title: Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies.
abstract: OBJECTIVE
  This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors.
  
  
  METHODS
  Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off x 3wks q4wks; S2).
  
  
  RESULTS
  Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2-4) and tremors (Grade 2-3). In S2, DLTs included tremors (Grade 2-3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations.
  
  
  CONCLUSIONS
  The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling.
authors.affiliation: Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), Scottsdale, AZ 85258, USA. gweiss@tgen.org
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Lisa
authors.initials: L
authors.lastname: Blaydorn
authors.forename: Gayle
authors.initials: G
authors.lastname: Jameson
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Angela
authors.initials: A
authors.lastname: Scaburri
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Pacciarini
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C550092:N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D020917:Receptor, trkA; D018844:Cyclin-Dependent Kinases