Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer

Purpose This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment. Methods Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m 2 weekly. Results Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m 2 ) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m 2 and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m 2 allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug–drug interactions. Conclusions Afatinib 40 mg QD plus vinorelbine 25 mg/m 2 weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.