Clofarabine for Relapsed or Refractory T-Cell or B-Cell Non-Hodgkin Lymphoma (NHL)

The safety profile of clofarabine appears acceptable within the target populations studied to
date in the clinical studies, with numerous responses observed in heavily pre-treated
patients with relapsed/refractory ALL or AML. Dose escalation of clofarabine in patients with
solid tumors and lymphoproliferative disorders has been limited because grade 3 and 4
myelosuppression was considered acceptable in patients with acute leukemia, provided that
hematologic recovery occurred within 6 weeks of therapy , and dose escalation has proceeded
as high as 40 mg/m2 in this patient population. Furthermore, no responses were observed in a
recent trial in which patients with relapsed CLL were treated with clofarabine 2 mg/m2, an
indolent B-cell lymphoproliferative disorder indicating that low doses are likely to be
ineffective in patients with aggressive NHL. (Personal Communication with ILEX Products,
INC.)

This Phase I/II study will evaluate escalating doses of clofarabine in patients with relapsed
and refractory diffuse large cell B-cell NHL starting at a dose of 4 mg/m2/day for 5
consecutive days and repeated every 28 days for a maximum of 6 cycles. This dosing regimen
should be evaluated in this patient population because there is no standard therapy at
relapse and grade 3 and 4 myelosuppression is frequently observed with traditional NHL
salvage. Additionally, patients will receive granulocyte colony stimulating factors at the
discretion of the investigator. Antifungal and antibacterial prophylaxis will be administered
to minimize the risk of infection.

Inclusion Criteria:

- Adult patients who are at least 18 years old with histology confirmed diffuse large
cell B-cell NHL who have failed prior systemic chemotherapy with or without monoclonal
antibody-based therapies.

- Measurable disease determined by Ct or PET scans or bone marrow involvement, defined
as lesions that can be accurately measured in two dimensions by CT or PET scan with
the longest diameter accurately as greater than or equal to 1.0 cm or palpable lesions
with both diameters greater than or equal to 2.0 cm. PET scan measurable disease is
defined based on SUV value as determined by nuclear medicine evaluation.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0,1,or 2.

- Life expectancy greater than 12 weeks.

- Laboratory values obtained less than or equal to 14 days prior to registration:

- Absolute neutrophil count (ANC) greater than or equal to 1500.

- White blood cell (WBC) count greater than 3.0.

- Platelets greater than or equal to 100.

- Hemoglobin (HG) greater than 9.0 g/dL.

- Total bilirubin less than or equal to 2.0 mg/dL.

- Aspartate transaminase (AST)/alanine transaminase (ALT) less than or equal to 3
times the upper limit of normal (ULN). Higher values are acceptable if it is
deemed that they are related to liver involvement with NHL.

- Serum creatinine less than or equal to 2.0 mg/dL.

- Cardiac function on pretreatment MUGA scan or echocardiogram that is considered normal
by institutional standards.

- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide valid informed consent.

- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment.

- Male and female patients must use an effective contraceptive method during the study
and for a minium of 6 months after study treatment.

Exclusion Criteria:

- Previously untreated NHL.

- Received previous treatment with clofarabine.

- History of T-cell lymphoma.

- Bulky disease (ie, any single mass greater than 10 cm or circulating malignant cells
greater than or equal to 24,000 cells/ul.

- Patients with known AIDS-related or HIV-positive lymphoma.

- Autologous bone marrow or stem cell transplant within 3 months of study entry.

- History of allogeneic bone marrow transplant or organ transplant.

- Prior radiotherapy to the only site of measurable disease.

- Any medical condition that requires chronic use of oral high-dose corticosteroids. (
in excess of 1 mg/kg/day).

- Autoimmune thrombocytopenia.

- Use if investigational agents within 30 days or any anticancer therapy within 3 weeks
before study entry. The patient must have recovered from all acute toxicities from any
previous therapy.

- Patients with an active, uncontrolled systemic infection considered to be
opportunistic, life threatening, or clinically significant at the time of treatment or
with a known or suspected fungal infection (ie, patients of parenteral antifungal
therapy).

- HIV-positive status.

- Active secondary malignancy.

- Pregnant or lactating patients.

- Any significant concurrent disease, illness , or psychiatric disorder that would
compromise patient safety or compliance, interfere with consent, study participation,
follow-up, or interpretation of study results.

- Patients with active or untreated central nervous lymphoma (CNS) lymphoma.