title: A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma.
abstract: OBJECTIVE
  CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC.
  
  
  METHODS
  CUDC-101 monotherapy was administered intravenously three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m(2) every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks.
  
  
  RESULTS
  Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-negative. The MTD of CUDC-101-based combination therapy was established at 275 mg/m(2)/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression.
  
  
  CONCLUSIONS
  CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Galloway
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.affiliation: Stanford Cancer Center, Stanford, California.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Colevas
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Curis Inc, Lexington, Massachusetts.
authors.forename: Anna W
authors.initials: AW
authors.lastname: Ma
authors.affiliation: Curis Inc, Lexington, Massachusetts.
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.affiliation: Curis Inc, Lexington, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania. Antonio.Jimeno@ucdenver.edu barbara.burtness@yale.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burtness
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado. Antonio.Jimeno@ucdenver.edu barbara.burtness@yale.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006655:Histone Deacetylases / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D011878:Radiotherapy / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D066246:ErbB Receptors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C549566:7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide