A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors

Abstract

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colonystimulating 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 (AUC 0-8h ), and maximum observed plasma concentration (C max ) increased on days 1 and 15 with increasing pexidartinib doses, and time at C max (T max ) 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).

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors

“…The analysis showed that the estimated exposure values for patients receiving pexidartinib 400 mg twice daily increased following multiple daily dosing, with accumulation ratios of 3.6 and 4.6 for pexidartinib and ZAAD, respectively. These results are in line with published phase 1 results evaluating pexidartinib in predominantly White patients 15 and Asian patients 16 with solid tumors. In the assessment of the effect of covariates on pexidartinib, small effect of study population was noted, with healthy subjects having 26% higher CL/F and 21% lower AUC 0-24,ss compared to patients with TGCT.…”

Pexidartinib: First Approval

“…In phase I studies, pexidartinib monotherapy (NCT01004861) [3], pexidartinib plus sirolimus (NCT02584647) [22], pexidartinib plus binimetinib (NCT03158103) [23], pexidartinib plus PLX9486 (NCT02401815) [24] and pexidartinib plus durvalumab (NCT02777710) [25] showed some antitumor activity in adult patients with solid tumors such as TGCT, unresectable malignant peripheral nerve sheath tumor (MPNST) and advanced gastrointestinal stromal tumor (GIST). Pexidartinib monotherapy was active against tumors in pediatric patients with neurofibromatosis type I related plexiform neurofibromas (NCT02390752; the recommended phase II dose was 800 mg/m 2 per day) [26] and produced an objective tumor response in one patient with TGCT in a trial in Asian patients with advanced solid tumors (NCT02734433; n = 8 evaluable) [27].…”

Next generation of immune checkpoint inhibitors and beyond

“…The results were available from 11 patients (6 males and 5 females) with a median age of 64 years. Among the 8 evaluable patients, the DCR was 67% with 1 PR and 4 SD [ 106 ]. The PR was ongoing at the time of cutoff at 7.6 months, and the mean duration of SD was 3.9 months.…”