A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. METHODS: Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. RESULTS: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. CONCLUSIONS: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133.

A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors.

BACKGROUND: In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m(2)/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m(2) (regimen A) or cisplatin 75-100 mg/m(2)/5-fluorouracil 750-1000 mg/m(2) (regimen B) in patients with advanced solid tumors. PATIENTS AND METHODS: The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). RESULTS: The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. CONCLUSIONS: The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.