A Study of BAY 43-9006 in Combination With Bicalutamide in Patients With Chemo-Naïve Hormone Refractory Prostate Cancer

Justification:

The biologic and clinical activity and tolerability of BAY 43-9006, the therapeutic needs of the proposed patient population, and the experimental evidence in support of targeting the VEGF/VEGFR and MAPK pathways in combination with androgen receptor blockade in prostate cancer, provides a strong rationale for the proposed phase II trial to evaluate the tolerability and anti-cancer activity of combined treatment with the non-steroidal anti-androgen bicalutamide with the multi-targeted kinase inhibitor BAY 43-9006 in patients with prostate cancer that is progressing after castration therapy.

Objectives:

The primary study objective is to define the efficacy (i.e. post treatment decrement in PSA (PSA response)) of BAY 43-9006 in combination with bicalutamide in patients with chemo-naïve hormone-refractory prostate cancer.

Secondary Objectives:

• To determine the safety and tolerability of BAY 43-9006 given in combination with bicalutamide in patients with HRPC.
• To determine the time to treatment failure, PSA progression and disease progression in HRPC patients treated with BAY 43-9006 in combination with bicalutamide.
• To determine objective response rates in HRPC patients with measurable disease treated with BAY 43-9006 in combination with bicalutamide.

Research Method:

This is a phase II clinical trial in patients with androgen independent prostate cancer which will evaluate the therapeutic activity and safety profile of BAY 43-9006 given orally at the recommended phase II dose of 400 mg PO BID continuously in combination with bicalutamide 50 mg PO daily continuously. Each 4 week period will be considered 1 cycle. Doses will be adjusted for toxicity.

Statistical Analysis:

Primary Endpoint The primary endpoint for this study will be the rate of PSA-response of the combination for patients with rising PSA post castration therapy.

Secondary Endpoints:

Secondary endpoints will include time to treatment failure, time to PSA progression, duration of PSA response, median survival time, 1 year survival rate, objective tumor response rate and stable disease rate as defined by the RECIST criteria, response duration, and incidence of toxicities by NCI CTCAE.

Inclusion criteria

• Patients must have a histologic or cytologic diagnosis of adenocarcinoma of the prostate.
• Patients must have low-bulk asymptomatic metastatic or biochemical recurrent disease for which no curative therapy exists.
• Patients must have documented evidence of PSA progression while receiving androgen ablative therapy, i.e. must be hormone refractory.
• The PSA must be > 5 μg/L at the time of study entry.
• ECOG performance status of 0 or 1.
• Age 18 years of age or older
• Patients must have a life expectancy of at least 12 weeks.
• Chemotherapy: No prior cytotoxic chemotherapy is permissible. Neoadjuvant or adjuvant chemotherapy is permissible provided it was > 12 months prior to registration.
• Hormonal Therapy:

• Prior hormone therapy in the form of medical or surgical castration is required. Patients must be hormone refractory and have been previously and currently treated with androgen ablative therapy.
• Patients may have received up to one line of non-steroidal anti- androgens in combination with chemical or surgical castration. Use of prior Bicalutamide is restricted to less than 3 months of continuous usage. Patients must be off anti-androgens for at least 6 weeks prior to study entry.
• Radiation: Prior external beam radiation is permitted provided a minimum of 4 weeks has elapsed between the last dose and enrollment to the trial.
• Steroids. Current treatment with steroids ≤ an equivalent of prednisone 20 mg day is permitted.
• Men of childbearing potential must use an effective form of contraception i.e. double barrier method.
• Laboratory Requirements - within 7 days prior to enrollment Hematology: Hemoglobin ≥ 100g/L Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L INR ≤ 1.5 x upper limit of normal Biochemistry: AST, ALT within normal limits Bilirubin within normal limits Serum creatinine ≤1.5 x upper limit of normal

• Patient consent must be obtained 16. Patients must be accessible for treatment and follow-up. 17. Protocol treatment is to begin within 5 working days of patient registration.

Exclusion criteria

• Prior use of BAY 43-9006 or other VEGF/VEGFR or EGFR targeting agents.
• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer or other solid tumours curatively treated with no evidence of disease for > 5 years.
• Patients with known brain metastases or leptomeningeal disease
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 43-9006 or other agents used in the study.
• Other serious intercurrent illness or medical condition that might be aggravated by protocol treatment including:myocardial infarction within 6 months prior to study entry:

• myocardial infarction within 6 months prior to study entry
• congestive heart failure
• unstable angina
• cardiomyopathy
• unstable ventricular arrhythmia
• uncontrolled hypertension (systolic blood pressure ≥ 160, diastolic blood pressure ≥100)
• controlled psychotic disorders
• serious infections
• peptic ulcer disease
• history of bleeding diathesis
• Upper gastrointestinal or other conditions that would preclude compliance with oral medication.
• Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated.
• Patients who require large amounts of narcotic therapy to control pain (e.g. morphine equivalent dose > 30 mg/day) since these patients would more appropriately be offered systemic chemotherapy.
• Patients who require therapeutic anticoagulation.