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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
Yale University
About
Eligibility
Locations
Outcomes
Full info

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

18 Years - 120 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

    First Posted
    February 8, 2007
    Last Updated
    September 21, 2016
    Sponsor
    Yale University
    Collaborators
    National Cancer Institute (NCI)
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    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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