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

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)

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.

Study Overview

• Status: Completed
• Conditions: Basal Cell Nevus Syndrome; Gorlin Syndrome
• Intervention / Treatment: Drug: GDC-0449

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
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital Oakland Research Institiute
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar pill; placebo pill by mouth once daily	Drug: GDC-0449; capsule, 150 mg, one pill daily, 18 months; Other Names: Hedgehog Inhibitor; Hedgehog Antagonist
Experimental: GDC-0449; vismodegib 150MG by mouth once daily	Drug: GDC-0449; capsule, 150 mg, one pill daily, 18 months; Other Names: Hedgehog Inhibitor; Hedgehog Antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of New Surgically Eligible Basal-cell Carcinomas	Number of new surgically eligible basal-cell carcinomas per patient per year	3 months of receiving study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Size of the Existing Carcinomas, Expressed as the Sum of Cumulative Diameters in Millimeters Over an 18 Month Period		Baseline and 18 months
Number of New Surgically Eligible Basal-cell Carcinomas After Stopping Vismodegib Treatment	The number of new surgically eligible basal-cell carcinomas per patient per month is reported.	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.

Collaborators and Investigators

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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: August 5, 2009
• First Submitted That Met QC Criteria: August 11, 2009
• First Posted (Estimate): August 12, 2009

Study Record Updates

• Last Update Posted (Actual): January 11, 2021
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Disease; Cysts; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Stomatognathic Diseases; Bone Diseases; Neoplastic Syndromes, Hereditary; Nevi and Melanomas; Jaw Diseases; Abnormalities, Multiple; Bone Diseases, Developmental; Odontogenic Cysts; Jaw Cysts; Bone Cysts; Carcinoma, Basal Cell; Neoplasms, Basal Cell; Syndrome; Nevus; Basal Cell Nevus Syndrome; Nevus, Pigmented
• Other Study ID Numbers: 2009-026; SHH-4685s (Other Grant/Funding Number: Genentech)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO