Abstract P4-16-11: Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors including breast cancer
Authors: Masuda N , Mukai H , Ishiguro H , Mitsuma A , Shibata T , Yamamura J , Toi M , Watabe A , Sarashina A , Ebisawa R , Uttenreuther-Fischer M , Ando Y 
Published: August 2014

Abstract
Background: Afatinib, a potent irreversible ErbB Family Blocker, inhibits signaling from HER1, HER2 and HER4 dimers, and transphosphorylation of HER3. A Phase I trial was conducted to assess if afatinib 40 mg/day in combination with vinorelbine (VNR) 25 mg/m2 i.v. weekly could be safely administered to Japanese patients (pts).
Patients and methods: The safety, tolerability and pharmacokinetics (PK) of daily oral afatinib plus weekly i.v. VNR in a 28-day cycle in Japanese pts was assessed using a 3+3 design. The primary endpoint was to determine the maximum tolerated dose (MTD), based on dose-limiting toxicities (DLTs) in Cycle 1 (see Table; dose Levels 1 and 2). When the MTD was exceeded, dose Levels 2a and 3 allowed modifications of VNR dosing as used in clinical practice. Eligible pts were ≥20 years old with histologically confirmed refractory advanced/metastatic solid tumours, and an ECOG performance status (PS) 0-1. Adverse events (AEs) were documented as per NCI CTCAE v3.0. Response was assessed using RECIST 1.1, and PK parameters for both drugs were analyzed by intra-individual comparison, based on frequent blood sampling.
Results: Seventeen pts were recruited. Median age was 60 (range 40-68) years, all pts had received previous chemotherapy, and 7/9 pts with BC had received HER2-targeted therapy. No DLTs were observed at dose Level 1. When 3/5 pts developed DLTs in Cycle 1 at an afatinib dose of 40 mg in Level 2 (see Table), an intermediate cohort 2a was introduced at 20 mg/m2 VNR i.v. weekly. Tolerability at Level 2a was confirmed. With afatinib dose modification permitted, and VNR dose skipping allowed for ANC &lt;1500/mm3, dose re-escalation to VNR 25mg/m2 i.v. weekly at Level 3 was performed to establish a recommended phase II dose. At Level 3, 7/24 planned doses of VNR were skipped due to Grade 2 and 3 neutropenia, not qualifying as DLTs. One DLT occurred in a pt with Grade 2 epigastralgia in Course 1, who required afatinib dose reduction. Overall, the most frequent drug-related AEs were leukopenia, neutropenia (100% each), diarrhea (94%), anemia (70%), stomatitis (64%) and rash (41%). Nine BC pts were treated in cohorts 2a and 3, and all experienced diarrhea, leukopenia and neutropenia. No PK drug-drug interactions between afatinib and VNR were observed. Safety and PK profiles did not appear to differ between Japanese pts and Caucasian pts in a previous Phase I study. Two pts with BC and prior trastuzumab treatment had partial responses. Tumor shrinkage was observed in four of six evaluable BC pts, but not in other tumor types.
Conclusions: Afatinib 40 mg/day plus vinorelbine 25 mg/m2/week was tolerable and showed early signs of clinical activity in Japanese pts. AEs were as expected and were managed by dose modifications of both compounds. Final data will be presented at this congress.
Dose LevelsAfatinibVinorelbineN treatedDLTs (n)120 mg/day25 mg/m2/week3None240 mg/day25 mg/m2/week5Grade 4 neutropenia for 7 days (1); Grade 3 febrile neutropenia (1); Grade 3 pharyngeal infection with Grade 4 lipase and amylase elevations (1)2a40 mg/day20 mg/m2/week3 (all BC)None340 mg/day25 mg/m2/week6 (all BC)Grade 2 epigastralgia (1)
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-11.