Topical Sirolimus in Patients With Basal Cell Nevus Syndrome and in Healthy Participants

Inclusion Criteria

• •DISEASE CHARACTERISTICS:
• •Patient
• •* Confirmed diagnosis of basal cell nevus syndrome (BCNS)
• •* Known patched (PTCH) gene mutation
• •* Must have full sequence of coding exons with intron/exon junctions in the PTCH gene OR prior genetic testing confirming PTCH mutation by the Yale University DNA Diagnostics Laboratory
• •Age- and sex-matched healthy participant (control)
• •* Unaffected relative of patient OR normal healthy volunteer with no family history of BCNS or features of BCNS
• •* No unrelated healthy participant meeting any of the following clinical criteria for BCNS:
• •* Lamellar calcification of the falx cerebri
• •* Prior odontogenic keratocyst or any jaw cyst for which a histopathologic diagnosis cannot be ascertained
• •* Palmar or plantar pits typical of BCNS
• •* More than 3 basal cell carcinomas (BCC) in a lifetime or 1 BCC under the age of 30
• •* History of medulloblastoma
• •* No unrelated healthy participant with 2 or more of the following features:
• •* History of ovarian or cardiac fibroma
• •* Mesenteric or pleural cysts
• •* Polydactyly
• •* Macrocephaly determined after adjustment for height
• •* Craniofacial features of BCNS, including cleft palate, frontal bossing, hypertelorism, iris coloboma or other developmental defects of the eye, or coarse facies
• •* Vertebral anomalies, including spina bifida occulta outside the lumbar region
• •* Bifid or splayed ribs
• •* Other radiographic findings, including bridging of the sella turcica, nonlamellar calcification of the falx cerebri, or flame-shaped lucencies in the phalanges = 1-3 BCCs over the age of 30
• •PATIENT CHARACTERISTICS:
• •WBC ≥ 4,000/mm³
• •Neutrophil count ≥ 2,000/mm³
• •Platelet count ≥ 150,000/mm³
• •Hemoglobin ≥ 11.5 g/dL
• •Bilirubin 0.3-1.0 mg/dL
• •AST 17-59 U/L
• •PTT 10-13 seconds OR INR 1.0-1.4
• •Creatinine clearance \> 50 mL/min
• •Cholesterol \< 350 mg/dL
• •Triglycerides \< 400 mg/dL
• •Not pregnant or nursing
• •Negative pregnancy test
• •Fertile participants must use effective contraception for ≥ 1 month before, during, and for ≥ 12 weeks after study treatment
• •No active infection
• •No alcohol or drug abuse
• •No psychiatric disorder or mental deficiency that would preclude study compliance
• •No uncontrolled hypertension (i.e., blood pressure \> 140/90 mm Hg on \> 2 measurements)
• •No chronic active infection requiring treatment
• •No untreated reactive purified protein derivative of tuberculin (PPD)
• •No HIV-1 infection
• •No infection requiring antibiotics within the past 30 days
• •No other skin disease affecting broad areas of the body, including the region to be treated and biopsied
• •No known hepatitis B or C infection (detectable RNA off antiviral therapy)
• •No immune deficiency disorder
• •No known hypersensitivity to sirolimus or macrolide antibiotics (e.g., erythromycin, azithromycin, or clarithromycin)
• •No cancer within the past 5 years except basal cell skin cancer
• •PRIOR CONCURRENT THERAPY:
• •At least 1 month since prior investigational drugs
• •No concurrent dietary supplements, including Hypericum perforatum (St. John's wort) or megadose vitamins
• •No other concurrent immunosuppressive medications, including corticosteroids
• •No concurrent medications known to interfere with sirolimus metabolism
• •No concurrent anticoagulants
• •No concurrent acetylsalicyclic acid or other drugs affecting platelet function or number
• •No routine (i.e., \> 2 doses/week) use of nonsteroidal anti-inflammatory drugs
• •No drugs or substances that would effect sirolimus blood concentrations, including any of the following:
• •* Nicardipine
• •* Verapamil
• •* Clotrimazole
• •* Fluconazole
• •* Itraconazole
• •* Troleandomycin
• •* Cisapride
• •* Metoclopramide
• •* Clarithromycin
• •* Erythromycin
• •* Bromocriptine
• •* Cimetidine
• •* Danazol
• •* HIV-protease inhibitors (e.g., ritonavir or indinavir)
• •* Phenobarbital
• •* Carbamazepine
• •* Phenytoin
• •* Rifabutin
• •* Rifapentine
• •* Grapefruit juice
• •* Vaccinations (especially live vaccines)