Pharmacokinetic (PK) and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma (HCC).

4135 Background: While HCC is one of the most common cancers worldwide, no effective chemotherapy for advanced stages exists. Expression of PDGF receptor has been demonstrated on some hepatoma cell lines. Furthermore HCC may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate the efficacy and safety of imatinib, a tyrosin kinase inhibitor of PDGFR and c-kit, in pts with advanced HCC, and of imatinib PKs in pts with impaired liver function.,Pts with histologically proven advanced HCC, not eligible for surgery or locoregional treatment, with adequate organ function (bilirubin < 2x ULN, ALT/AST < 5x ULN, creatinine < 1.5x ULN, platelets > 70,000) were treated with imatinib 400 mg daily. After 2 weeks the dose was increased to 600 mg depending on toxicity. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. 74 plasma samples for PKs were assessed.,17 pts, 15 evaluable for response were enrolled. 11 (65%) pts had liver cirrhosis, 5 (31%) were positive for anti-HCV, and 1 (6%) had hereditary hemochromatosis. Only 1 of 15 tumors assessed was positive for PDGFR and none of 14 positive for c-kit. Child-Pugh score was A and B in 13 (77%) and 4 (24%) pts and Okuda stage I and II in 8 (47%) and 9 (53%) pts, respectively. CLIP score was as follows: 1 (12%), 2 (18%), 3 (47%), 4 (24%). Grade 3-4 leukopenia occurred in 2 pts, of whom 1 had neutropenic fever. 1 episode of grade 3 diarrhea and 6 episodes of grade 3 edema occurred. There was no objective response and 5 (33%) pts had stable disease. Others failed treatment due to progression (60%, including 4 (27%) early deaths) and 1 (7%) early death not caused by HCC nor toxicity. Median time to treatment failure was 1.8 mos and 3.7 mos in pts with SD. In pts treated with 400 mg imatinib there were no significant differences in PKs (t 22.0 vs 26.6 h, AUC 32.0 vs 31.7 μg*h/ml, C 1.20 vs 1.38 μg/ml, clearance 210 vs 221 ml/min) compared with CML pts.,In this small group of pts with advanced, mostly PDGFR and c-kit negative HCC, imatinib showed no therapeutic effect. Imatinib PKs were not significantly influenced by impaired liver function as compared with CML pts. [Table: see text].