A phase I study of daily BIBW 2992, an irreversible EGFR/HER-2 dual kinase inhibitor, in combination with weekly paclitaxel

作者：J. Ang, Christos Mikropoulos, Flora Stavridi, Sarah Maria Rudman, M. Uttenreuther-Fisher, Maryam Shahidi, Karine Pemberton, Sven Wind, Johann Sebastian De Bono, James F. Spicer · 发表于：Journal of Clinical Oncology · 年份：2009 · DOI：10.1200/jco.2009.27.15_suppl.e14541 · 被引用次数：12 · 研究领域：Cancer Treatment and Pharmacology、HER2/EGFR in Cancer Research、Lung Cancer Treatments and Mutations

e14541 Background: BIBW 2992 is an oral, potent and irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases. The efficacy of cytotoxic agents can be enhanced by erbB inhibition. The primary objective of this Phase I open- label dose-escalation trial was to determine the maximum tolerated dose (MTD) of BIBW 2992 in combination with weekly paclitaxel. Methods: This study evaluated safety, pharmacokinetics (PK), and anti-tumor efficacy of daily BIBW 2992 combined with paclitaxel administered on Days 1, 8 and 15 of a 4-weekly cycle. The dose of paclitaxel was 80 mg/m2, and the BIBW 2992 starting dose was 20 mg, escalated in successive cohorts to 40 then 50 mg. After 6 cycles of combination therapy, patients benefiting and tolerating treatment were eligible to continue single agent BIBW 2992. Results: Sixteen patients with advanced solid tumors expressing erbB receptors and suitable for treatment with a taxane have been enrolled (6 male/10 female; median age: 59 [range: 39–72]; ECOG PS 0/1: 5/11). Two dose-limiting toxicities of fatigue and mucositis occurred at a BIBW 2992 dose of 50 mg. The most frequent adverse events were fatigue, rash, mucositis and diarrhea. Partial responses were seen in patients with non-small cell lung cancer (3), prostate cancer (1), oesophageal cancer (1) and cholangiocarcinoma (1). Eight patients have remained on treatment beyond 4 cycles. The PK data of paclitaxel (with and without BIBW 2992 administration) as well as of BIBW 2992 at st...