Pre-Prostatectomy Lovastatin on Prostate Cancer

• ClinicalTrials.gov Identifier: NCT01478828
• Recruitment Status: Terminated
• First Posted: November 23, 2011
• Results First Posted: November 9, 2015
• Last Update Posted: March 27, 2019
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: Patrick C Walsh Prostate Cancer Research Fund
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: November 3, 2011
• First Posted Date: November 23, 2011
• Results First Submitted Date: January 13, 2015
• Results First Posted Date: November 9, 2015
• Last Update Posted Date: March 27, 2019
• Actual Study Start Date: July 13, 2012
• Actual Primary Completion Date: April 8, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2019)

Number of Participants That Can Achieve 60% MYC Modulation Response [ Time Frame: 1 year ]

Number of participants who achieve V-myc Myelocytomatosis Viral Oncogene Homolog (MYC) down-regulation in prostatectomy specimens in intermediate-/high-risk localized prostate cancer patients.

Original Primary Outcome Measures (submitted: November 21, 2011)

Dose Determination [ 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.

Current Secondary Outcome Measures (submitted: March 14, 2019)

• Number of Participants Who Experience Specific Adverse Events at Different Dosing Points Prior to Surgery. [ Time Frame: 1 year ]
  Toxicity of the different doses of continuous daily oral lovastatin in generally healthy men with prostate cancer prior to surgery.
• Proportion of Men With MYC Target Inhibition in Prostate Tumor Tissue [ Time Frame: 1 year ]
  Proportion of men with MYC target inhibition in prostate tumor tissue using paired tumor biopsies before and after lovastatin administration.
• Change in Cholesterol Level After Lovastatin Treatments. [ Time Frame: 1 year ]
  Change in cholesterol level with each tested dose of oral lovastatin.
• Pharmacodynamic Changes in Participants After the Pre-treatment Biopsy as Measured by Number of Participants With Target Inhibition of MYC [ Time Frame: 1 year ]
  Number of participants with target inhibition of MYC in relationship with pretreatment prostate biopsy Gleason sum, Ki-67, and degree of MYC overexpression.
• Number of Participants With Target Inhibition of MYC and Increased Apoptosis and Proliferation [ Time Frame: 1 year ]
  Number of participants with target inhibition of MYC and markers of increased apoptosis (cleaved caspase-3) and proliferation (Ki-67).
• Study Compliance as Assessed by Number of Participants Who Follow All of the Study Rules. [ Time Frame: 1 year ]
• Number of Participants With MYC Downregulation [ Time Frame: 1 year ]
  Number of participants with MYC downregulation after high-dose lovastatin.

Original Secondary Outcome Measures (submitted: November 21, 2011)

• Number of Participants with Cholesterol Related Adverse Events [ Time Frame: 1 year ]
  To characterize the effect of continuous daily oral lovastatin on cholesterol level in this patient population, at the doses tested in this trial.
• Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 1 year ]
  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.
• Pharmacodynamics [ Time Frame: 1 year ]
  To assess the relationship of pharmacodynamic target inhibition of MYC with pretreatment prostate biopsy Gleason sum, Ki-67, and degree of MYC overexpression.
• Target Inhibition [ Time Frame: 1 year ]
  To assess an association of pharmacodynamic target inhibition of MYC with markers of increased apoptosis (cleaved caspase-3) and proliferation (Ki-67).
• Study Compliance [ Time Frame: 1 year ]
  To assess the study compliance.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pre-Prostatectomy Lovastatin on Prostate Cancer
• Official Title: Pharmacodynamic Trial of Pre-Prostatectomy Lovastatin on MYC (V-myc Myelocytomatosis Viral Oncogene Homolog) Down-Regulation in Localized Prostate Cancer
• 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.

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 Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

Drug: Lovastatin

oral qd varying dose escalations/de-escalations

Other Name: Altoprev®; Mevacor®

Study Arms

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.

Intervention: Drug: Lovastatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 9, 2013): 2
• Original Estimated Enrollment (submitted: November 21, 2011): 25
• Actual Study Completion Date: April 8, 2013
• Actual Primary Completion Date: April 8, 2013 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01478828
• Other Study ID Numbers: J1153; NA_00048234 ( Other Identifier: JHM IRB )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Patrick C Walsh Prostate Cancer Research Fund

Investigators

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

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: March 2019