Lovastatin in Treating Patients At High Risk of Melanoma

Study Overview
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Brief Summary
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The use of lovastatin may slow disease progression in patients at high risk of melanoma. It is not yet known whether lovastatin is more effective than a placebo in treating patients at high risk of melanoma. This randomized phase II trial studies how well giving lovastatin or placebo works in treating patients at high risk of melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the primary endpoint of the trial, by analysis of histopathologic regression of atypical nevi in response to a 6-month trial of oral (PO) lovastatin vs. placebo in subjects with atypical nevi. SECONDARY OBJECTIVES: I. To evaluate clinical regression of atypical nevi in the lovastatin vs. placebo group. II. To evaluate the secondary endpoint of changes in nevi numbers on subjects' backs in the lovastatin vs. placebo groups. III. To evaluate a number of molecular biomarkers as secondary endpoints in the lovastatin vs. placebo groups. IV. To evaluate the correlation of serum markers known to be affected by lovastatin with the endpoints chosen above. V. To evaluate the safety and tolerability of the dosing regimen, and the dose escalation. OUTLINE: Patients are randomized into 1 of 2 treatment arms per group. ARM I: Patients (with two matched nevi OR one large nevi) receive lovastatin PO once daily (QD) for up to 6 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients (with two matched nevi OR one large nevi) receive placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 2 weeks.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial of Lovastatin for Various Endpoints of Melanoma Pathobiology

Conditions
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Precancerous Condition, Stage 0 Melanoma, Stage I Melanoma, Stage II Melanoma

Intervention / Treatment
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* Drug: lovastatin
* Other: placebo
* Procedure: biopsy
* Procedure: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of at least 2 clinically atypical nevi on the body that are reasonably matched in regards to level of clinical atypia, or one atypical mole and another atypical mole >= 8 mm in diameter (for this pair the two moles do not have to be closely matched and only one of them must be >= 8 mm in diameter) A history of melanoma is not required for study entry Patients with completely resected stage I or II who have not received adjuvant therapy in the past 3 months Eastern Cooperative Oncology Group (ECOG) performance status of 1 or better (Karnofsky > 70%) Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 X within normal limits Creatinine within normal institutional limits Ability to understand and the willingness to sign the written informed consent Subjects willing and able to participate for the full duration of the study For women of child-bearing potential (women are considered not of childbearing potential if they are at least 2 years post-menopausal and/or surgically sterile), she: has been using adequate contraception (abstinence, intrauterine device [IUD], birth control pills, or spermicidal gel with diaphragm or condom) since her last menses and will use adequate contraception during the study is not lactating, and has had a documented negative serum pregnancy test within 30 days prior to the first dose of study medication Should a woman become pregnant or suspect she is pregnant while participating in this study, she will be taken off study and be advised to inform her treating physician immediately; a telephone follow-up with the subject post-delivery will be completed to obtain outcome of pregnancy Men partnered with a female of child-bearing age must agree to use adequate contraception while on the study (i.e. abstinence, IUD, birth control pills, or spermicidal gel with diaphragm or condom) Exclusion Criteria: Subjects with untreated melanoma of any stage or locally advanced (>= 4 mm in Breslow's thickness) or metastatic (stage III or IV) melanoma; subjects with melanoma may be considered for trial after complete resection of Stage I or II melanoma and those who have declined or are ineligible to go on any available adjuvant clinical trials known to the investigators or the subjects are eligible Subjects who are on adjuvant therapy or experimental therapy for melanoma currently or within the last 3 months prior to enrollment into this study Subjects currently or within the last three months before enrollment on lipid lowering agents of any type History of allergic reactions attributed to compounds of similar chemical or biologic composition to lovastatin Clinically significant unrelated systemic illness Subjects with any medical or psychosocial condition that, in the opinion of the investigator, could jeopardize his/her participation in and compliance with the study Subjects may not be receiving any other investigational agents Pregnant or breast feeding females, or females of child bearing age not using a reliable method of contraception (use of lovastatin is contraindicated in pregnancy) Subjects who have been diagnosed with malignancies other than cutaneous melanoma, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma within 5 years of study entry, unless they: are currently without evidence of disease have not received treatment for invasive malignancy in the last 6 months have no current or planned therapy, and have an expected disease-free survival of at least 5 years from study entry Chronic use of: itraconazole; ketoconazole; erythromycin; clarithromycin; telithromycin; human immunodeficiency virus (HIV) protease inhibitors; nefazodone; cyclosporine; gemfibrozil and other fibrates; danazol; amiodarone (amiodarone hydrochloride); verapamil; coumarin anticoagulants; niacin (nicotinic acid) (>= 1 g/day); or large quantities of grapefruit juice (> l quart daily) Subjects with a history of coronary artery disease or stroke

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Two matched nevi group - Lovastatin<br>Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity. | Drug: lovastatin<br>* Given PO<br>* Other names: Monacolin K;Procedure: biopsy<br>* Correlative studies<br>* Other names: biopsies;Procedure: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Two Matched Nevi Group - Placebo<br>Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity | Other: placebo<br>* Given PO<br>* Other names: PLCB;Procedure: biopsy<br>* Correlative studies<br>* Other names: biopsies;Procedure: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: One large nevi group - Lovastatin<br>Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity | Drug: lovastatin<br>* Given PO<br>* Other names: Monacolin K;Procedure: biopsy<br>* Correlative studies<br>* Other names: biopsies;Procedure: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: One Large Nevi Group - Placebo<br>Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity | Other: placebo<br>* Given PO<br>* Other names: PLCB;Procedure: biopsy<br>* Correlative studies<br>* Other names: biopsies;Procedure: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histopathologic Regression of Target Atypical Nevi With Treatment - Pathologist 1's Evaluation | The level of atypia will be graded in a standard fashion which leads to seven levels of atypia, with zero being no atypia and six being a melanoma. For each patient, the change from baseline in the level of atypia was calculated. Only the Two Matched Nevi Group - Lovastatin and Two Matched Nevi Group - Placebo data were used and analyzed for the primary outcome. One-Large Nevi Group - Lovastatin and One-Large Nevi Group - Placebo sample data were not used or analyzed due to insufficient numbers. | From baseline up to 24 weeks | 
| Histopathologic Regression of Target Atypical Nevi With Treatment - Pathologist 2's Evaluation | The level of atypia will be graded in a standard fashion which leads to seven levels of atypia, with zero being no atypia and six being a melanoma. For each patient, the change from baseline in the level of atypia was calculated. Only the Two Matched Nevi Group - Lovastatin and Two Matched Nevi Group - Placebo data were used and analyzed for the primary outcome. One-Large Nevi Group - Lovastatin and One-Large Nevi Group - Placebo sample data were not used or analyzed due to insufficient numbers. | From baseline up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Regression of Atypical Moles - Average of Three Reviewers' Evaluations | From close-up photos of target atypical nevi, lesions will be graded clinically. After unblinding of pre- or post-treatment status for photos, the grading score was as follows: 1= Post-treatment (Post-TX) photo shows a complete resolution of atypia relative to pre-treatment (Pre-TX) photo, 2 = Post-TX photo shows a strong lessening of atypia relative to Pre-TX photo, 3 = Post-TX photo shows a mild lessening of atypia relative to Pre-TX photo, 4 = Post-TX and Pre-TX photos show same degree of atypia, 5 = Pre-TX photo shows a mild lessening of atypia relative to Post-TX photo, 6 = Pre-TX photo shows a strong lessening of atypia relative to Post-TX photo, 7 = Pre-TX photo shows a complete resolution of atypia relative to Post-TX photo. The Wilcoxon rank sum test will be applied to compare the scores for patients treated with placebo vs. those treated with lovastatin. | From baseline up to 24 weeks | 
| Total Nevus Number on Patient's Back - Combined Three Reviewers' Evaluations | Assessed by photos of subjects' back pre and post treatment. These photos will be used to count, by blinded evaluators, the number of nevi on the back pre and post therapy. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - HIF1alpha: Pathologist 3's Evaluation | HIF1alpha expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 3's Evaluation | (e)-cadherin expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 3's Evaluation | (n)-cadherin expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - VEGF: Pathologist 3's Evaluation | VEGF expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - RelA: Pathologist 3's Evaluation | RelA expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 3's Evaluation | p21 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - Ki-67: Pathologist 3's Evaluation | Ki-67 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - HIF1alpha: Pathologist 4's Evaluation | HIF1alpha expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 4's Evaluation | (e)-cadherin expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 4's Evaluation | (n)-cadherin expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - VEGF: Pathologist 4's Evaluation | VEGF expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - RelA: Pathologist 4's Evaluation | RelA expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 4's Evaluation | p21 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Serum and Molecular Biomarkers - Ki-67: Pathologist 4's Evaluation | Ki-67 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated. | From baseline up to 24 weeks | 
| Change in Cholesterol (mg/dL) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in LDL (mg/dL) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in HDL (mg/dL) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in Triglycerides (mg/dL) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in SGOT/AST (U/L) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in SGOT/ALT (U/L) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in CPK (U/L) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| Change in C-reactive Protein (mg/dL) From Baseline After Treatment |  | Baseline up to 24 weeks | 
| At Least 1 Study-related Adverse Event Reported During the Study | All participants will be evaluable for toxicity from the time of their informed consent. Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0. | Baseline up to 26 weeks |