Pre-Prostatectomy Lovastatin on Prostate Cancer

Pharmacodynamic Phase 0 trial of pre-prostatectomy lovastatin to downregulate MYC in
localized prostate cancer.

Rationale: Based on available clinical and preclinical data, the investigators theorize that
high-dose lovastatin therapy will decrease MYC levels in human prostate cancers shown to have
MYC overexpression on biopsy.

Experimental Methods: The investigators propose a prospective, dose-finding pharmacodynamic
study of lovastatin in intermediate/high-grade localized prostate cancer. The study will
involve 30 eligible patients with localized prostate cancer with a Gleason sum of 7 to 10 who
elect to undergo prostatectomy at Johns Hopkins. Five eligible men will be scheduled to
receive oral lovastatin following a four times a day schedule, at the starting dose of 12
mg/kg/day. Patients will receive 2 weeks (14 days) of daily oral lovastatin prior to surgery.
Following an initial safety monitoring period of a month, the investigators enroll at the
next dose level (20 mg/kg/day). Similar dose de-escalation will continue over three more dose
levels (1, 4 and 8 mg/kg/day) until 25 patients total are enrolled. Following surgery,
prostatectomy specimens will undergo MYC immunohistochemistry (IHC) and compared to MYC IHC
from matched biopsy samples. Pharmacodynamic efficacy (PE) will be defined as greater than
60% inhibition of MYC expression by IHC in greater than 60% of patients in prostatectomy
tumor specimens compared to the matched biopsy.

Expected Results: The investigators expect lovastatin will enforce the downregulation of MYC
levels in prostatectomy samples as compared to pre-lovastatin treatment core biopsy samples.
The investigators also expect little toxicity to patients as reported in prior phase I and II
trials using similar doses of lovastatin.

Inclusion Criteria:

1. Adenocarcinoma of the prostate, without evidence of spread beyond to lymph nodes,
bone, or visceral organs, stage T1c or higher.

2. Tumor Gleason sum of 7 (4+3 and 3+4 allowed) in at least one core, after central
review of prostate biopsy at Johns Hopkins. However, in accordance with standard
clinical practices, adenocarcinoma must be present in at least two discrete biopsy
sections ( may vary in Gleason score).

3. Age ≥18 years of age.

4. Radical prostatectomy scheduled at Johns Hopkins.

5. Willingness to sign and ability to understand informed consent.

6. No history of treatment with any statin-class medication within 6 months of entry into
the trial.

7. ECOG (Eastern Cooperative Oncology Group) performance status 0-1.

8. Adequate bone marrow, hepatic, and renal function as determined by:

WBC (white blood cells) >3,500 cells/mm3 ANC (absolute neutrophil count) >1,500 cells/mm3
Hemoglobin >9 g/dl Platelet count >100,000 cells/mm3 Serum creatinine < 2.6 mg/dl Serum
bilirubin <2 mg/dl ALT (alanine aminotransferase), AST (aspartate aminotransferase), and
Alkaline Phosphatase <2 times the upper limit of normal Triglycerides and total cholesterol
<3 times the upper limit of normal

Exclusion Criteria:

1. Patients with evidence of metastatic prostate cancer, including bone, visceral, brain,
and lymph node metastases.

2. Other histologic prostate cancers, including ductal, sarcomatous, lymphoma, small
cell, and neuroendocrine tumors.

3. Uncontrolled medical conditions that could potentially increase the risk of toxicities
or complications of this therapy including active liver disease, unexplained
persistent elevation of serum transaminases, or medications that interfere with the
metabolism of lovastatin, or gastrointestinal disease that would limit the ability to
swallow or take oral medications or absorb them.

4. Concurrent malignancy other than prostate cancer.

5. Inability to provide informed consent.

6. Concomitant use of azole antifungals, cyclosporine, clarithromycin, erythromycin,
fibric acid derivatives, lopinavir/ritonavir, niacin, ritonavir/saquinavir

7. Prior chemotherapy, radiation therapy, biologic therapy, or immunotherapy for prostate
cancer.

8. Poor performance status (ECOG >1).

9. Prostatectomy at other hospital other than Johns Hopkins.

10. Prior history of allergy or severe reaction to statins or statin derivatives.