Phase I trial to assess the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumors.

Abstract

3104 Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with activity in a wide range of tumor cell lines dependent on ErbB signaling. Vinorelbine (VNR) interferes with tubulin polymerization and spindle formation during metaphase. Additive or supra-additive activity of A or EGFR TKI with VNR has been demonstrated in preclinical models. Methods: This dose-escalation Phase I study established the safety profile, MTD and PK of A with i.v. and p.o. VNR using a modified 3+3 design. Eligible patients (pts) were ≥18 years with refractory advanced or metastatic tumors, an ECOG PS 0–1, and adequate organ and bone marrow function. VNR i.v. (25 mg/m2)/oral (60 mg/m2 with escalation to 80 mg/m2 after 3 weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses. Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts in the PK expansion cohort (24 M/31 F), median age 54 years (range 34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively. Patients had NSCLC, breast, pancreatic (n=13/5/3), head and neck, stomach or colorectal cancer (n=2 each group); 28 pts had other cancers. At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50 mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o., 1/6 pts included for MTD determination experienced DLT, as did 7/13 pts and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main DLTs were diarrhea and febrile neutropenia. Median treatment duration (snapshot date 9 Dec 2011) across all dose groups was 80 days (range 10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o., respectively. Related AEs observed in most patients were diarrhea, asthenia, nausea, vomiting, neutropenia, decreased appetite, mucositis and rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses suggest no drug–drug interaction between A and i.v. VNR. Conclusions: Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with manageable, reversible, target-related side effects and promising signs of clinical activity in heavily pretreated patients. The MTD for A for both combinations is 40 mg daily.