Topical Sirolimus in Patients With Basal Cell Nevus Syndrome and in Healthy Participants
Primary Purpose
Neoplastic Syndrome, Non-melanomatous Skin Cancer
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
sirolimus
comparative genomic hybridization
gene expression analysis
microarray analysis
protein expression analysis
proteomic profiling
laboratory biomarker analysis
mass spectrometry
biopsy
Sponsored by
About this trial
This is an interventional prevention trial for Neoplastic Syndrome focused on measuring basal cell carcinoma of the skin, nevoid basal cell carcinoma syndrome
Eligibility 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)
Sites / Locations
Outcomes
Primary Outcome Measures
Alterations in RNA as measured by microarray analysis
Alterations in protein expression as measured by 2-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy
Secondary Outcome Measures
Full Information
NCT ID
NCT00433485
First Posted
February 8, 2007
Last Updated
September 21, 2016
Sponsor
Yale University
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00433485
Brief Title
Topical Sirolimus in Patients With Basal Cell Nevus Syndrome and in Healthy Participants
Official Title
In Vivo and In Vitro Pharmacology of Sirolimus in Subjects With Basal Cell Nevus Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
March 2008 (Actual)
Study Completion Date
March 2008 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
National Cancer Institute (NCI)
4. Oversight
5. Study Description
Brief Summary
RATIONALE: Studying samples of blood and tissue from patients with basal cell nevus syndrome and from healthy participants in the laboratory may help doctors learn more about changes that may occur in DNA and identify biomarkers related to basal cell nevus syndrome. Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of sirolimus may keep basal cell skin cancer from forming in patients with basal cell nevus syndrome.
PURPOSE: This phase I trial is studying topical sirolimus in patients with basal cell nevus syndrome and in healthy participants.
Detailed Description
OBJECTIVES:
Primary
Compare messenger RNA and protein expression patterns in patients with basal cell nevus syndrome (BCNS) vs in cultured cells of healthy participants (control) before treatment to identify a set of genes that are differentially expressed in BCNS.
Assess the effects of topical sirolimus on gene expression (genes identified in the primary objective) in vivo using keratinocytes, fibroblasts, and lymphocytes from patients with BCNS and from healthy participants (controls) by targeted expression methods.
OUTLINE: Patients and healthy participants receive topical sirolimus ointment twice daily for 12 weeks.
Blood and skin biopsies are obtained at baseline and at week 12 for gene and protein expression studies. Alterations in RNA are measured by microarray analysis. Alterations in protein expression are measured by 2-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
After completion of study therapy, patients and healthy participants are followed at 4 weeks.
PROJECTED ACCRUAL: A total of 16 patients and healthy participants will be accrued for this study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neoplastic Syndrome, Non-melanomatous Skin Cancer
Keywords
basal cell carcinoma of the skin, nevoid basal cell carcinoma syndrome
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 1
Masking
None (Open Label)
Enrollment
16 (Anticipated)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
sirolimus
Intervention Type
Genetic
Intervention Name(s)
comparative genomic hybridization
Intervention Type
Genetic
Intervention Name(s)
gene expression analysis
Intervention Type
Genetic
Intervention Name(s)
microarray analysis
Intervention Type
Genetic
Intervention Name(s)
protein expression analysis
Intervention Type
Genetic
Intervention Name(s)
proteomic profiling
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Other
Intervention Name(s)
mass spectrometry
Intervention Type
Procedure
Intervention Name(s)
biopsy
Primary Outcome Measure Information:
Title
Alterations in RNA as measured by microarray analysis
Title
Alterations in protein expression as measured by 2-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Allen E. Bale, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
12. IPD Sharing Statement
Learn more about this trial
Topical Sirolimus in Patients With Basal Cell Nevus Syndrome and in Healthy Participants
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