A Phase II Study of Clofarabine in Patients With Aggressive Non-Hodgkin's Lymphoma

Rationale: Two Food and Drug Administration drugs approved for blood cancers such as
non-Hodgkin's lymphoma (NHL) include fludarabine (Fludara) and cladribine (Leustat). The drug
offered in the current study, clofarabine was designed to combine the anti-cancer strength of
both fludarabine and cladribine. Laboratory research suggests that clofarabine targets
anti-cancer mechanisms in cells, helps repair DNA, and inhibits tumor growth. Research also
indicates that clofarabine has some efficacy against a variety of blood cancers and solid
tumors. Numerous tumor responses have been observed with high doses of clofarabine in heavily
pretreated patients with different types of lymphoma. The current study build on this
previous research to test clofarabine in patients with aggressive NHL.

Purpose: This study will evaluate the safety and efficacy of clofarabine for aggressive NHL.
Toxicities resulting from the combination of clofarabine and the supportive care drug GM-CSF
will also be analyzed in patients. GM-CSF is a blood-forming agent that stimulates the
production of white blood cells. In addition, several tests, including blood and tumor tissue
analysis, will assess immune response and biological changes to the tumor as a result of
study drugs.

Treatment: Patients in this study will be given clofarabine through intravenous infusions.
This drug will initially be provided to patients for five consecutive days. Several tests
will then be conducted and supportive care agents will be administered to stabilize patients'
blood cell counts, immune response, and reduce the risk of infection. The first ten patients
in this study will be hospitalized until recovery from the first five days of clofarabine to
carefully monitor any additional toxicities resulting from the dosing regimen. Patients will
receive another five day treatment cycle with clofarabine within seven days after recovering
from each previous cycle and no more than four weeks from the start of the previous cycle.
Disease response will be measured after every two cycles of treatment with clofarabine.
Patient with stable or reduced disease will receive a maximum of six treatment cycles with
clofarabine. Treatments will be discontinued due to disease growth, unacceptable side
effects, or a treatment delay of more than 21 days.

Inclusion Criteria:

- Must have histologically confirmed aggressive NHL

- B-cell NHL must be relapsed/ refractory

- T-cell & NK-cell and transformed lymphoma eligible at DX

- Patients with B-cell NHL (ie, diffuse large B-cell lymphoma, mantle cell lymphoma, and
Burkitt's lymphoma) must have relapsed or refractory disease after at least 1 prior
therapy.

- Patients previously treated with radioimmunotherapy (ie, ibritumomab tiuxetan
[Zevalin] or tositumomab [Bexxar]) or prior stem cell transplant (SCT) are eligible.

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

- Life expectancy of at least 12 weeks.

- Laboratory values obtained ≤ 7 days prior to registration:

- Absolute neutrophil count (ANC) ≥ 1500/mm3

- Platelets ≥ 100,000/mm3

- Total bilirubin ≤ upper limit of normal (ULN)

- Alkaline phosphatase ≤ 2 × ULN

- Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2 × ULN

- Serum creatinine ≤ ULN

Exclusion Criteria:

- No prior treatment with clofarabine.

- Full recovery from all acute toxicities associated with prior chemotherapy,
radiotherapy, or immunotherapy.- Patients with 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 on
parenteral antifungal therapy) are not eligible.

- Cardiac function (i.e. left ventricular ejection fraction) ≥ 50% on pretreatment
radionuclide ventriculography (RVG) or echocardiogram.

- Women that are pregnant or breastfeeding.

- Known HIV disease.

- No CNS lymphoma