
first dose of the study drug.

- Patient has an active concurrent malignancy requiring active therapy.

- The patient has been treated with radio- or toxin-immunoconjugates within 70 days of
the first dose of the study drug.

- Patient weighs <40kg

- Patient is allergic to components of the study drug.

- Patient is known to have human immunodeficiency virus (HIV) infection.

- Patient is known to have a history of active or chronic infection with hepatitis C
virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests.

- Severe, active medical co-morbidity such as unstable angina and/or congestive heart
failure, coronary artery disease, significant abnormalities on electrocardiogram
(EKG), uncontrolled or symptomatic arrhythmias or valvular disease; active infection,
severe chronic obstructive pulmonary disease or other respiratory illness, hepatic
insufficiency, known pre-existing immunodeficiency as seen in organ transplant
recipients, renal failure with CrCl <60 mL/min.

- Patient has a life-threatening illness, medical condition, or organ system dysfunction
that, in the opinion of the investigator, could compromise the subject‟s safety or put
the study outcomes at undue risk.

- Patient has large large pleural or ascetic fluid collection.

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic.

- Prior allergic reaction to any of the study drugs involved in this protocol.

- Patient has undergone prior allogenic stem cell transplant (autologous stem cell
transplant is NOT an exclusion).