270 Background: AVE1642 blocks IGF-1R signaling. Previous phase I studies recommended AVE1642 doses ranged from 3 to 6 mg/kg in solid tumors. AVE1642 alone and in combination has shown in vitro and in vivo antitumor activity warranting further investigations in HCC. Methods: Dose-escalation was performed using a 3+3 design in patients with advanced HCC. AVE1642 doses were 1 mg/kg (DL1) 3 mg/kg (DL2), 6 mg/kg (DL3) given IV for 30 min every 3 weeks (w). AVE1642 was given alone for 3 w and every 3 w thereafter in combination with sorafenib (400 mg bid/day). Dose-limiting toxicities (DLT) were assessed during the first two cycles. Safety, pharmacokinetic (PK), pharmacodynamic (PD), tumor response (RECIST) were evaluated. Results: Thirteen patients (median age: 70y, M/F: 10/3, Child-Pugh A: 13/13) received 83 cycles (range 3-13) of AVE1642: 3 patients at DL1 (31 cycles), 7 patients at DL2 (38 cycles), 3 patients at DL3 (14 cycles) All patients were evaluable for safety and PK/PD. HCC was located in liver in 11 patients and was metastatic in 2. At cycle 1, exposure to AVE1642 alone led to grade 2-3 anemia in 1 patient at DL2, non febrile neutropenia in 1 at DL3. Other adverse events were grade 1-2 gastrointestinal disorders in 1 patient at DL1, in 3 at DL2 and hyperglycemia in only 1 at DL2. No liver function failure or haemorrhagic complications were observed. The frequency of sorafenib induced adverse events was not increased under combination. AVE1642 was eliminated slowly from the serum (t1/2: 5 to 6.7 days). There was no apparent effect of the dose on the systemic clearance of AVE1642, no effect of sorafenib treatment on the PK of AVE1642. IGF1 and IGFBP3 plasma concentrations (not of IGF2) were increased following AVE1642 administration. Most patients (11/13) presented tumor stabilization during a mean time of 13.3 w (ranging 6 to 27 w). Conclusions: AVE1642 can be safely combined with active doses of sorafenib. PK of both AVE1642 and sorafenib were not modified at these relevant concentrations. Interesting long-lasting disease stabilizations were observed in these patients with progressive disease. No significant financial relationships to disclose.
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