A phase 1 study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies

Abstract

Background: BYL719 is an oral inhibitor that selectively targets the a‐isoform of class l PI3K. In a first‐in‐human ph1 study in mostly Western patients (pts) with PIK3CA alteration, the maximum tolerated dose for once‐daily (qd) BYL719 was declared as 400 mg and preliminary antitumor activity was observed. Previous preliminary findings showed tolerability, safety, and pharmacokinetic (PK) results in dose escalation of the first‐in‐Japanese ph1 study. Here, we report results of the food effect on the PK profile of BYL719 at steady state, additional safety, and preliminary efficacy in Japanese pts. Methods: Pts were aged ≥ 18 years with histologically confirmed, advanced solid tumors. Pts received BYL719 qd in 28‐day cycles until disease progression, unacceptable toxicity, or investigator/pts decision. The objectives in the expansion part were to assess food effect on PK profile, preliminary antitumor activity, and safety. Pts with PIK3CA alteration were selected in the expansion part and were randomized to receive BYL719 at the recommended dose 350 mg qd in fasted or fed condition on cycle 1 day 22 and cycle 2 day 1 in a crossover fashion. Pts received BYL719 ≥ 1 hr following a light breakfast and continued to be fasted for 1 hr after each dose. Results: Thirty‐three pts were enrolled and all pts discontinued treatment. The median duration of exposure was 71.0 days (range, 6‐462). The common BYL719‐related allgrade (Gr) AEs (>30%) were hyperglycemia, rash maculopapular (48.5%, each), diarrhea (45.5%), and decreased appetite (33.3%). BYL719‐related Gr 3 or 4 AEs (≥ 20%) were rash maculopapular (24.2%) and hyperglycemia (21.2%). Eight pts were enrolled in the expansion part; six of them were eligible for PK analysis. The geometric mean values of dose‐normalized Cmax and AUC0‐24 in fed state were 78% and 56% higher than those in fasted state, respectively. One pt experienced Gr 4‐infected neoplasmmeeting DLT criteria, 1 pt with uterus cancer and PIK3CA mutation had an unconfirmed partial response, and 18 pts had a stable disease. Conclusions: In this ph1 study of BYL719 in Japanese pts, a positive food effect and preliminary antitumor activity were observed at steady state in pts with PIK3CA mutation status.