Oral Hedgehog Inhibitors in the Treatment of Basal Cell Carcinoma in the Netherlands: a Prospective Registration Study

Official title

Registration of Oral Hedgehog Inhibitors Vismodegib and Sonidegib in the Treatment of Advanced and Multiple Basal Cell Carcinoma in the Netherlands: a Prospective Registration Study.

Overview

Background: Oral hedgehog inhibitors vismodegib and sonidegib have been used for the treatment of locally advanced (laBCC), metastatic basal cell carcinoma (mBCC) and in basal cell nevus syndrome (BCNS) patients. In the Netherlands, targeted therapy with vismodegib and sonidegib has been available since 2013 and 2021, respectively. No direct comparative studies have been performed between the two oral hedgehog inhibitors (HHI) vismodegib and sonidegib yet . In addition, data for sonidegib are not yet available. Objective: The aim of this study is 1) to evaluate the effectiveness of oral HHIs in the treatment of laBCC, mBCC and BCNS patients and 2) to compare the oral HHIs vismodegib and sonidegib. Study design: prospective registration study that includes all patients, regardless of age and gender, with histologically proven basal cell carcinoma receiving treatment with either vismodegib or sonidegib in the Netherlands. Patient, tumor and treatment information was gathered from patient records. Main study parameters/endpoints: The primary outcome for measuring efficacy/tumor response was median progression free survival (PFS) where the decrease, stagnation or increase in tumor size is measured by maximum diameter. Secondary outcomes are frequency, severity and reversibility of treatment-emergent adverse events and disease-specific quality of life expressed as mean scores on the EORTC-QLQ-C30 and aBCCdex questionnaires.

Detailed description

This is a prospective registration study conducted in eight academic hospitals in the Netherlands. Vismodegib and sonidegib are currently only prescribed in academic hospitals in the Netherlands. Therefore, this multicenter approach with all academic centers in the Netherlands provides a complete insight into the prescription of these oral HHIs in the Netherlands. The study takes place at the dermatology and oncology department of Maastricht University Medical Center+ (MUMC+), Erasmus University Medical Center (Erasmus MC) Rotterdam, Netherlands Cancer Institute (NKI) Amsterdam, University Medical Center Groningen (UMCG), University Medical Center Utrecht (UMC Utrecht), Amsterdam University Medical Center (Amsterdam UMC), Radboud University Medical Center (Radboudumc) and Leiden University Medical Center (LUMC).

All patients receiving at least one dose of vismodegib or sonidegib for the treatment of basal cell carcinoma (laBCC, mBCC, multiple BCCs in BCNS and in non-BCNS) (in regular care) will be included, provided they give permission and sign the informed consent form. Treating physicians then systematically register data on treatment using a uniform registration format. This registration includes the effectiveness of the drug measured by tumor diameter\*, adverse events according to the CTCAE version 5.0, and data such as age, gender, World health organization (WHO) status, scores on the G8 questionnaire, medication use, comorbidities, indication, dosage, treatment duration, laboratory values, and reason for discontinuation of treatment. In addition, twice a year scores on the EORTC-QLQ-C30 and aBCCdex questionnaires are registered. All data will be extracted from electronic patient files en will be entered anonymously in a Castor database.

The primary outcome for measuring efficacy/tumor response is median progression free survival (PFS) where the decrease, stagnation or increase in tumor size is measured by maximum tumor diameter\*. Secondary outcomes are frequency, severity and reversibility of treatment-emergent adverse events and disease-specific quality of life expressed as mean scores on the EORTC-QLQ-C30 and aBCCdex questionnaires. In addition, the association of patient characteristics on drug efficacy and adverse events will be analysed.

\*In case of gorlin goltz syndrome or multiple BCCs, at least 3 target lesions are registered whose diameters are monitored over time.

Interventions

• Drug Vismodegib
  Oral vismodegib (Erivedge), taken daily or every other day (depending on doctor's description)
• Drug Sonidegib
  Sonidegib (Odomzo), taken daily or every other day (depending on doctor's description)

Primary outcome measures

• Median progression free survival [Time frame: though study completion, an average of 3 years]

Secondary outcome measures (3)

• Adverse events [Time frame: At baseline (start of treatment), after 1 month and every 3 months thereafter during use of vismodegib or sonidegib, at discontinuation of the treatment and 3 months after discontinuation of the treatment.]
• Disease-specific quality of life [Time frame: At the start of treatment and every 6 months thereafter, until vismodegib or sonidegib is no longer used.]
• Disease-specific quality of life [Time frame: At the start of treatment and every 6 months thereafter, until vismodegib or sonidegib is no longer used.]

Eligibility criteria

Inclusion criteria

• Men and women
• All ages
• Diagnosed with locally advanced basal cell carcinoma (laBCC), metastatic basal cell carcinoma (mBCC), multiple basal cell carcinomas or Gorlin syndrome
• Use of oral hedgehog inhibitor vismodegib or sonidegib

Exclusion criteria

• None

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Netherlands · 8 centers

• Radboudumc — Nijmegen
• Maastricht University Medical Center + — Maastricht
• Amsterdam UMC — Amsterdam
• Netherlands Cancer Institute - AVL — Amsterdam
• UMCG — Groningen
• LUMC — Leiden
• Erasmus MC — Rotterdam
• UMC Utrecht — Utrecht

Publications

• Verkouteren BJA, Wakkee M, Reyners AKL, Nelemans P, Aarts MJB, Racz E, Terra JB, Devriese LA, Alers RJ, Kapiteijn E, van Doorn R, Bekkenk MW, Reinders MGHC, Mosterd K. Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study. Br J Cancer. 2021 Mar;124(7):1199-1206. doi: 10.1038/s41416-020-01220-w. Epub 2021 J PMID 33462360
• Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun 7;366(23):2171-9. doi: 10.1056/NEJMoa1113713. PMID 22670903
• Basset-Seguin N, Hauschild A, Kunstfeld R, Grob J, Dreno B, Mortier L, Ascierto PA, Licitra L, Dutriaux C, Thomas L, Meyer N, Guillot B, Dummer R, Arenberger P, Fife K, Raimundo A, Dika E, Dimier N, Fittipaldo A, Xynos I, Hansson J. Vismodegib in patients with advanced basal cell carcinoma: Primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017 Nov;86:334-348. doi: 10.1 PMID 29073584
• Dreno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, Grob JJ, Puig S, Gilberg F, Bergstrom D, Page DR, Rogers G, Schadendorf D. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):404-412. doi: 10.1016/S1470-2045(17)30072-4. Epub 2017 Feb 8. PMID 28188086
• Ben Ishai M, Tiosano A, Fenig E, Ben Simon G, Yassur I. Outcomes of Vismodegib for Periocular Locally Advanced Basal Cell Carcinoma From an Open-label Trial. JAMA Ophthalmol. 2020 Jul 1;138(7):749-755. doi: 10.1001/jamaophthalmol.2020.1539. PMID 32407451
• Dutch Society for Dermatology and Venereology (NVDV). Basal Cell Carcinoma: Dutch Guideline (Dutch Society for Dermatology and Venereology (NVDV). 2015).
• Xie P, Lefrancois P. Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis. J Am Acad Dermatol. 2018 Dec;79(6):1089-1100.e17. doi: 10.1016/j.jaad.2018.07.004. Epub 2018 Jul 10. PMID 30003981
• Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, Miller C, Mortier L, Murrell DF, Hamid O, Quevedo JF, Hou J, McKenna E, Dimier N, Williams S, Schadendorf D, Hauschild A; ERIVANCE BCC Investigators. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017 May 16;17(1):332. doi: 1 PMID 28511673

Identifiers

NCT: NCT05463757 · METC 2018-0452-A-10 Vismodegib

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗