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Melanoma

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Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

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Micronutrients

All Drugs and Chemicals

Boron

Trace Elements

boron neutron capture therapy

Paul M. Busse, MD, PhD

RATIONALE: Boron neutron capture therapy may selectively kill tumor cells without harming normal tissue.

PURPOSE: Phase II trial to study the effectiveness of boron neutron capture therapy in treating patients who have melanoma.

OBJECTIVES:

* Determine the clinical response, by serial objective measurements, in patients with melanoma treated with boron neutron capture therapy.
* Determine the time course, uniformity, and severity of acute dermal reactions in patients treated with this regimen.
* Determine the late dermal reactions in patients who are followed for at least 6 months after treatment with this regimen.
* Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: Patients are stratified according to tumor size (no greater than 15 cc vs greater than 15 cc).

Patients undergo boron neutron capture therapy.

Patients are followed for 3 years.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study within 3 years.

Boron Neutron Capture Therapy in Treating Patients With Melanoma

A Phase II Trial For Neutron Capture Therapy In Melanoma

Beth Israel Deaconess Medical Center

Precancerous Conditions

Lipid Regulating Agents

Lovastatin

L 647318

Dihydromevinolin

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Enzyme Inhibitors

Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

lovastatin

placebo

biopsy

laboratory biomarker analysis

Kenneth Linden

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.

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.

Lovastatin in Treating Patients At High Risk of Melanoma

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

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 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.

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.

HIF1alpha expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.

(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.

(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.

VEGF expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.

RelA expression was assessed via cytoplasmic staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.

p21 expression was assessed via nuclear staining, and the change in the percentage of positive stained cells from baseline to 24 weeks is calculated.

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.

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.

National Cancer Institute (NCI)

Patients with two matched nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

lovastatin: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Two Matched Nevi Group-Lovastatin

Patients receive placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Two Matched Nevi Group-Placebo

Patients who have one large nevi received lovastatin PO QD for up to 6 months

One Large Nevi Group-Lovastatin

Patients who have one large nevi receive placebo PO QD for up to 6 months

One Large Nevi Group-Placebo

Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Patients with one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

lovastatin: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Patients with one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr. Kenneth G. Linden

Two Matched Nevi Group - Lovastatin

Patients with two matched nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Two Matched Nevi Group - Placebo

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 1's Evaluation

One Large Nevi Group-Lovastatin and Two Matched Nevi Group-Lovastatin arms are combined into the "Lovastatin" arm. Patients received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

lovastatin: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

One Large Nevi Group-Placebo and Two Matched Nevi Group-Placebo arms are combined into the "Placebo" arm. Patients received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Placebo

One Large Nevi Group-Lovastatin and Two Matched Nevi Group-Lovastatin arms are combined into the "Lovastatin" arm while One Large Nevi Group-Placebo and Two Matched Nevi Group-Placebo arms are combined into the "Placebo" arm. The total number of participants who have complete data are analyzed in this outcome measure.

Clinical Regression of Atypical Moles - Average of Three Reviewers' Evaluations

Fewer nevi after the treatment

Same number of nevi after treatment

More nevi after the treatment

One Large Nevi Group-Lovastatin and Two Matched Nevi Group-Lovastatin arms are combined into the "Lovastatin" arm.

Patients received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

lovastatin: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Total Nevus Number on Patient's Back - Combined Three Reviewers' Evaluations

Serum and Molecular Biomarkers - HIF1alpha: Pathologist 3's Evaluation

Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 3's Evaluation

Histopathologic Regression of Target Atypical Nevi With Treatment - Pathologist 2's Evaluation

Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 3's Evaluation

Serum and Molecular Biomarkers - VEGF: Pathologist 3's Evaluation

Serum and Molecular Biomarkers - RelA: Pathologist 3's Evaluation

Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 3's Evaluation

Serum and Molecular Biomarkers - Ki-67: Pathologist 3's Evaluation

Serum and Molecular Biomarkers - HIF1alpha: Pathologist 4's Evaluation

Serum and Molecular Biomarkers - (e)-Cadherin: Pathologist 4's Evaluation

Serum and Molecular Biomarkers - (n)-Cadherin: Pathologist 4's Evaluation

Serum and Molecular Biomarkers - VEGF: Pathologist 4's Evaluation

Serum and Molecular Biomarkers - RelA: Pathologist 4's Evaluation

Serum and Molecular Biomarkers - p21 (WAF1/CIP1): Pathologist 4's Evaluation

Serum and Molecular Biomarkers - Ki-67: Pathologist 4's Evaluation

One Large Nevi Group-Placebo and Two Matched Nevi Group-Placebo arms are combined into the "Placebo" arm. Patients received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity.

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

Change in Cholesterol (mg/dL) From Baseline After Treatment

Change in LDL (mg/dL) From Baseline After Treatment

Change in HDL (mg/dL) From Baseline After Treatment

Change in Triglycerides (mg/dL) From Baseline After Treatment

Change in SGOT/AST (U/L) From Baseline After Treatment

Change in SGOT/ALT (U/L) From Baseline After Treatment

Change in CPK (U/L) From Baseline After Treatment

Change in C-reactive Protein (mg/dL) From Baseline After Treatment

One Large Nevi Group-Lovastatin and Two Matched Nevi Group-Lovastatin arms are combined into the "Lovastatin" arm while One Large Nevi Group-Placebo and Two Matched Nevi Group-Placebo arms are combined into the "Placebo" arm.

At Least 1 Study-related Adverse Event Reported During the Study

Patients who have one large nevi received lovastatin PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

lovastatin: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

One Large Nevi Group - Lovastatin

Patients who have one large nevi received placebo PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity

placebo: Given PO

biopsy: Correlative studies

laboratory biomarker analysis: Correlative studies

One Large Nevi Group - Placebo

Overall Study

Hereditary Melanoma

gene expression analysis

microarray analysis

molecular genetic technique

mutation analysis

mutation carrier screening

study of high risk factors

Julia Newton Bishop, MD

RATIONALE: Identifying gene mutations and other risk factors in patients with melanoma and in families with a history of hereditary melanoma may help doctors identify persons at risk for melanoma and other types of cancer. It may also help the study of cancer in the future.

PURPOSE: This clinical trial is studying gene mutations in patients with melanoma and in families with a history of hereditary melanoma.

OBJECTIVES:

* Determine the incidence and etiologic significance of variants of known melanoma susceptibility genes (MSGs) in families with multiple cases of melanoma.
* Determine the proportion of multiple-case families that are explained by high-penetrance mutations in known MSGs.
* Determine the proportion of multiple-case families that are explained by these mutations and whether it varies with latitude, as a surrogate for ultraviolet exposure, with number of affected relatives, with average age at onset of melanoma in relatives, with presence of multiple primary melanoma, or with other family-specific variables.
* Determine the penetrance of MSG mutations in these families.
* Determine if the penetrance varies with age, sex, or birth cohort.
* Determine if the penetrance varies with the gene involved or nature of the mutation.
* Assess the penetrance in mutations that also have a deleterious effect on the alternative splice product, p14ARF.
* Determine whether carriers of MSGs have an increased susceptibility to other types of cancer.
* Determine the risk of other types of cancers for mutation carriers.
* Determine environmental exposures, in particular sun exposure, that modify risk of melanoma in MSG mutation carriers.
* Determine the cutaneous phenotypes that correlate with melanoma risk in these families.
* Correlate cutaneous phenotypes with the presence of MSG variants.
* Determine the effect of other covariates, such as sun exposure or the presence of alleles of putative modifying genes (e.g., MC1R or CDKN2A), on phenotype.
* Determine if modifier genes, such as those controlling pigmentation of the skin, and therefore sun susceptibility, modify risk in MSG mutation carriers.
* Identify any histopathological correlates of MSG status in primary tumors arising in melanoma-susceptible individuals in these families.
* Identify any histopathological correlates of primary melanomas in carriers of MSG mutations with other covariates.

OUTLINE: This is a case-control, multicenter study.

Participants complete 2 questionnaires and assist in the creation and expansion of a family pedigree. Blood samples are examined for melanoma susceptibility gene mutations, including CDK4 and CDKN2A.

Participants are also examined for moles and photographed. Physical variables (e.g., skin, eye, and hair pigmentation) and sun damage (solar lentigines and freckling) are also noted.

If available, tissue samples are examined for Clark level, Breslow thickness, and frequency of mitoses. Peri-lesional skin from tumors is examined by p53 staining.

Participants are followed periodically to monitor cancer development.

Peer reviewed and funded or endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 5,000 participants will be accrued for this study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Boron Neutron Capture Therapy in Treating Patients With Melanoma	NCT00059800	Melanoma (Skin)	boron neutron c...	18 Years -	National Cancer Institute (NCI)
Lovastatin in Treating Patients At High Risk of Melanoma	NCT00462280	Precancerous Co... Stage 0 Melanom... Stage I Melanom... Stage II Melano...	lovastatin placebo biopsy laboratory biom...	18 Years -	National Cancer Institute (NCI)
Identifying Gene Mutations in Patients With Melanoma and in Families With a History of Hereditary Melanoma	NCT00450593	Hereditary Mult... Melanoma (Skin)	gene expression... microarray anal... molecular genet... mutation analys... laboratory biom... mutation carrie... study of high r...	-	National Cancer Institute (NCI)
Lovastatin in Treating Patients At High Risk of Melanoma	NCT00462280	Precancerous Co... Stage 0 Melanom... Stage I Melanom... Stage II Melano...	lovastatin placebo biopsy laboratory biom...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage 0 melanoma