BAY 43-9006 (Sorafenib) to Treat Patients With Kaposi's Sarcoma

BACKGROUND: This study is designed to test the toxicity and pharmacokinetics of different
doses of BAY 43-9006 (Sorafenib) in patients with Kaposi s sarcoma (KS). It will also assess,
in a preliminary manner, the activity of BAY 43-9006 in this disease and its effect on
biological markers. BAY 43-9006 is a potent inhibitor of wild-type and mutant c-Raf kinase
isoforms. In addition, this agent also inhibits p38, c-kit, vascular endothelial growth
factor receptor 2(VEGFR2), VEGF-R3, and platelet derived growth factor receptor beta
(PDGFR-B). There is evidence that several of these receptors, and especially VEGF-R2,
VEGF-R3, and PDGF-RB, are important in KS pathogenesis. The principle tumor cells of KS
lesions are spindle cells, which are derived from endothelial cells. Spindle cells
proliferate in response to VEGF, VEGF-C (a ligand for VEGF-R3), and PDGF, and the stimulation
of spindle cells by these factors appears to be an important component in the pathogenesis of
KS. There is also evidence that c-kit is important in KS. Because BAY 43-9006 can inhibit the
function of these receptors and c-kit, it may have specific activity against this tumor. BAY
43-9006 is metabolized at least in part by CYP 3A4, and ritonavir, an HIV protease inhibitor
commonly used in AIDS patients, is an inhibitor of CYP 3A4. Also, AIDS patients are often
quite sensitive to drug toxicities. Thus, patients with AIDS-KS on ritonavir may be
particularly sensitive to BAY 43-9006.

OBJECTIVES: To assess the toxicity profile and pharmacokinetics of BAY 43-9006 at oral dose
regimens of 200 mg once daily, 200mg twice daily, or 400 mg twice daily, up to the toxic
dose, in patients with HIV-associated Kaposi s sarcoma (KS) who are receiving ritonavir.
Also, to assess in a preliminary manner the pharmacokinetics and toxicity profile of BAY
43-9006 in patients who are not receiving ritonavir.

ELIGIBILITY: Key eligibility criteria are as follows: patients 18 years of age or older, with
or without HIV infection, and with KS and at least 5 cutaneous lesions untreated by local
therapy; patients with HIV infection must have KS that is progressing or stable on highly
active antiretroviral therapy (HAART); patients with extensive active, visceral, or
symptomatic KS are excluded.

DESIGN: Patients with AIDS-KS who are receiving ritonavir will be administered BAY 43-9006.
An initial group of patients will be administered 200 mg BAY 43-9006 once daily, and
subsequent groups will receive 200 mg twice daily and 400 mg twice daily respectively. Also
two groups of patients with KS and not on ritonavir will be administered 200 mg and 400 mg
BAY 43-9006 twice daily respectively. Patients will be studied for toxicity,
pharmacokinetics, KS response, the effect on biological markers such as target receptor
kinase phosphorylation and signaling molecules in KS tissue. Other parameters that will be
assessed will include VEGF levels, the viral load of KSHV, and KS lesion blood flow by
non-invasive techniques. If patients tolerate BAY 43-9006, they will receive it for up to 24
weeks. If they have evidence of stable KS or a tumor response, they may receive the drug for
up to 54 weeks total.

- INCLUSION CRITERIA:

1. Age 18 years or greater.

2. Kaposi's sarcoma (KS) pathologically confirmed by CCR Pathology. Patients with
both HIV-associated and HIV-negative KS will be eligible.

3. Either (1) at least 5 measurable cutaneous KS lesions with no previous local
therapy, or (2) other measurable non-cutaneous disease that permits a response to
be assessed.

4. Patients with HIV-related KS must be receiving and be willing to comply with a
regimen of highly active antiretroviral therapy (HAART) consistent with DHHS
treatment guidelines that either (1) utilizes 3 or more drugs or (2) attains
suppression of HIV below the limit of detection (50 copies HIV/ml using Roche
Amplicor Monitor assay or similar standard test).

5. For patients with HIV-associated KS, KS lesions must either (1) be increasing
during the 3 months prior to screening while the patient is receiving HAART or
has unchanged suppression of HIV to below the limits of detection; or (2) must be
stable for at least four months while the patient is taking highly active
antiretroviral therapy (HAART).

6. ECOG performance status less than or equal to 2

7. Life expectancy greater than 6 months

8. The following hematologic parameters:

- Hemoglobin greater than 9 g/l

- WBC greater than 1000/mm(3)

- Platelets greater than 75,000/mm(3)

- PT and PTT less than or equal to 120% of control, unless the patient has the presence
of a lupus anticoagulant

The following hepatic parameters:

- For patients not receiving protease inhibitor therapy: bilirubin less than or equal to
1.5 times the upper limit of normal (ULN). For patients receiving protease inhibitor
therapy and for whom the elevated bilirubin is felt to be related to this therapy
total bilirubin should be less than or equal to 3.7 mg/dl with a direct fraction less
than or equal to 0.2 mg/dl.

- AST/GOT less than or equal to 2.5 times the ULN

- Either serum creatinine less than or equal to 1.5 mg/dl or measured creatinine
clearance greater than 60 mL/min.

- Patients must be willing to use effective birth control.

EXCLUSION CRITERIA:

1. Patients with extensive active or symptomatic pulmonary KS

2. Patients with symptomatic visceral KS, except for that involving the oral cavity

3. KS that appears to be improving after other therapy

4. Inability to provide informed consent

5. Patients requiring systemic therapy with ketoconazole or itraconazole

6. Cytotoxic chemotherapy or other specific KS therapy (except for antiretroviral
therapy) within the past 3 weeks.

7. Prior therapy with BAY 43-9006

8. Known hypersensitivity to BAY 43-9006

9. Supraphysiologic doses of corticosteroids within 3 weeks

10. Pregnancy (because of unknown potential for fetal malformation)

11. Breast feeding (because of unknown potential for adverse infant developmental
considerations)

12. Past or present history of malignant tumors other than KS unless: a) in complete
remission for greater than or equal to 1 year from the time a response was first
documented; b) completely resected basal cell carcinoma; or c) in situ squamous cell
carcinoma of the cervix or anus

13. Evidence of severe or life-threatening infection within 2 weeks of entry into the
study

14. Elevated lipase greater than 2 times the ULN or amylase greater than 2 times the ULN
(unless documented to be of non-pancreatic origin or associated with macroamylasemia

15. Patients with any other abnormality that would be scored as a grade 3 or greater
toxicity, except:

- lymphopenia

- direct manifestation of KS

- direct manifestation of HIV infection, except for neurologic or cardiac
manifestations.

- direct manifestation of HIV therapy, except for neurologic or cardiac
manifestations or those addressed elsewhere in the eligibility requirements or
that would be scored as grade 4.

- asymptomatic hyperuricemia

16. Any condition that, in the opinion of the principal Investigator or Study Chairperson
would preclude the inclusion of a patient into this research study.

17. Patients must not have evidence of a bleeding diathesis.

18. Patients must not be on therapeutic coagulation. Prophylactic anticoagulation (i.e.
low dose warfarin) of venous or arterial access devices is allowed provided that the
requirements for PT and PTT are met.

19. Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs
(phenytoin, carbamazepine, and Phenobarbital), rifampin, or St. Johns Wort.

20. Patients are excluded if they have uncontrolled hypertension (diastolic blood pressure
greater than 99 mm Hg or systolic blood pressure greater than 159 mm Hg)

21. Patients are excluded if they have uncontrolled intercurrent illness including, but
not limited to, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.

22. Patients must be able to understand and be willing to sign a written informed consent
document, and express willingness and the ability to comply with the requirements of
the protocol.