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

Skin Cancer Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05463757
• Other study ID #: METC 2018-0452-A-10 Vismodegib
• Status: Recruiting
• Start date: November 1, 2021
• Est. completion date: December 2024

Study information

• Verified date: January 2023
• Source: Maastricht University Medical Center
• Contact: Emmy Cruts, MD
• Phone: +31(0)43 3877295
• Email: e.cruts[@]mumc.nl
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Basal Cell Carcinoma
• Basal Cell Nevus Syndrome
• Carcinoma
• Carcinoma, Basal Cell
• Gorlin Syndrome
• Locally Advanced Basal Cell Carcinoma
• Metastatic Basal Cell Carcinoma
• Neoplasm of Skin
• Neoplasms
• Neoplasms, Basal Cell
• Skin Cancer
• Skin Neoplasms
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC	Amsterdam	Noord-Holland
Netherlands	Netherlands Cancer Institute - AVL	Amsterdam	Noord-Holland
Netherlands	UMCG	Groningen
Netherlands	LUMC	Leiden	Zuid-Holland
Netherlands	Maastricht University Medical Center +	Maastricht	Limburg
Netherlands	Radboudumc	Nijmegen	Gelderland
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	UMC Utrecht	Utrecht

Sponsors (2)

Lead Sponsor	Collaborator
Maastricht University Medical Center	Sun Pharmaceutical Industries Limited

Country where clinical trial is conducted

Netherlands, 

References & Publications (13)

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: 10.1016/j.ejca.2017.08.022. Epub 2017 Nov 5. — View Citation

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. — View Citation

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. — View Citation

Dummer R, Ascierto PA, Basset-Seguin N, Dreno B, Garbe C, Gutzmer R, Hauschild A, Krattinger R, Lear JT, Malvehy J, Schadendorf D, Grob JJ. Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion. J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1944-1956. doi: 10.1111/jdv.16230. Epub 2020 Mar 4. — View Citation

Dutch Society for Dermatology and Venereology (NVDV). Basal Cell Carcinoma: Dutch Guideline (Dutch Society for Dermatology and Venereology (NVDV). 2015).

Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008 Oct;8(10):743-54. doi: 10.1038/nrc2503. — View Citation

Lewis K, Dummer R, Farberg AS, Guminski A, Squittieri N, Migden M. Effects of Sonidegib Following Dose Reduction and Treatment Interruption in Patients with Advanced Basal Cell Carcinoma During 42-Month BOLT Trial. Dermatol Ther (Heidelb). 2021 Dec;11(6):2225-2234. doi: 10.1007/s13555-021-00619-4. Epub 2021 Oct 20. — View Citation

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: 10.1186/s12885-017-3286-5. Erratum In: BMC Cancer. 2019 Apr 18;19(1):366. — View Citation

Sekulic A, Migden MR, Lewis K, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Dirix L, Hou J, Yue H, Hauschild A; ERIVANCE BCC investigators. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol. 2015 Jun;72(6):1021-6.e8. doi: 10.1016/j.jaad.2015.03.021. — View Citation

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. — View Citation

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 Jan 19. — View Citation

Villani A, Costa C, Fabbrocini G, Ruggiero A, Scalvenzi M. Dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor sonidegib to manage adverse effects: A retrospective case series. J Am Acad Dermatol. 2021 Apr;84(4):e211-e212. doi: 10.1016/j.jaad.2020.12.006. Epub 2020 Dec 7. No abstract available. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Median progression free survival	The main study outcome measure is the median progression free survival (PFS) where the decrease, stagnation or increase in tumor size is measured by maximum diameter.	though study completion, an average of 3 years
Secondary	Adverse events	Frequency, severity and reversibility of treatment-emergent adverse events, measured according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.	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.
Secondary	Disease-specific quality of life	Disease-specific quality of life expressed as mean scores on the validated European Organisation for Research and Treatment of Cancer (EORTC) core quality of life (EORTC-QLQ-C30) questionnaire.; The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	At the start of treatment and every 6 months thereafter, until vismodegib or sonidegib is no longer used.
Secondary	Disease-specific quality of life	Disease-specific quality of life expressed as mean scores on the validated advanced basal cell carcinoma index (aBCCdex) questionnaire.; The aBCCdex consists of 26 questions related to symptoms, emotions, worry, avoidance behavior and influence on daily life. Scales range in score from 1 to 7 and from 1 to 6. A higher score correlates with a poorer quality of life.	At the start of treatment and every 6 months thereafter, until vismodegib or sonidegib is no longer used.