title: Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors.
abstract: OBJECTIVE
  This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.
  
  
  METHODS
  Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m(2)/day) following a standard 3 + 3 dose escalation design.
  
  
  RESULTS
  The MTD was determined to be 275 mg/m(2). Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m(2) dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease.
  
  
  CONCLUSIONS
  CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m(2) is recommended for further clinical testing.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Kyri P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: South Texas Oncology Hematology (STOH), San Antonio, Texas.
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.affiliation: South Texas Oncology Hematology (STOH), San Antonio, Texas.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Smith
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Drew W
authors.initials: DW
authors.lastname: Rasco
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Mays
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas.
authors.forename: Glenda
authors.initials: G
authors.lastname: Chambers
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Ma
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Laliberte
authors.affiliation: Curis, Inc., Lexington, Massachusetts.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio Texas. atolcher@start.stoh.com.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C549566:7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide