Linifanib (ABT-869), a potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinases, potentiates the action of carboplatin/paclitaxel (CP) in preclinical tumor models including NSCLC. This study assessed safety and tolerability of linifanib plus CP pharmacokinetics (PK), and preliminary anti-tumor activity in Japanese NSCLC patients.Methods
Adult patients with ECOG PS score <1 and no prior chemotherapy for NSCLC received standard CP [C area under the concentration–time curve 6 mg/ml/min; P 200 mg/m2 on day (d) 1 of every 21-day cycle (c)] and oral linifanib 7.5 mg or 12.5 mg daily starting d3c1 until progressive disease or unacceptable toxicity. 7.5 and 12.5 mg cohorts were enrolled sequentially. CT scans were carried out every 6 weeks. Evaluations included adverse events (AE, NCI CTCAE v4), efficacy (RECIST 1.1) and PK interactions between CP and linifanib.Results
Enrollment was 6 patients at 7.5 mg linifanib and 6 patients at 12.5 mg. One patient in each cohort had a dose-limiting toxicity of grade (G) 4 thrombocytopenia. One patient in each cohort had a serious AE of febrile neutropenia at c2. Most common AEs leading to treatment interruption were thrombocytopenia (9), neutropenia (5), leukopenia (4), febrile neutropenia (3), hand and foot syndrome (2) and also sensory disturbance (2). Other G3/4 AEs (all G3) were lung infection, anaemia, hypertension, lymphocyte count decrease, anaphylaxis and hypokalaemia. Dose reductions were required in four of eight patients treated for 4c. Partial responses (PR) and confirmed PR were observed in nine and six patients, respectively. Results from the PK analysis will be presented.Conclusions
Preliminary findings suggest that CP with daily linifanib is tolerable in Japanese patients with advanced/metastatic NSCLC. PRs have been observed. These data will be reviewed in the context of an ongoing global study in a similar population receiving similar treatments.