Abstract A080: A phase 1 study of single-agent pexidartinib in Asian patients with advanced solid tumors (NCT02734433)
Authors: Lin Chia-Chi , Lee Jih-Hsiang , Hsu Chih-Hung , Chen Wei-Wu , Yen Yu-Hsin , Yang Chih-Hsin , Zhang Ling , Sasaki Shun-ichi , Chiu Lillian , Cheng Ann-Lii 
Published: August 2018

Abstract
Background: Pexidartinib is a novel, orally active, small-molecule kinase inhibitor that selectively targets the colony-stimulating factor-1 receptor (CSF1R), as well as the receptors c-kit and oncogenic Flt3. Based on these targets, pexidartinib may inhibit tumor growth directly by blocking oncogenic drivers such as CSF-1, c-kit, and Flt3, or indirectly by modulating the tumor microenvironment and interactions between stromal cells and tumors. This first study in Asia evaluated the safety, tolerability, and pharmacokinetic (PK) profile in an Asian population. Methods: This phase 1 non-randomized, open-label, multiple-dose study evaluated the safety and tolerability of pexidartinib in Asian patients with advanced solid tumors. This dose-escalation study employed a 3+3 design and included 2 dose levels. Patients at dose level 1 received 600 mg/day and patients at dose level 2 received 1000 mg/day for the first 2 weeks followed by 800 mg/day thereafter. Patients still receiving treatment after four 28-day cycles were eligible to continue pexidartinib in an extension phase. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Study objectives included assessment of pexidartinib safety and tolerability, PK, and pharmacodynamic effects on circulating CSF-1 and adiponectin, as well as determination of the maximum tolerated and recommended phase 2 doses (MTD and RP2D). Results: Eleven patients (6 males and 5 females, median age 64, range 23-82) were treated with pexidartinib in the dose-escalation phase. Preliminary PK data indicate that exposure (Cmax and AUC0-8h) increased proportionally with dose and the plasma concentration level increased after multiple doses. CSF-1 and adiponectin plasma concentrations increased after administration of pexidartinib. Grade ≥3 adverse events (AEs) observed were increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin, as well as anemia and lower back pain. No patients experienced dose-limiting toxicities, and the MTD was determined to be 1000 mg/day. At the time of this analysis, 7 patients had experienced disease progression, 3 patients had withdrawn from the study, and 1 patient with tenosynovial giant cell tumor continued to receive pexidartinib for more than 341 days. Conclusions: Pexidartinib was determined to be safe and tolerable at the 1000 mg/day dose for Asian patients, and the most common treatment-related AEs were elevated liver enzyme levels. Pexidartinib demonstrated clinical activity in a patient with tenosynovial giant cell tumor, and is being evaluated in a phase 3 study for patients with tenosynovial giant cell tumors in Western countries (NCT02371369).
Citation Format: Chia-Chi Lin, Jih-Hsiang Lee, Chih-Hung Hsu, Wei-Wu Chen, Yu-Hsin Yen, Chih-Hsin Yang, Ling Zhang, Shun-ichi Sasaki, Lillian Chiu, Ann-Lii Cheng. A phase 1 study of single-agent pexidartinib in Asian patients with advanced solid tumors (NCT02734433) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A080.