Abstract B188: A Phase l study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies.
Authors: Kogure Yoshihito , Yamada Yasuhide , Saka Hideo , Kitagawa Chiyoe , Iwasa Satoru , Yamamoto Noboru , Aoki Takuji , Kakizume Tomoyuki , Robson Matthew , Quadt Cornelia , Mitsuma Ayako , Shibata Takashi , Ando Yuichi 
Published: August 2014

Abstract
Background: BYL719 is an oral inhibitor that selectively targets the α-isoform of class l PI3K, which is encoded by PIK3CA, a frequently altered gene in human cancers. In a first-in-man Phase I study in mostly Western patients (including one Asian patient) with advanced solid malignancies harboring a PIK3CA alteration (mutation and/or amplification), the maximum tolerated dose (MTD) for once-daily (QD) BYL719 was declared as 400 mg, and preliminary antitumor activity was observed (Gonzalez-Angulo et al. ASCO 2013). Here, we report preliminary findings of an ongoing multicenter, open-label Phase l dose-escalation study in Japanese patients with advanced solid malignancies irrespective of PIK3CA alterations (NCT01387321).
Methods: Patients were aged ≥18 years with histologically confirmed, advanced unresectable solid tumors, who had progressed despite standard therapy or for whom no standard therapy existed. Patients received continuous oral BYL719 QD in 28-day cycles until disease progression, unacceptable toxicity, or investigator/patient decision. Dose escalation was guided by an adaptive Bayesian logistic regression model with overdose control. The primary objective was to determine the MTD and/or recommended phase 2 dose (RP2D) of BYL719 QD. MTD was defined as the highest drug dosage not causing medically unacceptable does limiting toxicities (DLTs) in &gt;33% of treated patients during Cycle 1. Secondary objectives included assessments of preliminary antitumor activity (RECIST v1.1), safety (CTCAE v4), and PK profiles.
Results: As of May 20, 2013, 24 patients (median age 56 years) were enrolled, receiving BYL719 QD at 90 mg (n=3), 180 mg (n=4), 270 mg (n=5), 350 mg (n=5), or 400 mg (n=7). DLTs occurred in 2 out of 4 evaluable patients at 400 mg QD (both had Grade [G] 3 maculopapular rash). Nineteen (79%) patients discontinued treatment [5 due to adverse event (AE); 11 disease progression; 2 patient/guardian decision; 1 death (due to disease progression)]. Median duration of exposure was 7.6 (range: 2.4-55.9) weeks. The most common suspected BYL719-related all-grade AEs (&gt;25%) were maculopapular rash (50%), diarrhea (42%), hyperglycemia (38%), decreased appetite (29%), and pruritus (29%), and G3/4 AEs (≥10%) were maculopapular rash (29%) and hyperglycemia (13%). After May 20, 2013, one additional patient was enrolled at 350 mg QD, and no DLTs were observed out of 6 evaluable patients. Based on the Bayesian logistic regression model, 380 mg QD was the next recommended dose; however, considering the DLTs observed at 400 mg QD, 350 mg QD was declared as the RP2D. One patient with uterine clear cell carcinoma receiving 350 mg QD had an unconfirmed partial response. A dose-dependent increase of plasma exposure was observed and accumulation ratios were generally &lt;1.5.
Conclusions: In this Phase l, first-in-Japanese patients study of BYL719, 350 mg QD was declared as the RP2D and preliminary antitumor activity was observed. An expansion cohort is open at the RP2D in patients whose tumors harbor PIK3CA alterations.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B188.
Citation Format: Yoshihito Kogure, Yasuhide Yamada, Hideo Saka, Chiyoe Kitagawa, Satoru Iwasa, Noboru Yamamoto, Takuji Aoki, Tomoyuki Kakizume, Matthew Robson, Cornelia Quadt, Ayako Mitsuma, Takashi Shibata, Yuichi Ando. A Phase l study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B188.