Study objectives and plan
nausea, DLTs, neutropenia, diarrhea, toxicities, thrombocytopenia, rash, paronychia, mucositis
NEUTROPENIA, FEBRILE NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, SECONDARY, PARONYCHIA, MUCOSITIS, INTERSTITIAL PNEUMONITIS
The primary endpoint was the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs) recorded over 28 days. DLTs were defined as any of the following adverse events despite adequate management: persistent Grade 4 neutropenia or thrombocytopenia lasting 4 days; Grade ≥ 3 febrile neutropenia; Grade ≥ 3 diarrhea; persistent Grade 2 diarrhea lasting 4 days; Grade ≥ 3 rash and/or paronychia; Grade ≥ 3 mucositis; persistent Grade 2 mucositis lasting 7 days; persistent Grade ≥ 2 nausea lasting 4 days; and Grade ≥ 2 interstitial pneumonitis.This open-label phase I study was planned as a standard 3 + 3 dose-escalation study. The enrolled patients were treated with afatinib at three different doses in combination with osimertinib at a standard dose of 80 mg once per day. The starting dose of afatinib was 20 mg once per day, with planned dose escalation at the subsequent dose levels of 30 and 40 mg once per day. The MTD was the highest dose level at which < 33% of the patients experienced DLTs during 28 days (the observation period). If one or two out of three patients experienced DLTs, then three more patients were treated with the same dose. If no more than two patients experienced DLTs among six patients, then the dose was escalated to the next level. The secondary endpoints included the overall response rate (ORR), survival outcomes, and biomarker analysis using liquid biopsy.