Abstract 29: Phase I study of intravenous PI3K inhibitor BAY 80-6946 in Japanese subjects.
Authors: Doi Toshihiko , Fuse Nozomu , Yoshino Takayuki , Kojima Takashi , Bando Hideaki , Miyamoto Hideaki , Kaneko Masato , Osada Motonobu , Ohtsu Atsushi 
Published: August 2014

Abstract
Background: BAY 80-6946 is an intravenous, potent and highly selective pan-Class I PI3K inhibitor with anti-tumor activity in a panel of preclinical models. A phase I study to evaluate safety, tolerability and pharmacokinetics at the maximum tolerated dose (MTD) in Western patients was performed in Japanese patients with advanced or refractory solid tumors.
Methods: Ten patients received 1-hr intravenous infusions of BAY 80-6946 at doses of 0.4 mg/kg (3 patients) and 0.8 mg/kg (7 patients); 0.8 mg/kg had been determined as the MTD in a previous phase I study conducted in the US (Patnaik et al., J Clin Oncol 29: 2011; suppl, abstr 3035). A cycle consisted of 3 weekly doses, every 4 weeks, with treatment continuing until disease progression or unacceptable toxicity. Tumor types included 4 colorectal, 2 non-small cell lung, 1 renal, pancreatic, GIST and bladder cancer, respectively. Pharmacokinetics (PK) were evaluated following the first and third doses. Safety evaluations included monitoring of glucose and blood pressure, EKGs and echocardiogram.
Results: Safety and tolerability were evaluated in cycle 1 and no DLTs were observed in the either cohort. Anticipated adverse events (AEs), hyperglycemia and hypertension related to BAY 80-6946, were observed but easily managed by appropriate medication. Transient hyperglycemia Gr 1 was seen in 4 (40%), Gr 2 in 2 (20%) and Gr 3 in 1 patient (10%), respectively. Transient hypertension Gr 1 was seen in 2 (20%) and Gr 2 in 4 (40%) patients, respectively. Other drug-related AEs more than 2 patients in the cycle 1 included Gr 1/2 anemia (20%), oral mucositis (20%), nausea (20%), neutropenia (40%), leukocytopenia (40%), pruritus (20%) and skin acneiform (20%) and Gr 2/3 lymphocytopenia. One patient with a serious adverse event related to the study drug was observed showing Gr 3 diarrhea with Gr 2 pre-syncope in the 2nd cycle whom recovered but needed prolonged hospitalization. Seven patients discontinued the study due to progressive disease and 3 due to AEs; 2 in 1st, 5 in 2nd, 2 in 3rd and 1 in 5th cycle, respectively. The GIST patient previously progressed on both imatinib and sunitinib had stable disease (SD) through the end of 5th cycle but discontinued due to the drug-related thrombocytopenia. PK analyses yielded results similar to that reported in Western patients. The AUC for BAY 80-6946 was approximately dose proportional. There was no accumulation between Day 1 and Day 15 in AUC for BAY 80-6946. The half-life of BAY 80-6946 averaged approximately 32 to 36 hours after C1D1 of dosing.
Conclusions: BAY 80-6946 was generally well tolerated at the MTD of 0.8 mg/kg. Study drug related hyperglycemia and hypertension were well managed. There are no relevant ethnic differences in PK between Japanese and Western patients.
Citation Format: Toshihiko Doi, Nozomu Fuse, Takayuki Yoshino, Takashi Kojima, Hideaki Bando, Hideaki Miyamoto, Masato Kaneko, Motonobu Osada, Atsushi Ohtsu. Phase I study of intravenous PI3K inhibitor BAY 80-6946 in Japanese subjects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 29. doi:10.1158/1538-7445.AM2013-29