Sorafenib and Docetaxel in Patients With Prostate Cancer That Did Not Respond to Previous Hormone Therapy

OBJECTIVES:

Primary

• To determine the proportion of patients achieving a 50% reduction in serum PSA from baseline in patients with androgen-independent prostate cancer (AIPC) receiving sorafenib tosylate and docetaxel.

Secondary

• To estimate the progression-free survival of patients with AIPC.
• To quantify the number and percent of patients who have stable disease at 6 months of therapy (failure to progress).
• To estimate median time to progression for all patients.
• To estimate the objective response rate of patients with AIPC treated with this regimen.
• To measure the percentage of patients surviving at 2 years.
• To determine the toxicities and estimate toxicity rates for patients treated with this regimen.
• To measure changes in tumor vasculature in response to therapy in selected patients with dynamic contrast-enhanced MRI (DCE-MRI) and correlate primary and secondary objectives to these measurement changes.
• To measure changes in serum HMGB1 in response to therapy and correlate primary and secondary objectives with these changes.
• To measure changes in serum cathepsin D in response to therapy and correlate primary and secondary objectives with these changes.

OUTLINE: Patients receive oral sorafenib tosylate twice daily on days 2-19 and docetaxel IV on day 1. Treatment repeats every 21 days for up to 10 courses. Patients then receive oral sorafenib tosylate alone twice daily on days 1-19 with treatment repeating every 21 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically to measure serum HMGB1 and cathepsin D levels before and after therapy.

Inclusion criteria

• Histologically or cytologically confirmed adenocarcinoma of the prostate with clinical or radiological evidence of metastatic disease.
• Serum PSA >5 ng/mL.
• Patients must have discontinued flutamide or nilutamide for at least 4 weeks and bicalutamide for at least 6 weeks
• Disease progression during hormonal therapy defined as at least one of the following:

• increasing serum PSA levels on at least two measurements at least two weeks apart.
• Progressive measurable disease (by RECIST criteria) independent of PSA
• Bone scan progression with at least one new lesion.
• Serum testosterone ≤ 50 ng/dL. Patients must be receiving primary androgen ablation therapy with a GnRH agonist as maintenance therapy unless surgically castrated.
• Age > 18 years.
• ECOG performance status of ≤ 1.
• Baseline laboratory values (evaluated within 14 days of randomization):

White Blood Count > 3,000/mm3 Absolute Granulocyte Count > 1,500/mm3 Platelet Count > 100,000/mm3 Serum creatinine < 2.0 x upper limit of normal (ULN) INR < 1.5 before the start of chronic anticoagulation and a PTT within normal limits

• Liver Function Total Bilirubin less or equal to ULN AST and ALT must be <5X ULN for eligibility. In determining eligibility the more abnormal of the two values (AST or ALT) should be used.
• Prior radiation therapy is allowed. However, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions. 4 weeks must have elapsed between radiation therapy and entry into study.
• Prior vaccine therapy is allowed
• Prior and/or concurrent zoledronic acid (Zometa) therapy is allowed.
• Men of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.

Exclusion criteria

• Prior therapy with cytotoxic chemotherapy
• Prior therapy with radioisotopes
• History of brain metastasis or leptomeningeal disease
• Symptomatic neuropathy >grade2
• Prior history of cancer (except basal cell or squamous-cell skin cancer) within the past 5 years (exceptions must be approved by the PI)
• Prior history of DVT or Pulmonary embolism in the last 1 year
• Patients must not have a serious medical illness including, but not limited to, ongoing or active infection requiring parental antibiotics; clinically significant cardiovascular disease (e.g. uncontrolled hypertension, recent myocardial infarction, unstable angina), New York heart association grade II or greater congestive heart failure, or grade II or greater peripheral arterial vascular within 1 year prior to study entry, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), rifampin or St. John's wort.
• Patients must not be taking drugs that inhibit CYP3A at the time of enrollment to prevent drug-drug interactions with docetaxel. These include ketoconazole, voriconazole, itraconazole, fluconazole, cimetidine, clarithromycin, erythromycin, troleandomycin, and grapefruit juice. These agents should be avoided during treatment while on study.
• Because patients with immune deficiency are at increased risk of lethal infections when treated with bone marrow-suppressive therapy, HIV-positive patients are excluded from the study. For patients receiving combination anti-retroviral therapy, the potential impact of pharmacokinetic interactions with sorafenib and docetaxel is unknown. Appropriate studies may be undertaken in patients with HIV and those receiving combination anti-retroviral therapy in the future.
• Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80