Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors

作者：Geoffrey I. Shapiro, Edward O’Mara, Oscar L. Laskin, Lan Gao, John D. Baird, Robert J. Spiegel, Diksha Kaushik, Marla Weetall, Joseph M. Colacino, Kylie O’Keefe, Arthur Branstrom, Elizabeth Goodwin, Jeffrey R. Infante, Philippe L. Bédard, Ronald Kong · 发表于：Clinical Pharmacology in Drug Development · 年份：2021 · DOI：10.1002/cpdd.904 · 被引用次数：25 · 研究领域：Cancer therapeutics and mechanisms、Synthesis and biological activity、Cancer-related Molecular Pathways

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of n...