Phase II Trial: Higher Dose Casodex in Hormone Refractory Prostate Cancer Patients.

Condition(s) targeted: Prostate Cancer

Intervention: Bicalutaminde-Casodex (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Sunnybrook Health Sciences Centre

Official(s) and/or principal investigator(s):
Laurence Klotz, MD, FRCSC, Principal Investigator, Affiliation: Canadian Urology Research Consortium

Overall contact:
Irene McNeill, Pharmacist, Phone: 416-480-6100, Ext: 2431, Email: irene.mcneill@sw.ca

For patients who have been told by their doctor that they have progressive cancer of the prostate gland for which they have been receiving the luteinizing hormone-releasing hormone, goserelin acetate (Zoladex®) and bicalutamide (Casodex®) 50mg therapy, hormonal therapy with medical or surgical castration with or without an anti-androgen drug is considered to be standard first line therapy for advanced prostate cancer. Medical castration is usually achieved by the administration of a medication called luteinizing hormone-releasing hormone (LHRH) analog, which causes a reduction in the testosterone levels in your body. Anti-androgens are drugs that work directly by interfering with how testosterone affects your prostate tumor cells. The combination of an LHRH analog with an anti-androgen will be giving you Combined Androgen Blockade (CAB).

Patients develop progressive disease, termed hormone refractory prostate cancer, when the standard first line of therapy no longer works. What we hope to find out with this trial is whether or not there is a benefit of starting bicalutamide (Casodex®) at a higher dosage (150mg) plus medical castration now as a second line of therapy for the treatment of progressive prostate cancer.

Official title: An Open-Label, Phase II Trial of Maximum Androgen Blockage (MAB) Dose Escalation From 50 Mg to 150 Mg Bicalutamide (Casodex®) for Biochemical Failure in Prostate Cancer Patients

Study design: Interventional, Treatment, Non-Randomized, Open Label, Dose Comparison, Single Group Assignment, Efficacy Study

Primary outcome: With 100 subjects and assuming alpha of 0.5, the study would have a 90% chance of identifying a true response rate of 25% or greater.

Detailed description: Recent laboratory evidence indicates that the non-steroidal anti-androgens have important effects in blocking androgen independent activation of the androgen receptor in the androgen depleted environment. In addition, the non-steroidal agents vary in the degree to which they block androgen independent activation. Bicalutamide binds more avidly to the androgen receptor (AR), and interacts more favourably with nuclear co-repressors and co-activators of the AR. A recently updated meta-analysis incorporating the one randomized trial comparing bicalutamide to flutamide (and goserelin to leuprolide) into this analysis indicates that bicalutamide 50 mg used as for MAB reduces prostate cancer mortality by 20% in men with metastatic prostate cancer. (Klotz, 2004)

The rationale for the hypothesis that increasing the dose of bicalutamide may be effective in the early stages of androgen independence in patients who are on LHRH agonists + bicalutamide 50 mg daily is derived from several pieces of indirect evidence.

The effect of anti-androgens in blocking androgen independent activation of the androgen receptor is dependent on nuclear concentrations of bicalutamide. It is therefore likely to be dosage dependent.

Gender(s): Male.

Criteria:

Inclusion Criteria:

1. Provision of written informed consent.

2. Men, over 18 years of age, with histologically-confirmed prostate cancer

3. Treatment with Zoladex (goserelin acetate) for greater than 3 months prior to Day 1

4. Serum testosterone level < 50 ng/ml

5. Current treatment with bicalutamide 50 mg daily.**

6. Two consecutive rises in PSA above a nadir value, with the absolute value of the latest PSA > 2. 0 ng/ml.

7. Highest PSA level no greater than or equal to 30 ng/ml.

8. Life expectancy of greater than 1 year. -

Exclusion Criteria:

1. Patients may not have received prolonged anti-androgen therapy other than with bicalutamide. Patients who have received short term (2 months or less) non-steroidal anti-androgen therapy with an agent other than bicalutamide to block flare are not excluded.*

2. PSA level greater than 30 ng/ml.

3. In the opinion of the investigator, any evidence of severe or uncontrolled systemic disease which would make it undesirable for the patient to participate in the trial.

4. Subjects who have received prior chemotherapy.

5. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or superficial transitional cell carcinoma of the bladder.

6. Absolute neutrophil count less than 1. 5 x 109/L or platelets less than 100 x 109/L.

7. Serum bilirubin greater than 1. 25 times the upper limit of reference range (ULRR).

8. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2. 5 times the ULRR.

9. Serum creatinine greater than 1. 5 times the ULRR

* The prior use of steroidal anti-androgens, i. e. cyproterone acetate, is not an exclusion criterion as long as patients were taken off those drugs prior to the determination of successive rise in PSA.

Irene McNeill, Pharmacist, Phone: 416-480-6100, Ext: 2431, Email: irene.mcneill@sw.ca

Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M4N3M5, Canada; Recruiting
Irene McNeill, Pharmacist, Phone: 416-480-6100, Ext: 2431, Email: irene.mcneill@sw.ca
Kusum Sharma, RN, Phone: 416-480-6100, Ext: 7939, Email: kusum.sharma@sw.ca
Laurence Klotz, MD, FRCSC, Principal Investigator

Starting date: November 2005
Ending date: November 2006
Last updated: September 14, 2006