A phase II study of ABT-869 in hepatocellular carcinoma (HCC): Interim analysis

Abstract

4581 Background: ABT-869 is a novel orally active, potent and selective inhibitor of the vascular endothelial growth factor and platelet derived growth factor families of receptor tyrosine kinases. Results of an interim analysis of a phase 2 trial of ABT-869 in HCC are presented. Methods: An open-label, multicenter phase II trial (M06–879) of oral ABT-869 at 0.25 mg/kg daily in Child-Pugh A (C-PA) or QOD in Child-Pugh B (C-PB) patients (pts) until progressive disease (PD) or intolerable toxicity, is ongoing. Key eligibility criteria included unresectable or metastatic HCC; up to one prior line of systemic treatment; and at least one measurable lesion by computed tomography (CT) scan. The primary endpoint was the progression free (PF) rate at 16 weeks. Secondary endpoints included objective response rate (ORR), time to progression (TTP), progression free survival (PFS) and overall survival (OS). CT scans were assessed centrally and by the investigators; presented results are from central assessment. Results: 44 pts were enrolled from 09/07 to 08/08 at 6 centers internationally, with interim data available for 34 pts. There were 28 C-PA pts (median age, 63.5 y [range, 20- 81]) and 6 C-PB pts (median age, 64.5 y [range, 36–69]) and 73.5% received no prior systemic therapy. For the 19 evaluable C-PA pts included in the per-protocol interim analysis, 8 (42.1%) were progression free at 16 weeks [95% CI 20.3, 66.5]. The estimated ORR was 8.7% [95% CI, 1.1, 28] for the 23 C-PA pts and 0% for the 2 C-PB pts who had at least one post-baseline CT scan reviewed by central imaging. For all 34 pts, median TTP was 112 d [95% CI, 110, -], median PFS was 112 d [95% CI, 61, 168] and median OS was 295 d [95% CI, 182, 333]. The most common adverse events (AEs) for all pts were hypertension (41%), fatigue (47%), diarrhea (38%), rash (35%), proteinuria (24%), vomiting (24%), cough (24%) and oedema peripheral (24%). The most common grade 3/4 AEs for all pts were hypertension (20.6%) and fatigue (11.8%). Most AEs were mild/moderate and reversible with interruption/dose reductions/or discontinuation of ABT-869. Conclusions: ABT-869 appears to benefit HCC patients, with an estimated TTP of 112 days and an acceptable safety profile. Updated results from this ongoing study will be presented. [Table: see text]

Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats

“…48 VEGF is a key angiogenic factor, and several agents that target VEGF or VEGFR are currently in development for the treatment of HCC. 49,50 Also, ligands that bind to the EGFR, such as EGF, have a vital role in both tumor angiogenesis and proliferation, thought to be primarily through activation of the RAF/MAPK kinase (MEK)/ERK and PI3K/AKT/mechanistic target of rapamycin (mTOR) pathways. It was hypothesized that agents such as tyrosine kinase inhibitors targeting epidermal growth factor (EGF)/ EGR receptor (EGFR) signaling may be beneficial in HCC treatment.…”

Update on new approaches in the management of hepatocellular carcinoma

“…Linifanib (ABT-869) is an oral agent that acts as a selective inhibitor of VEGF and PDGF tyrosine kinase receptors that was recently evaluated in a Phase II trial conducted on Child–Pugh A or B cirrhotic patients that reported a median time to progression and progression-free survival of 112 days with a median overall survival of 295 days. 36 Preliminary pharmacokinetics analysis in Child Pugh A and B patients showed that degree of hepatic impairment of tumor extent do not influence linifanib pharmacokinetics. 37 Its safety profile was acceptable and therefore a new Phase III study comparing linifanib with sorafenib in patients with advanced HCC is ongoing.…”

New agents on the horizon in hepatocellular carcinoma

“…Linifanib (ABT-869) is an orally active, potent, and selective inhibitor of VEGFR and PDGFR. Preliminary results from an open-label, multicenter phase II study of linifanib in advanced HCC were reported [Toh et al . 2009].…”