Phase I dose escalation study of the pan-HER inhibitor, PF00299804, in patients with advanced malignant solid tumors

摘要: Purpose: PF00299804 is a potent, orally available, irreversible inhibitor of the HER1, HER2, and HER4 tyrosine kinase receptors. This first-in-human study investigated the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF00299804 in patients with advances solid malignancies.Patients and methods: PF00299804 was administered once daily continuously (part A), and intermittently (part B). Dose escalation proceeded until the occurrence of unmanageable toxicities. Toxicities were monitored, and blood samples were drawn for pharmacokinetic analyses. Skin biopsies were taken predose, and after 14 days of treatment, to establish a PK/PD relationship. Tumor response was measured once every 2 cycles. Results: A total of 121 patients was included (111 in schedule A and 10 in schedule B). The MTD was set at 45 mg daily, the DLTs included stomatitis and skin toxicities. Most adverse events were mild (grade 1-2), and consisted of skin toxicities, fatique, and gastrointestinal side-effects, including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increase of exposure to PF00299804, and a long terminal half-life of 46 to 72 hours. A dose-dependent increase in target inhibition was observed in skin biopsy samples. Four patients, all with non-small cell lung cancer, had a partial response following treatment with PF00299804. Conclusions: PF00299804 can be safely administered up to a dose of 45 mg/day. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of anti-tumor activity were observed in patients with NSCLC. The …