Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors

A H Awada, H Dumez, A Hendlisz, P Wolter, T Besse-Hammer, M Uttenreuther-Fischer, P Stopfer, F Fleischer, M Piccart, P Schöffski, A H Awada, H Dumez, A Hendlisz, P Wolter, T Besse-Hammer, M Uttenreuther-Fischer, P Stopfer, F Fleischer, M Piccart, P Schöffski

Abstract

Background: A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors.

Methods: Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed.

Results: Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤ 2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed.

Conclusion: Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.

Figures

Fig. 1
Fig. 1
a Individual and gMean plasma concentration–time profiles of afatinib;* b Individual and gMean dose-normalized AUC0–24 values of afatinib.† *After multiple oral administration of 90 mg afatinib tablets on days 2–4 of treatment cycles 1–4. †After single oral administration of 10–160 mg afatinib tablets on day 2 of treatment cycle 1 (overall gMean: 8.44; n = 38). Abbreviations: gMean = geometric mean; AUC0–24 = area under the concentration–time curve of the analyte in plasma over the time interval from 0 to 24 h
Fig. 2
Fig. 2
gMean plasma concentration–time profiles of docetaxel after IV administration (75 mg/m2) on day 1 of treatment cycles 1 and 2 in the MTD group (semi-log scale). Abbreviation: TC = treatment cycle

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