title: Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors.
abstract: OBJECTIVE
  PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271.
  
  
  METHODS
  Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients.
  
  
  RESULTS
  Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles.
  
  
  CONCLUSIONS
  The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA. jinfante@tnonc.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Linda R
authors.initials: LR
authors.lastname: Mileshkin
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: Howard
authors.initials: H
authors.lastname: Fingert
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Pierce
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Roberts
authors.forename: S Martin
authors.initials: SM
authors.lastname: Shreeve
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001315:Australia; D002170:Canada; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D019788:Fluorodeoxyglucose F18; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017711:Nonlinear Dynamics; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C573150:PF-00562271; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D019788:Fluorodeoxyglucose F18; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human; C103547:PTK2B protein, human; D008874:Midazolam