Everolimus as First-Line Therapy in Treating Patients With Prostate Cancer

OBJECTIVES:

Primary

• Determine the progression-free survival at 12 weeks of patients with non-rapidly progressive castration-resistant prostate cancer treated with everolimus as first-line therapy.
• Assess the activity and safety of this regimen in these patients.

Secondary

• Determine the progression-free survival at 24 weeks of patients treated with this regimen.
• Determine the percentage of PSA response from baseline to 12 weeks in patients treated with this regimen.
• Determine the changes in PSA-doubling time in patients treated with this regimen.
• Determine the overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up at 28 days and then every 3 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic or locally advanced adenocarcinoma of the prostate

• No curative therapy available
• Oligosymptomatic or asymptomatic patients
• Tumor progression after ≥ 1 hormonal treatment (orchiectomy or luteinizing-hormone releasing-hormone [LHRH] agonist) with documented total testosterone levels ≤ 1.7 nmol/L (≤ 50 ng/dL)

• Concurrent LHRH agonist therapy is required for patients who have not been surgically castrated
• Must have stopped antiandrogen therapy ≥ 6 weeks before the start of trial treatment without withdrawal response
• PSA progression defined as an increase in PSA ≥ 25% (and an absolute increase of 2 ng/mL or more) over nadir value on hormonal therapy measured on 3 successive occasions ≥ 1 week apart

• If the third measurement is not higher than the second, a fourth measurement will be taken (patient allowed if the fourth measurement is higher than the second)
• PSA doubling time ≥ 55 days
• No known or suspected CNS metastases

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 90 g/L
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ≤ 2.5 times ULN
• Creatinine clearance ≥ 40 mL/min
• Fasting serum cholesterol ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 times ULN

• Appropriate lipid-lowering medication allowed in case one or both of these thresholds are exceeded
• Patient compliance and geographic proximity that would allow proper staging and follow-up are required
• No malignancy within the past 5 years except curatively treated localized nonmelanoma skin cancer or Ta and Tis bladder cancer
• No known history of HIV
• No serologically confirmed hepatitis B or C
• No serious underlying medical condition that, in the judgment of the investigator, could impair the ability of the patient to participate in the trial including, but not limited to, any of the following conditions:

• Uncontrolled or acute severe infection
• Uncontrolled diabetes
• Advanced chronic obstructive pulmonary disease
• No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, or interfering with compliance for oral drug intake
• No known hypersensitivity to trial drug or hypersensitivity to any of its components

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy, radioisotopes, small molecules, immunotherapy, or investigational drug therapy for prostate cancer
• No local radiotherapy within the past 2 weeks
• No major surgery within the past 4 weeks
• No concurrent radiotherapy
• No concurrent angiotensin converting enzyme inhibitors
• No concurrent chronic immunosuppressive therapy including high-dose corticosteroids (i.e., > 25 mg prednisone equivalent per day)
• No products known to affect PSA levels (e.g., PC Calm, PC Plus, PC SPES, finasteride, or fluconazole) within the past 4 weeks or concurrently
• No strong CYP3A4 inhibitors (e.g., itraconazole, erythromycin, clarithromycin, diltiazem, verapamil, or grapefruit or its juice) within the past 2 weeks or concurrently
• No strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, or St. John wort) within the past 2 weeks or concurrently
• No concurrent bisphosphonates

• Patients must continue to receive bisphosphonates regularly if it was started prior to entering the trial
• No concurrent experimental drugs or other anticancer therapy in a clinical trial within the past 30 days
• No concomitant drugs contraindicated for use with the trial drug according to the investigator's drug brochure