Pharmacodynamic Study of Abiraterone in the Treatment of Advanced Prostate Cancer

From the protocol:

The primary objectives of this study are:

- To determine the ability of abiraterone in patients with metastatic CRPC resistant to LHRH
agonist ± antiandrogen to suppress tumor testosterone at one month compared to baseline
tissue testosterone, to confirm proposed mechanism of action. Tumor levels of
testosterone, DHT, DHEA and androstenedione will also be analyzed at baseline, one month,
three months and progression with each time point being addressed in different cohorts.

The exploratory objectives of this study are:

- To determine response to dose escalation of abiraterone and associate response to tumor
androgen levels prior to dose escalation

- To determine potential mechanisms of resistance to abiraterone by analyzing tissue
microarray, tissue androgen levels at progression and evaluating wild type and splice
variant AR levels at baseline and at time of progression.

- To determine whether circulating tumor cells acquired from peripheral blood reflect
molecular changes in tumor metastases and are a potential biomarker for mechanisms of
sensitivity and resistance.

- To determine if microRNA acquired from peripheral blood reflect molecular changes in
tumor metastases and are a potential biomarker for mechanisms of sensitivity and
resistance.

Inclusion Criteria:

- Willing and able to provide written informed consent

- Written Authorization for Use and Release of Health and Research Study Information
has been obtained

- Male aged 18 years and above

- Histologically proven adenocarcinoma of the prostate.

- ECOG performance status <2 (Karnofsky >60%; see Appendix B).

- Castration resistant prostate cancer as defined by serum testosterone < 50 ng/ml and
one of the following:

- PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions
at least 1 week apart.

- Evaluable disease progression by modified RECIST (Response Evaluation Criteria
in Solid Tumors)

- Progression of metastatic bone disease on bone scan with > 2 new lesions

- Maintenance of LHRH agonist or antagonist unless previously treated with orchiectomy.

- The presence of metastatic disease amenable to CT or ultrasound guided biopsy. This
may include thoracolumbar vertebral bodies, pelvis, femur or humerus, or soft tissue
or nodal metastasis amenable to biopsy (excluding lung or pleural lesions).

- Patients may have received secondary hormonal manipulations or up to two cycles of
chemotherapy.

- Laboratory values within protocol parameters

- Able to swallow the study drug whole as a tablet

- Patients who have partners of childbearing potential must be willing to use a method
of birth control with adequate barrier protection as determined to be acceptable by
the principal investigator and sponsor during the study and for 13 weeks after last
study drug administration.

Exclusion Criteria:

- Active infection or other medical condition that would make prednisone/prednisolone
(corticosteroid) use contraindicated

- Patients who are currently receiving active therapy for other neoplastic disorders
will not be eligible.

- Patients with histologic evidence of small cell carcinoma of the prostate will not be
eligible.

- Known brain metastasis

- Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg) Patients
with a history of hypertension are allowed provided blood pressure is controlled by
anti-hypertensive treatment

- Active or symptomatic viral hepatitis or chronic liver disease

- History of pituitary or adrenal dysfunction

- Clinically significant heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or New
York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction
measurement of < 45 % at baseline

- Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy

- Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1

- Patients with dementia/psychiatric illness/social situations that would limit
compliance with study requirements or would prohibit the understanding and/or giving
of informed consent will not be eligible

- Patients with medical conditions, which, in the opinion of the investigators, would
jeopardize either the patient or the integrity of the data obtained will not be
eligible.

- Any condition which, in the opinion of the investigator, would preclude participation
in this trial.