Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors

Abstract

e14505 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. In non-Japanese pts, neratinib was found to have clinical activity against solid tumors and dose-limiting toxicity (DLT) of diarrhea. The maximum tolerated dose (MTD) was 320 mg daily and the recommended dose (RD) was 240 mg because of the diarrhea. In this phase 1 study, the MTD was determined and safety and preliminary efficacy were assessed in Japanese pts with advanced solid tumors. Methods: Pts (3- 6/cohort) received 80, 160, 240, or 320 mg oral neratinib. Each pt participated in only 1 dose group and received single doses of neratinib followed by 1 wk of observation; pts then received daily continuous administration at the same dose. DLTs were assessed from the first single dose to the end of 14 days of continuous treatment. Pharmacokinetics (PK) will be analysed via a noncompartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Results: Preliminary data for 21 pts as of 30 Oct 2008 are presented. Pts had a median age [range] of 61 yrs [39–78], were 62% male, and had all received ≥2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal (81%), breast (14%), and gastric (5%) cancer. Median duration of neratinib treatment [range] was 10 wks [3–29].Two patients at the 320-mg dose had DLTs of diarrhea plus anorexia. Therefore the MTD was determined to be 240 mg. Neratinib-related AEs, any grade in ≥25% of pts included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Neratinib-related AEs, grade ≥3 in ≥1 pts were anorexia (3 pts) and diarrhea (2 pts). Two pts had partial response (PR), 8 pts had stable disease (SD) ≥8 wks, 2 had SD≥16 wks, 9 had progressive disease. The 2 pts with PR had ErbB-2+ advanced breast cancer. PK analysis is still ongoing. Conclusions: In Japanese pts, the MTD for neratinb was determined to be 240 mg and the RD will be confirmed as 240 mg. Neratinib is tolerable and demonstrates preliminary antitumor activity in pts with solid tumors. [Table: see text]