Sorafenib for the Treatment of Chronic Lymphocytic Leukemia (CLL)

The UCSD Moores Cancer is conducting a Phase 2 clinical trial to evaluate the activity of
sorafenib in relapsed or refractory CLL patients.

Sorafenib (BAY 43-9006) is an oral multi-kinase inhibitor with effects on tumor
proliferation and tumor angiogenesis. It was initially selected based on inhibition of the
serine/threonine kinases Raf-1 and wild-type B-Raf, which are pivotal components of the
Ras/Raf/MEK/ERK signaling pathway. CLL cells derive survival support from their
microenvironment, in part by activation of this pathway. Preclinical studies performed in
our lab demonstrated that sorafenib was cytotoxic to CLL cells, including those from
patients with more aggressive disease and from patients with chemotherapy (fludarabine)
resistant disease.

The purpose of this study is to evaluate for evidence of anti-leukemic activity / clinical
activity of sorafenib by assessing decrease in absolute lymphocyte count (ALC)/leukemia cell
counts, lymphadenopathy, splenomegaly, and leukemia infiltration of bone marrow and to
assess the impact of sorafenib on the CLL B cells through corollary studies. Patients will
continue treatment for up to 3 monthly cycles unless toxicity or progressive disease.
Patients with noted stable disease (or better) in the absence of significant toxicity will
be allowed to receive another 1-9 cycles of single agent sorafenib. All patients will be
assessed for response following 3 cycles of treatment and/or following all therapy per
iwCLL-WG 2008 guidelines.

Inclusion Criteria:

- Diagnosis of relapsed or refractory CLL.

- Experiencing progressive disease with an iwCLL-WG indication to receive therapy.

- Age ≥ 18 years.

- ECOG performance status ≤ 2 at study entry.

- Adequate organ and marrow function as defined below:

- platelets ≥ 50 x 109/L

- serum creatinine ≤ 1.5 mg/dL

- total bilirubin ≤ 1.5 mg/dL

- AST(SGOT)/ALT(SPGT) ≤ 2 X institutional upper limit of normal or if known liver
involvement <5X institutional upper limit of normal

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.

- Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

- No investigational agents within 28 days prior to entering the study.

- No concurrent use of other anti-cancer agents or treatments.

- No congestive heart failure > class II NYHA. Patients must not have unstable angina
(anginal symptoms at rest) or new onset angina (beginning within the last 3 months)
or myocardial infarction within the past 6 months.

- No known brain metastases (progressive neurologic dysfunction may confound the
evaluation of neurologic and other adverse events).

- No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- No uncontrolled hypertension defined as systolic blood pressure > 140 mmHg or
diastolic pressure > 90 mmHg, despite optimal medical management.

- No known active Hepatitis or HIV.

- No history of allergic reactions attributed to compounds sorafenib or its excipients.

- No uncontrolled intercurrent illness such as ongoing or active infection (fungal,
bacterial, and/or viral), CTCAE grade 2 or greater.

- No thrombolic or embolic events such as a cerebrovascular accident including
transient ischemic attacks within the past 6 months.

- No serious non-healing wound, ulcer, or bone fracture.

- No major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug.

- No condition that may impair the patient's ability to swallow whole pills.

- Patient must not have any malabsorption problem.

- Patients receiving St. John's Wort or rifampin (rifampicin) are ineligible.

- Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune
thrombocytopenia (ITP) are ineligible.

- Patients must not be experiencing psychiatric illness/social situations that would
limit compliance with study requirements.

- Patients must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.

- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from CLL except cervical cancer in-situ, treated basal cell
carcinoma, squamous cell carcinoma of the skin, or superficial bladder tumor (Ta and
Tis). Subjects surviving a cancer that was curatively treated and without evidence of
disease for more than 3 years before study entry are allowed. All cancer treatments
must be completed at least 3 years prior to study entry (ie, signature date of the
informed consent form).