title: A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma.
abstract: BACKGROUND
  This phase 1, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), antitumor activity, and molecular correlates of IPI-926, a Hedgehog pathway (HhP) inhibitor, combined with cetuximab in patients with relapsed/metastatic squamous cell carcinoma of the head and neck.
  
  
  METHODS
  Cetuximab was given with a 400mg/m(2) loading dose followed by 250mg/m(2) weekly. IPI-926 was given daily starting two weeks after cetuximab initiation. A "3+3" study design was used. Prior therapy with cetuximab was allowed. Tumor biopsies occurred prior to cetuximab initiation, prior to IPI-926 initiation, and after treatment with both drugs.
  
  
  RESULTS
  Nine patients were enrolled. The RP2D was 160mg, the same as the single-agent IPI-926 MTD. Among 9 treated, 8 evaluable patients, the best responses were 1 partial response (12.5%), 4 stable disease (50%), and 3 disease progressions (37.5%). The median progression free survival was 77days (95% confidence interval 39-156). Decreases in tumor size were seen in both cetuximab-naïve patients (one HPV-positive, one HPV-negative). The most frequent treatment-emergent adverse events were fatigue, muscle cramps, and rash. No DLTs were observed. Tumor shrinkage and progression free survival were associated with intra-tumoral ErbB and HhP gene expression down-regulation during therapy, supporting the preclinical hypothesis.
  
  
  CONCLUSIONS
  Treatment with IPI-926 and cetuximab yielded expected toxicities with signs of anti-tumor activity. Serial tumor biopsies were feasible and revealed proof-of-concept biomarkers.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Eagles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Glogowska
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: McDermott
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Phuong N
authors.initials: PN
authors.lastname: Le
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States.
authors.forename: Dexiang
authors.initials: D
authors.lastname: Gao
authors.affiliation: Division of Interventional Radiology, Department of Radiology, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Ray
authors.affiliation: Division of Interventional Radiology, Department of Radiology, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rochon
authors.affiliation: Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Serracino
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology. Electronic address: antonio.jimeno@ucdenver.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D000068818:Cetuximab / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010865:Pilot Projects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D000068818:Cetuximab
keywords: Cetuximab; Combination therapy; Head and neck squamous cell carcinoma; Hedgehog signaling pathway; Phase 1