A Phase II Study of BAY 43-9006 (Sorafenib) in Metastatic, Androgen-Independent Prostate Cancer

BAY 43-9006 (Sorafenib) is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase isoforms in vitro. In addition, this agent also inhibits p38, c-kit, vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor beta (PDGFR-beta) affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf. At this time, over 500 patients have been treated with this drug with tolerable side effects.

The primary objective of this study is to determine if BAY 43-9006 (Sorafenib) is associated with a 50% 4 month probability of progression free survival in patients with metastatic androgen independent prostate cancer (AIPC) as determined by clinical, radiographic, and prostatic specific antigen (PSA) criteria.

The secondary objective of this study will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible). Correlative studies will be conducted on serially obtained tissue biopsies, bone marrow biopsies, and white blood cell collections. These laboratory correlates will include elucidation of activation of components of the Raf-extracellular-signal regulated kinase (ERK)-methyl ethyl ketone (MEK) and angiogenesis pathways using protein microarray technologies developed by the National Cancer Institute (NCI)/Food and Drug Administration (FDA) clinical proteomics program.

Per Amendment D, a secondary objective of this study will also be to determine the time to progression measured by clinical and radiographic criteria. The 22 patients treated on the first stage of this protocol will be retrospectively evaluated with respect to this secondary endpoint possible. Please refer to the statistics section for further details.

The combination of correlated clinical and laboratory endpoints with emphasis on molecular signaling will provide new information on the anti-tumor effects helping to characterize its role in the treatment of androgen independent prostate cancer (AIPC).

• INCLUSION CRITERIA

Patients must have histopathological confirmation of prostate cancer by the Laboratory of Pathology of the National Cancer Institute (NCI) or Pathology Department of the National Naval Medical Center prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled in the trial if the patient has a clinical course consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. In cases where original tissue blocks or archival biopsy material is available, all efforts should be made to have the material forwarded to the research team for use in correlative studies.

Patients must have metastatic progressive androgen-independent prostate cancer. There must be radiographic evidence of disease after primary treatment with either surgery or radiotherapy that has continued to progress despite hormonal agents. Progression requires that a measurable lesion is expanding, new lesions have appeared, and/or that prostatic specific antigen (PSA) is continuing to rise on successive measurements. Patients on flutamide must have disease progression at least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal.

Patients may have had no more than 1 previous cytoxic chemotherapeutic line.

Because no dosing or adverse event data are currently available on the use of BAY 43-9006 (Sorafenib) in patients less than 18 years of age, children are excluded from this study.

Patients must have a life expectancy of more than 3 months.

Patients must have a performance status of 0 to 2 according to the Eastern Cooperative Oncology Group (ECOG) criteria.

Patient must have adequate organ function as defined below:

Leukocytes greater than or equal to 3,000/microL

Absolute neutrophil count greater than or equal to 1,500/microL

Platelets greater than or equal to 100,000/microL

Total bilirubin less than or equal to 1.5 X institutional upper limits of normal

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase(SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 X institutional upper limit of normal

Creatinine less than or equal to 1.5 X institutional upper limits of normal OR:

Creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.

Hormonal profile: all patients who have not undergone bilateral surgical castration must continue suppression of testosterone production by appropriate usage of gonadotropin releasing hormone (GnRH) agonists.

Patients must not have other invasive malignancies (within the past two years with the exception of non-melanoma skin cancers or non-invasive bladder cancer).

Patients must be able to understand and sign an informed consent form.

Concurrent use of bisphosphonates will be allowed for patients with known bone metastases

Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin), non-steroidal anti-inflammatory drug (NSAIDs), and other maintenance medications prior to study entry will be allowed to continue their supportive therapies.

The effects of BAY 43-9006 (Sorafenib) on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because Raf-kinase inhibitors are known to be teratogenic, men must agree to use adequate contraception (abstinence; hormonal or barrier method of birth control) prior to study entry and for the duration of study participation.

Exclusion criteria

Patients who have had chemotherapy or radiotherapy (including radioisotopes) within 4 weeks (6 weeks for nitrosoureas or mitomycin C, greater than 3 months for suramin) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

Patients may not be receiving any other investigational agents.

Patients with known brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 (Sorafenib)

Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Hypertension as defined by systolic blood pressure in excess of 170 mmHg or diastolic pressure in excess of 100 mmHg. Patients with a history of hypertension that is well controlled on medication will not be excluded. Patients may not be on either verapamil or diltiazem while on study. Use of calcium channel blocker should be discouraged.

Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006 (Sorafenib). Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.

History of bleeding diathesis

Patients on therapeutic anticoagulation are at increased risk from bleeding while on BAY 43-9006 (Sorafenib). Prophylactic anticoagulation (i.e. low dose warfarin) of venous or arterial access devices is allowed provided that the requirements for prothrombin time (PT), International normalized ratio (INR) or partial thromboplastin time (PTT) are met: PT less than 1.1 x institutional upper limit of normal; INR less than 1.1; PTT within the institutional limits of normal. These requirements will only be made upon those patients on warfarin.

INCLUSION OF WOMEN AND MINORITIES

Men of all races and ethnic groups are eligible for this trial. Women are excluded by the nature of the disease.