A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours

F A L M Eskens, C H Mom, A S T Planting, J A Gietema, A Amelsberg, H Huisman, L van Doorn, H Burger, P Stopfer, J Verweij, E G E de Vries, F A L M Eskens, C H Mom, A S T Planting, J A Gietema, A Amelsberg, H Huisman, L van Doorn, H Burger, P Stopfer, J Verweij, E G E de Vries

Abstract

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

Figures

Figure 1
Figure 1
Chemical structure of BIBW 2992.
Figure 2
Figure 2
Grade 3 facial skin rash with ulceration and desquamation (BIBW 2992 100 mg OD).
Figure 3
Figure 3
Individual (n=18/15) and gMean drug plasma concentration–time profiles of BIBW 2992 BS after multiple oral administration of 70 mg BIBW 2992 once-daily for 14 days to patients in treatment cycle 1 (linear scale).
Figure 4
Figure 4
Ki-67 staining of paired skin biopsies of cancer patients treated with BIBW 2992. Pretreatment samples (A and C) and on-therapy sample treated with 10 mg day−1 (B) or at the MTD of 70 mg day−1. (D) Original magnification of the photomicrographs 400 × . Overall effect of BIBW 2992 treatment (all dose levels pooled) on percentage Ki-67-positive epidermal keratinocytes (mean±s.d.) in pretreatment versus on-therapy samples (E) and the effect of treatment for each individual patient (F).

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