To Determine The Efficacy and Safety of GDC-0449 in Patients With Basal Cell Nevus Syndrome (BCNS) (GDC-0449)

• ClinicalTrials.gov Identifier: NCT00957229
• Recruitment Status: Completed
• First Posted: August 12, 2009
• Results First Posted: January 11, 2021
• Last Update Posted: January 11, 2021
• Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): UCSF Benioff Children's Hospital Oakland

Tracking Information

• First Submitted Date: August 5, 2009
• First Posted Date: August 12, 2009
• Results First Submitted Date: October 8, 2020
• Results First Posted Date: January 11, 2021
• Last Update Posted Date: January 11, 2021
• Study Start Date: August 2009
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2020)

Number of New Surgically Eligible Basal-cell Carcinomas [ Time Frame: 3 months of receiving study drug ]

Number of new surgically eligible basal-cell carcinomas per patient per year

• Original Primary Outcome Measures (submitted: August 11, 2009): OBJECTIVES Primary: - To evaluate the efficacy of GDC-0449 in reducing new surgically eligible BCCs in BCNS patients during month 3-18 of ingestion of 150 mg/day. - To evaluate the safety of this dose of GDC-0449 in these patients [ Time Frame: Monthly ]

Current Secondary Outcome Measures (submitted: December 16, 2020)

• Change in Size of the Existing Carcinomas, Expressed as the Sum of Cumulative Diameters in Millimeters Over an 18 Month Period [ Time Frame: Baseline and 18 months ]
• Number of New Surgically Eligible Basal-cell Carcinomas After Stopping Vismodegib Treatment [ Time Frame: These five patients were given placebo for a mean of 7.4 months (SD 2.3). After receiving vismodegib for a mean of 13.8 months (SD 6.8) and then discontinuing vismodegib for a mean of 11.8 months (SD 7.9) the new basal-cell carcinoma rate is reported. ]
  The number of new surgically eligible basal-cell carcinomas per patient per month is reported.

• Original Secondary Outcome Measures (submitted: August 11, 2009): Secondary: - To assess the effect of GDC-0449 in reducing the total number of BCCs of diameter 5mm or greater on the upper back. - To determine the duration of any anti-BCC effect of GDC-0449 after administration of the drug is stopped. [ Time Frame: Effacacy will assessed at 1 year and duration of anti-BCC effect will be assessed 6 months after study med is stopped. ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: To Determine The Efficacy and Safety of GDC-0449 in Patients With Basal Cell Nevus Syndrome (BCNS)
• Official Title: A Randomized, Phase II Multicenter Trial Evaluating the Efficacy and Safety of a Systemic Hedgehog Pathway Antagonist (GDC-0449) in Patients With Basal Cell Nevus Syndrome (BCNS)
• Brief Summary: The purpose of this study is to reduce the number of new surgically eligible BCCs by 50% appearing during month 3-18 of medication ingestion.
• Detailed Description: This is a Phase II, 18 month, double blind, randomized placebo-controlled, two arm multicenter clinical study design. During the 18-month treatment period, the safety and chemopreventive efficacy of 150 mg/day GDC-0449 versus placebo will be assessed, and include evaluations of the skin at monthly intervals for the first three months and then every 3 months for the next 15 months. Removal of new surgically eligible BCCs (SEBs) will be done by primary skin care physicians (PSCPs) or at Study Centers. A Data Safety Monitoring Board (DSMB) will review unblinded results for an interim analysis when 20 subjects have completed 12 months of drug. This review will focus on adverse events and efficacy results. Subjects will be monitored for the development of new SEBs after they discontinue study treatment. At the end of the 18 months, given that the observed adverse events are minimal, patients on placebo will be offered the opportunity to take GDC-0449 for 18 months in an open label continuation, followed by six months observation, and patients on GDC449 will be monitored for the next 24 months for assessment of the duration of benefit after stopping the drug.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Basal Cell Nevus Syndrome
• Gorlin Syndrome

Intervention

Drug: GDC-0449

capsule, 150 mg, one pill daily, 18 months

Other Names:

• Hedgehog Inhibitor
• Hedgehog Antagonist

Study Arms

• Placebo Comparator: Sugar pill
  placebo pill by mouth once daily
  Intervention: Drug: GDC-0449
• Experimental: GDC-0449
  vismodegib 150MG by mouth once daily
  Intervention: Drug: GDC-0449

Publications *

• Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, Coppola C, Chanana AM, Marji J, Bickers DR, Epstein EH Jr. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012 Jun 7;366(23):2180-8. doi: 10.1056/NEJMoa1113538.
• Ally MS, Tang JY, Joseph T, Thompson B, Lindgren J, Raphael MA, Ulerio G, Chanana AM, Mackay-Wiggan JM, Bickers DR, Epstein EH Jr. The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol. 2014 May;150(5):542-5. doi: 10.1001/jamadermatol.2013.7444.
• Tang JY, Ally MS, Chanana AM, Mackay-Wiggan JM, Aszterbaum M, Lindgren JA, Ulerio G, Rezaee MR, Gildengorin G, Marji J, Clark C, Bickers DR, Epstein EH Jr. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1720-1731. doi: 10.1016/S1470-2045(16)30566-6. Epub 2016 Nov 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 11, 2009): 41
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: January 2014
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

The subject:

• has had diagnosed at least 10 SEB (of diameter 3 mm diameter or greater on the nose or periorbital skin, 5 mm or greater elsewhere on the face, or 9 mm or greater on non-facial areas excluding the skin below the knees) during the two years before study entry, as documented histologically in physicians' records and/or diagnosed clinically by a Study Investigator at baseline.
• meet diagnostic criteria for basal cell nevus syndrome
• is willing to abstain from application of non-study topical medications to the skin for the duration of the study, including prescription and over the counter preparations. Subjects will be encouraged to use sunscreen (SPF 15) at least once daily on all exposed skin sites.
• is willing to forego treatment of BCCs unless the BCCs are documented by Study Investigators, preferably on two separate visits, except when the PSCP believes that delay in treatment potentially might compromise the health of the subject.
• has normal laboratory tests as defined by the following: Normal hematopoietic capacity, Normal hepatic function: AST and ALT greater than or equal to 2x the upper limit of normal (ULN) Total bilirubin within normal range 0.20 mg/dl to 1.50 mg/dl or within 3x ULN for patients with Gilbert's disease Normal renal function: normal serum creatinine or measured creatinine clearance less than 50 mL/minute. Fasting cholesterol greater than or equal to 220 untreated
• be willing to not donate blood or semen for three months following discontinuation of Study medications.
• is willing to avoid pregnancy in his partner as defined by the following: Male subject is willing to use a latex condom during the study and for 3 months after the last dose during sexual contact with a female of childbearing potential, even if he has had a successful vasectomy. His partner must also use a form of birth control

Exclusion Criteria:

The subject:

• has used topical or systemic therapies that might interfere with the evaluation of the study medication during the study. Specifically these include the use of: (i) glucocorticoids to more than 5% of the skin (ii) retinoids systemically or topically to more than 5% of the skin during the six months prior to study entry; (iii) alpha-hydroxy acids to more than 5% of the skin during the six months prior to study entry (iv) 5-fluorouracil or imiquimod systemically or topically to the skin above the knees during the six months prior to study entry. (v) treatment with systemic chemotherapy within one year prior to starting study medication.
• has a history of hypersensitivity to any of the ingredients in the study medication formulations.
• is unable to return for follow-up visits and tests.
• has uncontrolled systemic disease, including known HIV positive patients.
• has history of congestive heart failure.
• has uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia
• has clinically important history of liver disease, including viral or hepatitis, current alcohol abuse, or cirrhosis.
• has any condition or situation which in the Investigator's opinion may put the subject at significant risk, could confound the study results, or could interfere significantly with the subject's participation in the study.
• has a history of invasive cancer within the past five years excluding non-melanoma skin cancer, Stage I cervical cancer, ductal carcinoma in situ of the breast, or CLL Stage 0.
• has current, recent (within 4 weeks of Day 1), or planned participation in an experimental drug study while enrolled in this study.
• is a female who is pregnant, plans to ever to become pregnant, capable of becoming pregnant or is breast feeding.
• is a male who is unwilling or unable to comply with pregnancy prevention measures.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 35 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00957229
• Other Study ID Numbers: 2009-026; SHH-4685s ( Other Grant/Funding Number: Genentech )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: UCSF Benioff Children's Hospital Oakland
• Study Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborators: Genentech, Inc.

Investigators

• Principal Investigator: Ervin Epstein, MD; UCSF Benioff Children's Hospital Oakland

• PRS Account: UCSF Benioff Children's Hospital Oakland
• Verification Date: December 2020