Final result of a phase I/II trial of the oral anti-angiogenesis inhibitor TSU-68 in patients with advanced hepatocellular carcinoma

Abstract

4589 Background: Advanced hepatocellular carcinoma (HCC) has a poor prognosis. Liver function needs to be considered in a clinical trial, since most patients (pts) with HCC have cirrhosis or hepatitis. Previously, we proposed a feasibility study design based on hepatic function to evaluate TSU-68, an oral multikinase inhibitor (VEGFR, PDGFR, FGFR), and determined that 400 mg/d of TSU-68, which is half of the dose for other types of cancer, was the recommended dose for phase II (Kanai et al., A4145, ASCO 2006). Here, we show the efficacy of TSU-68 in phase II and confirmed the validity of the study design. Methods: Pts previously treated with surgery, radiofrequency ablation, transcatheter arterial embolization, chemotherapy, or radiotherapy, were eligible. The primary endpoint of phase II was the objective response rate using RECIST. Nine plasma angiogenic markers were evaluated at baseline and on day 28. Results: 35 pts (12 pts in phase I and 23 pts in phase II) were enrolled: median age = 68 years, male/female = 29/6, chronic hepatitis/Child-Pugh A/B = 4/23/8, HCV/HBV/nBnC = 26/5/4, and the pts were pretreated 8.1 times on average by different modalities. Common adverse events were hypoalbuminemia, diarrhea, abdominal pain, fever, and AST/ALT elevation, and most of them were grade 1 or 2. Only one patient (pt) discontinued administration due to toxicities. One pt achieved CR, 2 pts achieved PR, 15 pts had SD, 16 pts had PD, and 1 pt was not evaluable. The response rate (CR+PR) was 8.6%, and the disease control rate (CR+PR+SD) was 51.4% (6 pts for over 6 months). Tumor necrosis was observed in 9 pts (25.7%). While the PDGF levels in the non-PD group (18 pts) did not change from baseline to day 28 (median 1,980 to 1,960 pg/ml), those of the PD group (16 pts) were significantly elevated (median 1,265 to 3,470 pg/ml). Conclusions: TSU-68 showed promising efficacy with a high safety profile, even in heavily pretreated HCC pts with Child-Pugh B liver cirrhosis. This study design with stepwise adjustment of doses based on liver function constitutes an appropriate approach for HCC. No significant financial relationships to disclose.