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Pre-Prostatectomy Lovastatin on Prostate Cancer

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ClinicalTrials.gov Identifier: NCT01478828
Recruitment Status : Terminated (The study was stopped due to an unanticipated serious adverse event.)
First Posted : November 23, 2011
Results First Posted : November 9, 2015
Last Update Posted : March 27, 2019
Sponsor:
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  ICMJE November 3, 2011
First Posted Date  ICMJE November 23, 2011
Results First Submitted Date  ICMJE January 13, 2015
Results First Posted Date  ICMJE November 9, 2015
Last Update Posted Date March 27, 2019
Actual Study Start Date  ICMJE July 13, 2012
Actual Primary Completion Date April 8, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Pre-Prostatectomy Lovastatin on Prostate Cancer
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Cancer
Intervention  ICMJE Drug: Lovastatin
oral qd varying dose escalations/de-escalations
Other Name: Altoprev®; Mevacor®
Study Arms  ICMJE 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 9, 2013)
2
Original Estimated Enrollment  ICMJE
 (submitted: November 21, 2011)
25
Actual Study Completion Date  ICMJE April 8, 2013
Actual Primary Completion Date April 8, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01478828
Other Study ID Numbers  ICMJE J1153
NA_00048234 ( Other Identifier: JHM IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE Patrick C Walsh Prostate Cancer Research Fund
Investigators  ICMJE
Principal Investigator: Phouc Tran, M.D. Johns Hopkins University
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP