1. Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer.
- Author
-
Mukai H, Masuda N, Ishiguro H, Mitsuma A, Shibata T, Yamamura J, Toi M, Watabe A, Sarashina A, Uttenreuther-Fischer M, and Ando Y
- Subjects
- Adult, Afatinib, Aged, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic adverse effects, Antineoplastic Agents, Phytogenic pharmacokinetics, Antineoplastic Agents, Phytogenic therapeutic use, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms blood, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cohort Studies, Dose-Response Relationship, Drug, Drug Monitoring, Female, Humans, Japan, Leukopenia chemically induced, Male, Middle Aged, Neoplasms blood, Neoplasms pathology, Patient Dropouts, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors therapeutic use, Quinazolines administration & dosage, Quinazolines pharmacokinetics, Quinazolines therapeutic use, Tumor Burden drug effects, Vinblastine administration & dosage, Vinblastine adverse effects, Vinblastine pharmacokinetics, Vinblastine therapeutic use, Vinorelbine, Antineoplastic Combined Chemotherapy Protocols adverse effects, ErbB Receptors antagonists & inhibitors, Neoplasms drug therapy, Protein Kinase Inhibitors adverse effects, Quinazolines adverse effects, Vinblastine analogs & derivatives
- Abstract
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.
- Published
- 2015
- Full Text
- View/download PDF