Pre-Prostatectomy Lovastatin on Prostate Cancer

Study Description

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Brief Summary:

To determine the dose of continuous daily oral lovastatin needed to achieve MYC [v-myc myelocytomatosis viral oncogene homolog (avian)] down-regulation in prostatectomy specimens in intermediate-/high-risk localized prostate cancer patients.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Drug: Lovastatin	Not Applicable

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	2 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacodynamic Trial of Pre-Prostatectomy Lovastatin on MYC (V-myc Myelocytomatosis Viral Oncogene Homolog) Down-Regulation in Localized Prostate Cancer
Study Start Date :	March 2012
Actual Primary Completion Date :	April 2013
Estimated Study Completion Date :	April 2016

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Lovastatin; After informed consent and central pathology review of the core prostate biopsy, eligible patients who decide to undergo prostatectomy at Johns Hopkins will be scheduled to receive po lovastatin following a four times a day schedule, at the starting dose of 20 mg/kg/day. Following an initial period of monitoring for safety at this entry dose level of one month, we will then accrue patients to dose de-escalation (to 1, and 10 mg/kg/day) cohorts.

Drug: Lovastatin; oral qd varying dose escalations/de-escalations; Other Name: Altoprev®; Mevacor®

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants That Can Achieve 60% MYC Modulation Response [ Time Frame: 1 year ]
   To determine the dose of continuous daily oral lovastatin needed to achieve MYC down-regulation in prostatectomy specimens in intermediate-/high-risk localized prostate cancer patients.

Secondary Outcome Measures :

1. Number of Participants Who Experience Specific Adverse Events at Different Dosing Points Prior to Surgery. [ Time Frame: 1 year ]
   1. To assess the tolerability and toxicity of the different doses of continuous daily oral lovastatin in generally healthy men with prostate cancer prior to surgery.
2. To Estimate What the Doses Given to Men With MYC Target Inhibition When Factoring in Their Tumor Biopsies Before and After Lovastatin Treatment. [ Time Frame: 1 year ]
   2. To estimate an overall and per dose proportion of men with MYC target inhibition in prostate tumor tissue using paired tumor biopsies before and after lovastatin administration.
3. Number and Type of Cholesterol Changes After Lovastatin Treatments. [ Time Frame: 1 year ]
   3. To characterize the effect of continuous daily oral lovastatin on cholesterol level in this patient population, at the doses tested in this trial.
4. Capture the Pharmacodynamic Changes in Participants After the Pre-treatment Biopsy. [ Time Frame: 1 year ]
   4. To assess the relationship of pharmacodynamic target inhibition of MYC with pretreatment prostate biopsy Gleason sum, Ki-67, and degree of MYC overexpression.
5. Capture the Associated Changes in Participants With Regards to the Relationship Between MYC and Increased Apoptosis. [ Time Frame: 1 year ]
   5. To assess an association of pharmacodynamic target inhibition of MYC with markers of increased apoptosis (cleaved caspase-3) and proliferation (Ki-67).
6. Number of Participants Who Follow All of the Study Rules. [ Time Frame: 1 year ]
   6. To assess the study compliance.
7. Capture Difference in MYC Downregulation Between Treated Participants and Non-treated Patients [ Time Frame: 1 year ]
   7. To compare the MYC downregulation between our prostatectomy samples treated with high-dose lovastatin and up to 21 matched prostatectomy reference samples from untreated patients from a pre-existing reference dataset.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 100 Years (Adult, Senior)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center

Investigators

Principal Investigator:	Phouc Tran, M.D.	Johns Hopkins University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01478828 History of Changes
Other Study ID Numbers:	J-1153; NA_00048234 ( Other Identifier: Johns Hopkins University School of Medicine )
First Posted:	November 23, 2011
Results First Posted:	November 9, 2015
Last Update Posted:	November 9, 2015
Last Verified:	October 2015

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Lovastatin; L 647318	Dihydromevinolin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors