Lovastatin in Treating Patients At High Risk of Melanoma

Phase 2

Completed

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

Interventions: Other: placebo
Drug: lovastatin
Procedure: biopsy
Procedure: laboratory biomarker analysis

Registration Number: NCT00462280

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Two matched nevi group - Lovastatin	biopsy	Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.
Two Matched Nevi Group - Placebo	placebo	Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
Two Matched Nevi Group - Placebo	biopsy	Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
Two Matched Nevi Group - Placebo	laboratory biomarker analysis	Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
One large nevi group - Lovastatin	biopsy	Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
One Large Nevi Group - Placebo	placebo	Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
Two matched nevi group - Lovastatin	laboratory biomarker analysis	Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.
One Large Nevi Group - Placebo	laboratory biomarker analysis	Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
One Large Nevi Group - Placebo	biopsy	Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
One large nevi group - Lovastatin	laboratory biomarker analysis	Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity
Two matched nevi group - Lovastatin	lovastatin	Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.
One large nevi group - Lovastatin	lovastatin	Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

Primary Outcome Measures

Name	Time	Method
Histopathologic Regression of Target Atypical Nevi With Treatment - Pathologist 1's Evaluation	From baseline up to 24 weeks	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.
Histopathologic Regression of Target Atypical Nevi With Treatment - Pathologist 2's Evaluation	From baseline up to 24 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Total Nevus Number on Patient's Back - Combined Three Reviewers' Evaluations	From baseline up to 24 weeks	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.
Clinical Regression of Atypical Moles - Average of Three Reviewers' Evaluations	From baseline up to 24 weeks	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.
Serum and Molecular Biomarkers - HIF1alpha: Pathologist 3's Evaluation	From baseline up to 24 weeks	HIF1alpha expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - VEGF: Pathologist 3's Evaluation	From baseline up to 24 weeks	VEGF expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 4's Evaluation	From baseline up to 24 weeks	(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.
Change in LDL (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
Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 3's Evaluation	From baseline up to 24 weeks	(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.
Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 3's Evaluation	From baseline up to 24 weeks	(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.
Serum and Molecular Biomarkers - RelA: Pathologist 3's Evaluation	From baseline up to 24 weeks	RelA expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 3's Evaluation	From baseline up to 24 weeks	p21 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - RelA: Pathologist 4's Evaluation	From baseline up to 24 weeks	RelA expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
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
Serum and Molecular Biomarkers - Ki-67: Pathologist 3's Evaluation	From baseline up to 24 weeks	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.
Serum and Molecular Biomarkers - HIF1alpha: Pathologist 4's Evaluation	From baseline up to 24 weeks	HIF1alpha expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - Ki-67: Pathologist 4's Evaluation	From baseline up to 24 weeks	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.
Change in HDL (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
Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 4's Evaluation	From baseline up to 24 weeks	(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.
Serum and Molecular Biomarkers - VEGF: Pathologist 4's Evaluation	From baseline up to 24 weeks	VEGF expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 4's Evaluation	From baseline up to 24 weeks	p21 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.
Change in Cholesterol (mg/dL) From Baseline After Treatment	Baseline up to 24 weeks
At Least 1 Study-related Adverse Event Reported During the Study	Baseline up to 26 weeks	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.

Trial Locations

Locations (3): University of California Medical Center At Irvine-Orange Campus
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Orange, California, United States
Huntsman Cancer Institute
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Salt Lake City, Utah, United States
H. Lee Moffitt Cancer Center and Research Institute
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Tampa, Florida, United States