Ando, Yuichi, Inada-inoue, Megumi, Mitsuma, Ayako, Yoshino, Takayuki, Ohtsu, Atsushi, Noumi, Naoko, Sato, Masahiko, Kakizume, Tomoyuki, Robson, Matthew, Quadt, Cornelia and Doi, Toshihiko (2014) A Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Science, 105 (3). pp. 347-353.

Abstract

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ, δ). This open-label, Phase I, dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity, and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n=3), 50 mg/day (n=3), and 100 mg/day (n=9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib, further dose escalation was stopped and 100 mg/day was declared the recommended dose. Most common treatment-related adverse events included rash, abnormal hepatic function (including increased transaminases), increased blood insulin levels, and increased eosinophil count. Hyperglycemia was experienced by two patients, one each Grade 1 and 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.

Item Type:	Article
Keywords:	PI3K inhibitor, BKM120, buparlisib, solid tumors, Japanese patients, Phase I
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/11122