Combination of Pentostatin, Bendamustine and Ofatumumab for Treatment of Chronic Lymphocytic Leukemia and Lymphoma

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States.
There has been considerable progress in understanding the biology and treatment of CLL in the
last 20 years. However, even with modern therapies, complete responses (CR) are achieved in
approximately 25% of the patients with relapsed/refractory disease. Multiple studies have
demonstrated that patients who achieve CR have better clinical outcomes than patients who do
not achieve a CR with therapy. B-cell NHL is composed of multiple subtypes of neoplasm. These
diseases are closely related to CLL in terms of natural history, biology, and responsiveness
to similar therapeutic agents. These diseases are not usually cured by available chemotherapy
and ultimately patients succumb to progression of resistant disease. Therefore, there is a
need to develop better therapies to improve survival in patients with CLL and B-cell NHL.

Preclinical and clinical data suggests that pentostatin, bendamustine, ofatumumab are active
drugs for the treatment of B-cell malignancies. In an earlier clinical trial conducted by Dr.
Weiss (lead site PI), the combination of pentostatin and cyclophosphamide had very good
activity in previously treated patients with B-cell neoplasms. This regimen was also better
tolerated than similar fludarabine-based regimen. The response rates were improved with
addition of rituximab, anti CD 20 antibody, to the above regimen. Studies have demonstrated
synergy between bendamustine and purine analogs like pentostatin in killing cancer cell types
of CLL and NHL. The combination of these three drugs (pentostatin, bendamustine and
ofatumumab) has not been tested in clinical setting and we anticipate that the combination
regimen will be more active than individual drugs alone. The aim of this trial is to find a
safe dose of bendamustine to be used in combination with pentostatin and ofatumumab in
patients with previously treated CLL and B-cell NHL.

Inclusion Criteria:

1. Previously treated CLL or other B-cell neoplasm including small lymphocytic lymphoma,
hairy cell leukemia, follicular, lymphoma, Waldenstrom's macroglobulinemia, marginal
zone lymphomas, mantle cell lymphomas, lymphoplasmacytic lymphoma and diffuse large
B-cell lymphoma. Patients with composite lymphoma and transformed disease will be
included. Immunophenotypic (or immunohistochemical) analysis of the malignant
lymphocytes should demonstrate that the cells are B-cells.

2. Patients must have had prior cytotoxic therapy for their disease. Patients with
diffuse large B-cell lymphoma must have been treated with at least 2 prior cytotoxic
therapies.

3. Age ≥ 18 years of age.

4. ECOG performance statue 0 to 2.

5. Reasonable life-expectancy greater than 12 weeks.

6. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia will be
eligible for treatment.

7. Signed informed consent, which indicates the investigational nature of this study, is
required.

8. No patient may be entered onto the study without consultation with the principal
investigator or his designee.

Exclusion Criteria:

1. Subjects who have current active hepatic or biliary disease (with exception of
patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable
chronic liver disease per investigator assessment)

2. No prior cytotoxic therapy for at least 4 weeks before enrollment.

3. Currently participating in any other interventional clinical study.

4. Other currently active malignancy.

5. Active uncontrolled infection.

6. History of significant cerebrovascular disease in the past 6 months or ongoing event
with active symptoms or sequelae.

7. Known HIV positive.

8. Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within six months prior to randomization, congestive heart failure (NYHA
III-IV), and uncontrolled symptomatic arrhythmia.

9. Significant concurrent, uncontrolled medical condition including, but not limited to,
renal, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric
disease which in the opinion of the investigator may represent a risk for the patient.

10. Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB
DNA test will be performed and if positive the subject will be excluded.

11. Active hepatitis C infection. If positive serology for hepatitis C (HC) defined as a
positive test for HCAb, HC quantitative PCR will be performed. If PCR is positive the
subject will be excluded

12. Screening laboratory values:

1. creatinine > 2.0 times upper normal limit and creatinine clearance < 30
ml/min/m2. Patients with creatinine > 2 times upper limit of normal will have
creatinine clearance estimated. At the discretion of treating physician,
creatinine clearance can be measured and that value can be used instead of
calculated creatinine clearance.

2. total bilirubin > 2 times upper normal limit (unless due to tumor involvement of
liver or a known history of Gilbert's disease)

3. ALT (alanine transaminase) > 2.5 times upper normal limit (unless due to disease
involvement of liver.

13. Pregnant or lactating women. Women of childbearing potential must have a negative
pregnancy test at screening.

14. Women of childbearing potential, including women whose last menstrual period was less
than one year prior to screening, unable or unwilling to use adequate contraception
from study start to one year after the last dose of protocol therapy. Adequate
contraception is defined as hormonal birth control, intrauterine device, double
barrier method or total abstinence.

15. Male subjects unable or unwilling to use adequate contraception methods from study
start to one year after the last dose of protocol therapy