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 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).

Keywords: Pexidartinib; Pharmacokinetics; Safety; Solid tumors; Tenosynovial giant cell tumor.

Conflict of interest statement

Ann-Lii Cheng has received remuneration as an officer or advisor from Bristol-Myers Squibb, Ono, Bayer, Merck Sharp & Dohme, Novartis, and Eisai Corporation and has received honoraria from Novartis, Eli Lilly, AstraZeneca, and Eisai. Shun-ichi Sasaki, LiYin (Lillian) Chiu, Masahiro Sugihara, Tomoko Ishizuka, Toshihiro Oguma, and Naoyuki Tajima have received remuneration as an officer or advisor from Daiichi Sankyo. The other authors have no conflicts of interest.

Figures

Fig. 1

Schematic of overall study design and plan. DLT, dose-limiting toxicity; MTD, maximum tolerated dose; SMC, safety monitoring committee

Fig. 2

CONSORT diagram

Fig. 3

Percentage change in sum of longest diameters of target lesions from baseline. *The stable disease of this patient is only 53 days after first dosing date, so cannot be considered best overall response. Instead, this patient is classified as having progressive disease

Fig. 4

Longest diameter for right wrist synovial cavity by magnetic resonance imaging

Fig. 5

Mean (±STD) plasma concentrations of pexidartinib versus time—day 1. Cohorts 1 and 2: linear (a) and semi-logarithmic (b) scales

Fig. 6

Mean (±STD) plasma concentrations of pexidartinib versus time—day 15. Cohorts 1 and 2: linear (a) and semi-logarithmic (b) scales

Fig. 7

Mean (±STD) plasma concentrations of ZAAD-1006a versus time—day 1. Cohorts 1 and 2: linear (a) and semi-logarithmic (b) scales

Fig. 8

Mean (±STD) plasma concentrations of ZAAD-1006a versus time—day 15. Cohorts 1 and 2: linear (a) and semi-logarithmic (b) scales

Fig. 9

Individual CSF1 (a-b) and adiponectin (c-d) plasma levels by time. C, cycle; CSF1, colony-stimulating factor 1; D, day