A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours

Abstract

2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]