Trial of Patidegib Gel 2%, 4%, and Vehicle to Decrease the Number of Surgically Eligible Basal Cell Carcinomas in Gorlin Syndrome Patients
Condition: Basal Cell Nevus Syndrome
MeSH terms: Carcinoma; Carcinoma, Basal Cell; Basal Cell Nevus Syndrome; Syndrome
Intervention: Patidegib; Vehicle gel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Gorlin Syndrome; Basal Cell; Nevus Syndrome; BCNS; nevoid basal cell carcinoma syndrome; Basal cell carcinoma; Hedgehog; Surgically Eligible Basal Cell Carcinomas

Summary:

      Multicenter, double-blind, randomized, vehicle-controlled study that evaluates the efficacy
      and safety of patidegib gel 2% and 4% in comparison with vehicle in participants at least 18
      years of age that meet the diagnostic criteria for basal cell nevus syndrome (BCNS).
      Participants will be randomized to receive patidegib gel 2%, patidegib gel 4%, or the vehicle
      gel for a 26-week treatment period.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The participant is from 18 to 85 years of age, inclusive.

          2. The participant must provide written informed consent prior to any study procedures.

          3. The participant must meet diagnostic criteria for BCNS, including the first listed
             major criterion below plus one additional major criterion, or the first listed major
             criterion below plus 2 of the minor criteria outlined below:

             Major Criteria:

               -  More than 2 histologically confirmed BCCs or one under the age of 20 years

               -  Odontogenic keratocysts of the jaw proven by histology

               -  Three or more palmar and/or plantar pits

               -  Bilamellar calcification of the falx cerebri (if less than 20 years old)

               -  Fused, bifid, or markedly splayed ribs

               -  First degree relative with basal cell nevus syndrome

               -  Patched 1 (PTCH1) gene mutation in normal tissue

             Minor Criteria:

               -  Macrocephaly

               -  Congenital malformations: cleft lip or palate, frontal bossing, "coarse face",
                  moderate or severe hypertelorism

               -  Skeletal abnormalities: sprengel deformity, marked pectus deformity, or marked
                  syndactyly of the digits

               -  Radiological abnormalities: bridging of the sella turcica, vertebral anomalies
                  such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling
                  defects of the hands and feet, or flame shaped lucencies of the hands or feet

               -  Ovarian fibroma

               -  Medulloblastoma

          4. The participant must have a history of at least 10 BCCs in toto present at Baseline
             and/or treated within 24 months prior to screening.

          5. The participant has at Baseline a total of at least 5 previously untreated SEBs
             (greatest diameter 5 millimeters [mm] or greater on the face excluding the nose and
             periorbital skin, 9 mm or greater on non-facial areas excluding the skin below the
             knees), as documented clinically by the Investigator at Baseline. Untreated is define
             as no previous surgical or topical or intralesional drug treatment. Previous treatment
             with systemically administered drugs more than 6 months prior to Baseline is not
             considered previous treatment as long as there was no clinical evidence of resistance
             to oral hedgehog (HH) pathway inhibitors (such as vismodegib, patidegib, and
             sonidegib). Baseline treatment-targeted SEBs must not exceed a diameter of >2
             centimeters (cm). At least one of these tumors must be appropriate for a 2 mm punch
             biopsy for biomarker analysis at Baseline and Week 6 visits. If a participant has 5 or
             more facial, excluding periorbital and nasal skin, SEBs at Baseline, non-facial SEBs
             will not be treatment-targeted SEBs.

          6. The participant is willing to have SEBs biopsied for biomarkers and plasma to be
             collected to measure drug levels as required in the protocol.

          7. The participant is willing to abstain from application of non-study topical
             prescription and over the counter medications to facial skin and within 5 cm of
             treatment targeted SEBs at other anatomical areas for the duration of the study except
             as prescribed by the Investigator. Moisturizers and emollients are allowable.
             Participants will be encouraged to use sunscreen with a sunscreen protection factor
             (SPF) 15 or higher at least once daily on all exposed skin sites.

          8. Female participants must have a negative serum pregnancy test at Screening.

          9. If the participant is a male with a female sexual partner who is of childbearing
             potential the couple is willing to use two effective methods of birth control during
             the duration of the trial and for one month after the last application of the gel. A
             female of childbearing potential is a sexually mature woman who: 1) has not undergone
             a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
             for at least 24 consecutive months (that is, has had menses at any time in the
             preceding 24 consecutive months), must agree to use 2 effective methods of
             contraception for the duration of the study and at least 1 month after the last study
             drug application. The two forms of birth control authorized are defined as the use of
             a barrier method of contraception (condom with spermicide) in association with one of
             the following methods of birth control: bilateral tubal ligation; combined oral
             contraceptives (estrogens and progesterone) or implanted or injectable contraceptives
             with a stable dose for at least 1 month prior to Baseline; hormonal intra-uterine
             device (IUD) inserted at least 1 month prior to Baseline.

         10. The participant is willing to contact the study center after each primary skin care
             physician (PSCP) visit to provide the study center details of the visit and any
             treatment of skin tumors.

         11. The participant is willing to forego treatment of the treatment targeted baseline SEBs
             except when the Investigator and/or primary care giver believes that delay in
             treatment potentially might compromise the health of the participant.

        Exclusion Criteria:

          1. The participant is a woman of childbearing potential. This proscription is based on
             the key role of the HH pathway in embryogenesis, the known preclinical teratogenic
             effects of systemic cyclopamine, a naturally occurring inhibitor of SMO, and the
             unknown level of systemic exposure following topical application in humans. A female
             of childbearing potential is a sexually mature woman who: 1) has not undergone a
             hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
             for at least 24 consecutive months (that is, has had menses at any time in the
             preceding 24 consecutive months).

          2. The participant has used topical products to the face or within 5 cm of a treatment
             targeted SEB or systemic therapies that might interfere with the evaluation of the
             study medication during the study. Specifically, these include the use of:

               -  Topical glucocorticoids 30 days prior to screening

               -  Retinoids (such as etretinate, isotretinoin, tazarotene, tretinoin, adapalene)
                  systemically or topically or > 5% of an alphahydroxy acid (such as glycolic acid,
                  lactic acid) or 5-fluorouracil or imiquimod (except as topical treatment to
                  discrete BCCs) systemically or topically to the skin during the 6 months prior to
                  entry.

               -  Systemic chemotherapy within one year prior to screening. (Note: field therapy
                  with topically applied treatments can be done as long as they are not applied
                  within 5 cm of a treatment targeted tumor).

               -  Known inhibitors of the HH signaling pathway (such as vismodegib, patidegib, and
                  sonidegib) topically or systemically within 6 months of entry into the study.

          3. The participant has a history of hypersensitivity to any of the ingredients in the
             study drug formulation.

          4. The participant is unable or unwilling to make a good faith effort to return for all
             follow-up visits and tests.

          5. The participant has uncontrolled systemic disease.

          6. The participant has clinically important history of liver disease, including viral
             hepatitis, current alcohol abuse, or cirrhosis.

          7. The participant has any condition or situation which in the Investigator's opinion may
             put the participant at significant risk, could confound the study results, or could
             interfere significantly with the participant's participation in the study. This
             includes history of other skin conditions or diseases, metabolic dysfunction, physical
             examination findings, or clinical laboratory findings giving reasonable suspicion of a
             disease or condition that contraindicates use of an investigational drug or that might
             affect interpretation of the results of the study or render the participant at high
             risk from treatment complications.

          8. The participant has a history of invasive cancer within the past 5 years excluding
             non-melanoma skin cancer, Stage I cervical cancer, ductal carcinoma in situ of breast,
             or chronic lymphocytic lymphoma (Stage 0).

          9. The participant has current, recent (within 4 weeks of Baseline visit), or planned
             participation in an experimental drug study while enrolled in this study.

         10. Female sexual partner(s) of male participants who are unwilling or unable to comply
             with pregnancy prevention measures.