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.

Autor: Weiss GJ; Virginia G. Piper Cancer Center at Scottsdale Healthcare (VGPCC), Scottsdale, AZ 85258, USA. gweiss@tgen.org, Hidalgo M, Borad MJ, Laheru D, Tibes R, Ramanathan RK, Blaydorn L, Jameson G, Jimeno A, Isaacs JD, Scaburri A, Pacciarini MA, Fiorentini F, Ciomei M, Von Hoff DD
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2012 Dec; Vol. 30 (6), pp. 2334-43. Date of Electronic Publication: 2011 Dec 09.
DOI: 10.1007/s10637-011-9774-6
Abstrakt: 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 dose-proportionality 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.
Databáze: MEDLINE
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