title: Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial.
abstract: Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas.
  
  
  
  In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing.
  
  
  
  Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0-72·3) in treatment group A and 54·0% (43·6-64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment.
  
  
  
  Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted.
  
  
  
  F Hoffmann-La Roche.
authors.affiliation: Service de Dermato-Cancérologie, Nantes University, Nantes, France. Electronic address: brigitte.dreno@wanadoo.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dréno
authors.affiliation: University Dermatology Clinic, Medical University of Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kunstfeld
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Dermatology, Saint Louis University Medical School, St Louis, MO, USA; Department of Dermatology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Fosko
authors.affiliation: Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Zloty
authors.affiliation: Dermatology, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Labeille
authors.affiliation: Service de Dermatologie, Aix Marseille University and Timone Hospital, Marseille, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.affiliation: Department of Dermatology, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain; Research, Oncology and Haematology, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.affiliation: Biostatistics, F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Gilberg
authors.affiliation: Global Product Development, Medical Affairs, Oncology, F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bergström
authors.affiliation: Global Product Development, Medical Affairs, Oncology and Haematology, F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Damian R
authors.initials: DR
authors.lastname: Page
authors.affiliation: Department of Surgery, Oncology Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Rogers
authors.affiliation: Klinik für Dermatologie, Venereologie und Allergologie, Universitätsklinikum Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000813:Anilides; C538724:HhAntag691; D011725:Pyridines