Abstract C37: A Phase 1 open-label study evaluating pharmacokinetics, safety, and tolerability of linifanib in Japanese patients with solid tumors

Abstract

Abstract Background: Linifanib (ABT-869) is a novel orally active and selective inhibitor of vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Linifanib demonstrated antitumor activity in a variety of advanced solid tumor pts enrolled in early-phase clinical trials. Preliminary data from an international phase 1 multicenter study (M04-710) showed specific single-agent antitumor activity with a recommended tolerated dose of 0.25 mg/kg and a maximum tolerated dose of 0.30 mg/kg. Efficacy was observed in 3 phase 2 studies in pts with hepatocellular carcinoma, non-small cell lung cancer and renal cell carcinoma. Methods: This is a phase 1, open-label, dose-escalating study evaluating the PK, safety/tolerability of linifanib in Japanese pts with solid tumors. Pts were assigned to 4 dosing cohorts (0.05, 0.10, 0.20 and 0.25 mg/kg) of linifanib given orally once daily (QD) on Cycle (C) 1 Day (D) 1 under fasting conditions for 21 days. PK samples were collected at various time points after single dose on C1D1 and multiple doses on C1D15. CT scans were performed at baseline and at D1 of every second cycle; efficacy was evaluated using RECIST criteria. Adverse events (AEs) were graded by NCI CTCAE V3.0. Results: As of August 2009, 15 pts have received linifanib in this study: 3 at 0.05 mg/kg; 6 at 0.10 mg/kg; 3 at 0.20 mg/kg and 3 at 0.25 mg/kg. Pts had NSCLC (5), lung carcinoid (1) sarcoma (4), breast cancer (3), thymic carcinoma (1) and angioendothelioma (1). Partial response was noted in 1 breast cancer pt in the 0.20 mg/kg cohort (32% reduction from baseline). 15 pts had ≥ Grade 2 AEs; hypertension (12); neutropenia (4), thrombocytopenia (3) and hand foot syndrome (2). Among all pts, 2 experienced a dose limiting toxicity; 1 each at 0.10 mg/kg (Grade 3 ALT increase) and at 0.25 mg/kg (ECG T wave inversion). 4 pts had AEs leading to dose interruptions (3 pts at C3 and 1pt at C1) and 1 pt had an AE leading to dose reduction in C5. 5 pts have discontinued study at the time of this analysis; 2 due to radiographic progressive disease (PD), 1 due to clinical PD and 2 due to AEs. At 0.25 mg/kg dose, the exposures (AUC24) after single and multiple doses were 6.2±1.2 µg*hr/mL (mean±SD) and 10.7±3.1 µg*hr/mL, respectively. These multiple dose exposures are approximately 2-fold higher than efficacious exposures predicted based on observed results in preclinical animal models. The estimation of effective half-life based on observed accumulation was approximately 1 day. Conclusion: Preliminary ongoing results show that linifanib is tolerated in Japanese pts at ≤ 0.25 mg/kg and has antitumor activity as a single-agent in 1 pt with breast cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C37.