Abstract
SummaryBackground Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23–82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).
Highlights
Twelve patients were enrolled from one study center (National Taiwan University Hospital), 11 of whom (6 males and 5 females; median age 64, range 23–82) received pexidartinib; 1 patient was not treated due to a screen failure
Pexidartinib exposure increased after multiple doses, and plasma levels of biomarkers colonystimulating factor 1 (CSF1) and adiponectin increased after pexidartinib administration
Two patients experienced a total of 6 serious adverse events (AEs) during the dose-escalation phase, one of whom died of malignant neoplasm progression, which the investigator deemed to be unrelated to pexidartinib treatment
Summary
Pexidartinib is a novel, orally administered small-molecule tyrosine kinase inhibitor (TKI) with strong selective activity against the colony-stimulating factor 1 receptor (CSF1R) [1]; the receptors KIT and FMS-like tyrosine kinase 3 internal tandem duplication mutation (FLT3-ITD) are inhibited [2] Based on these targets, pexidartinib may inhibit tumor growth directly by blocking the oncogenic drivers colonystimulating factor 1 (CSF1), tyrosine protein kinase KIT (cKIT), and FMS-like tyrosine kinase 3 (FLT3) [3,4,5,6], or indirectly by modulating the tumor microenvironment and affecting interactions between stromal and tumor cells [7,8,9]. In the extension part of study (n = 23), pexidartinib treatment resulted in a 52% overall response rate (ORR) and an 83% disease control rate by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in patients with recurrent or inoperable tenosynovial giant cell tumor (TGCT) [1]
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