3556 Background: BIBW 2992 (Tovok) is a potent, irreversible, new generation TKI, an inhibitor of EGFR and HER-2 (IC50 0.5 and 14 nM, respectively). A Phase I dose finding study of BIBW 2992 with docetaxel is reported. Methods: Patients (pts) had advanced solid malignancies and received docetaxel 75 mg/m2 i.v. on Day 1 and oral BIBW 2992 once daily on Days 2–4, in 3-week cycles. The BIBW 2992 dose was doubled in successive cohorts of 3–6 pts until ≥Grade 2 CTC, after which dose escalation occurred in increments of ≤50%. The MTD cohort expanded to 12 pts. PK profiles were taken on Days 1 and 2 of treatment cycles 1 and 2. Results: 40 evaluable pts (17 male) were treated at the following doses of BIBW 2992: 10 mg (6), 20mg (3), 40 mg (6), 60 mg (4), 90 mg (13), 120 mg (5) and 160 mg (3). Common adverse events (AEs) (% of patients) were fatigue (62.5%), diarrhea (57.5%), anorexia and stomatitis (52.5%), alopecia (50%), rash (42.5%), nausea and pyrexia (40%), vomiting (35%), general physical health deterioration (32.5%), and peripheral sensory neuropathy (30%). Two DLTs occurred: one pt had Grade 4 neutropenia (a DLT if complicated or lasting >5 or 7 days) and one had Grade 3 nausea, vomiting and diarrhea (BIBW 2992 120 mg). Both fully recovered upon treatment interruption/dose reduction (docetaxel 60 mg/m2/BIBW 2992 90 mg). The MTD was 90 mg BIBW 2992 with docetaxel 75 mg/m2. Four pts (breast cancer [2], thymoma [1], oesophageal carcinoma [1]) had a PR. One breast cancer pt had a confirmed CR. Two of these pts had prior taxane treatment. Ten pts had SD and received treatment for ≥6 courses with 4 receiving treatment for ≥9 courses. There was no deviation from dose-linearity of BIBW 2992 and docetaxel. Docetaxel (75 mg/m2) plasma concentration-time profiles, Cmax and AUC0-∞ before and after BIBW 2992 dosing were comparable. Conclusions: BIBW 2992 90mg administered for 3 days after docetaxel 75 mg/m2 is well tolerated and is the recommended dose for further trials. Objective responses or durable SD (≥6 months) were seen in 15 (39%) pts. No PK interaction was observed between BIBW 2992 and docetaxel. [Table: see text]
Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer