Trial of Patidegib Gel 2%, 4%, and Vehicle to Decrease the Number of Surgically Eligible Basal Cell Carcinomas in Gorlin Syndrome Patients

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 listedmajor criterion below plus one additional major criterion, or the first listed majorcriterion 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 markedsyndactyly of the digits

• Radiological abnormalities: bridging of the sella turcica, vertebral anomaliessuch as hemivertebrae, fusion or elongation of the vertebral bodies, modelingdefects 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 Baselineand/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 andperiorbital skin, 9 mm or greater on non-facial areas excluding the skin below theknees), as documented clinically by the Investigator at Baseline. Untreated is defineas no previous surgical or topical or intralesional drug treatment. Previous treatmentwith systemically administered drugs more than 6 months prior to Baseline is notconsidered previous treatment as long as there was no clinical evidence of resistanceto oral hedgehog (HH) pathway inhibitors (such as vismodegib, patidegib, andsonidegib). Baseline treatment-targeted SEBs must not exceed a diameter of >2centimeters (cm). At least one of these tumors must be appropriate for a 2 mm punchbiopsy for biomarker analysis at Baseline and Week 6 visits. If a participant has 5 ormore facial, excluding periorbital and nasal skin, SEBs at Baseline, non-facial SEBswill not be treatment-targeted SEBs.

6. The participant is willing to have SEBs biopsied for biomarkers and plasma to becollected to measure drug levels as required in the protocol.

7. The participant is willing to abstain from application of non-study topicalprescription and over the counter medications to facial skin and within 5 cm oftreatment targeted SEBs at other anatomical areas for the duration of the study exceptas 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 childbearingpotential the couple is willing to use two effective methods of birth control duringthe duration of the trial and for one month after the last application of the gel. Afemale of childbearing potential is a sexually mature woman who: 1) has not undergonea hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausalfor at least 24 consecutive months (that is, has had menses at any time in thepreceding 24 consecutive months), must agree to use 2 effective methods ofcontraception for the duration of the study and at least 1 month after the last studydrug application. The two forms of birth control authorized are defined as the use ofa barrier method of contraception (condom with spermicide) in association with one ofthe following methods of birth control: bilateral tubal ligation; combined oralcontraceptives (estrogens and progesterone) or implanted or injectable contraceptiveswith a stable dose for at least 1 month prior to Baseline; hormonal intra-uterinedevice (IUD) inserted at least 1 month prior to Baseline.

10. The participant is willing to contact the study center after each primary skin carephysician (PSCP) visit to provide the study center details of the visit and anytreatment of skin tumors.

11. The participant is willing to forego treatment of the treatment targeted baseline SEBsexcept when the Investigator and/or primary care giver believes that delay intreatment potentially might compromise the health of the participant.

Exclusion Criteria:

1. The participant is a woman of childbearing potential. This proscription is based onthe key role of the HH pathway in embryogenesis, the known preclinical teratogeniceffects of systemic cyclopamine, a naturally occurring inhibitor of SMO, and theunknown level of systemic exposure following topical application in humans. A femaleof childbearing potential is a sexually mature woman who: 1) has not undergone ahysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausalfor at least 24 consecutive months (that is, has had menses at any time in thepreceding 24 consecutive months).

2. The participant has used topical products to the face or within 5 cm of a treatmenttargeted SEB or systemic therapies that might interfere with the evaluation of thestudy 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 todiscrete BCCs) systemically or topically to the skin during the 6 months prior toentry.

• Systemic chemotherapy within one year prior to screening. (Note: field therapywith topically applied treatments can be done as long as they are not appliedwithin 5 cm of a treatment targeted tumor).

• Known inhibitors of the HH signaling pathway (such as vismodegib, patidegib, andsonidegib) 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 thestudy drug formulation.

4. The participant is unable or unwilling to make a good faith effort to return for allfollow-up visits and tests.

5. The participant has uncontrolled systemic disease.

6. The participant has clinically important history of liver disease, including viralhepatitis, current alcohol abuse, or cirrhosis.

7. The participant has any condition or situation which in the Investigator's opinion mayput the participant at significant risk, could confound the study results, or couldinterfere significantly with the participant's participation in the study. Thisincludes history of other skin conditions or diseases, metabolic dysfunction, physicalexamination findings, or clinical laboratory findings giving reasonable suspicion of adisease or condition that contraindicates use of an investigational drug or that mightaffect interpretation of the results of the study or render the participant at highrisk from treatment complications.

8. The participant has a history of invasive cancer within the past 5 years excludingnon-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 plannedparticipation in an experimental drug study while enrolled in this study.

10. Female sexual partner(s) of male participants who are unwilling or unable to complywith pregnancy prevention measures.