title: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.
abstract: BACKGROUND
  Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma.
  
  
  METHODS
  BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053.
  
  
  RESULTS
  Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group.
  
  
  CONCLUSIONS
  The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat.
  
  
  BACKGROUND
  Novartis Pharmaceuticals Corporation.
authors.affiliation: Mohs Surgery Center, Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mrmigden@mdanderson.org.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Migden
authors.affiliation: Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Guminski
authors.affiliation: Department of Dermatology and Allergy, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Department of Medical Oncology, Sint-Augustinus Ziekenhuis, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.affiliation: Department of Onco-Dermatology, Anticancer Institute, Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Combemale
authors.affiliation: Department of Dermatology, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Herd
authors.affiliation: Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Ragini
authors.initials: R
authors.lastname: Kudchadkar
authors.affiliation: Dermatologikum Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.affiliation: Oncology Clinical Development, Novartis Pharma, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Gogov
authors.affiliation: Oncology Clinical Development, Novartis Pharma, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Pallaud
authors.affiliation: Biometrics and Data Management, Oncology Business Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yi
authors.affiliation: Oncology Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Mone
authors.affiliation: Department of Dermatology and Allergology, University Hospital Jena, Jena, Germany; SRH Wald-Klinikum Gera, Gera, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaatz
authors.affiliation: Deparment of Dermatology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Deparment of Dermatology, Andreas Sygros Hospital, University of Athens, Athens, Greece.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stratigos
authors.affiliation: Fachklinik Hornheide, Münster, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schulze
authors.affiliation: Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Deparment of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
authors.forename: Anne Lynn S
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Cornélis
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: Lear
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Dalila
authors.initials: D
authors.lastname: Sellami
authors.affiliation: Universitätsspital Zürich-Skin Cancer Center University Hospital, Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D016896:Treatment Outcome
chemical_list: D001713:Biphenyl Compounds; D011725:Pyridines; C561435:sonidegib