Prostate Cancer
Conditions
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.
Interventions
DRUGLovastatin
oral qd varying dose escalations/de-escalations
Sponsors
Patrick C Walsh Prostate Cancer Research Fund
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Can Achieve 60% MYC Modulation Response | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experience Specific Adverse Events at Different Dosing Points Prior to Surgery. | 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 | 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. | 1 year | Change in cholesterol level with each tested dose of oral lovastatin. |
| Number of Participants With MYC Downregulation | 1 year | Number of participants with MYC downregulation after high-dose lovastatin. |
| Number of Participants With Target Inhibition of MYC and Increased Apoptosis and Proliferation | 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. | 1 year | — |
| Pharmacodynamic Changes in Participants After the Pre-treatment Biopsy as Measured by Number of Participants With Target Inhibition of MYC | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Lovastatin: oral qd varying dose escalations/de-escalations | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Lovastatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex/Gender, Customized Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Participants That Can Achieve 60% MYC Modulation Response
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lovastatin | Number of Participants That Can Achieve 60% MYC Modulation Response | 0 Participants |
Secondary
Change in Cholesterol Level After Lovastatin Treatments.
Change in cholesterol level with each tested dose of oral lovastatin.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Number of Participants Who Experience Specific Adverse Events at Different Dosing Points Prior to Surgery.
Toxicity of the different doses of continuous daily oral lovastatin in generally healthy men with prostate cancer prior to surgery.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Number of Participants With MYC Downregulation
Number of participants with MYC downregulation after high-dose lovastatin.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Number of Participants With Target Inhibition of MYC and Increased Apoptosis and Proliferation
Number of participants with target inhibition of MYC and markers of increased apoptosis (cleaved caspase-3) and proliferation (Ki-67).
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Pharmacodynamic Changes in Participants After the Pre-treatment Biopsy as Measured by Number of Participants With Target Inhibition of MYC
Number of participants with target inhibition of MYC in relationship with pretreatment prostate biopsy Gleason sum, Ki-67, and degree of MYC overexpression.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Proportion of Men With MYC Target Inhibition in Prostate Tumor Tissue
Proportion of men with MYC target inhibition in prostate tumor tissue using paired tumor biopsies before and after lovastatin administration.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.
Secondary
Study Compliance as Assessed by Number of Participants Who Follow All of the Study Rules.
Time frame: 1 year
Population: Data was not collected for this outcome measure due to early study termination.