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

Glen J. Weiss, Manuel Hidalgo, Mitesh J. Borad, Daniel Laheru, Raoul Tibes, Ramesh K. Ramanathan, Lisa Blaydorn, Gayle Jameson, Antonio Jimeno, Jeffrey D. Isaacs, Angela Scaburri, Maria Adele Pacciarini, Francesco Fiorentini, Marina Ciomei, Daniel D. Von Hoff

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Purpose 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. Patients and 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 doseproportionality with accumulation by a factor of 3 after repeated administrations. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)2334-2343
Number of pages10
JournalInvestigational New Drugs
Volume30
Issue number6
DOIs
StatePublished - Dec 2012

Keywords

  • Cyclin-dependent kinase
  • Investigational agent
  • PHA-848125AC
  • Phase I clinical trial
  • Tropomyosin receptor kinase A

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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