Randomized, phase I, and pharmacokinetic (PK) study of RAD001, an mTOR inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC)

Abstract

4587 Background: RAD001, an orally administered, novel mTOR inhibitor has recently been extensively evaluated in cancer therapy. Up-regulation of mTOR expression has been noted in 40–45% of HCC, and preclinical studies suggest mTOR inhibitor can effectively inhibit proliferation of HCC cells as well as growth of HCC xenograft in mice. In addition, cytochrome P450 system is known to involve in metabolism of rapamycin analogues, and elimination of RAD001 is impaired in pts with hepatic dysfunction. The study aims to define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and PK of daily- and weekly-dosing RAD001 in advanced HCC pts. Methods: Advanced HCC pts who were not feasible for or progressed after local therapy (surgery, percutaneous ablation or transcatheter arterial chemoembolization), ECOG PS 0–2, Child-Pugh's score < 8, and adequate hepatic, renal and hematological functions were eligible. The doses of RAD001 for daily-dosing arm would be escalated from 2.5, 5.0, 7.5 to 10.0 mg, and from 20, 30, 50 to 70 mg in weekly-dosing arm. Four weeks of treatment was regarded as one cycle. PK samples were collected on days 1 of cycle 1 and 2. Results: A total of 36 pts (M/F 34/2; median age 58.5, range 28–75; Child-Pugh's class of A/B 31/5) were enrolled. Number of pts with DLT/enrollment for dose level I, II, III and IV in daily arm was 1/6 (grade 3 hyperbilirubinemia), 1/6 (grade 4 thrombocytopenia), 0/3 and 2/3 (grade 3 diarrhea and rectal bleeding in 1 and grade 3 diarrhea and cardiac ischemia in 1), respectively; whiles in weekly arm was 0/3, 1/6 (grade 3 ALT elevation), 0/3 and 1/6 (grade 3 infection), respectively. MTD for weekly- and daily- dosing schedule was 70 mg and <7.5 mg, respectively. Reactivation of HBV and HCV was observed in 4 and 1 pts, respectively. The disease control response (DCR) of 31 evaluable pts was 61% (10/16) and 46.7% (7/15, including one PR) of pts receiving daily and weekly treatment, respectively. However, the DCR for weekly-dosing pts received >50 mg was 75% (4/6). Conclusions: Patient accrual is ongoing to complete. However, preliminary data suggest RAD001 is moderately active in stabilizing the progression of HCC, and PK data will be important to determine the optimal dosing schedule of RAD001 for HCC pts. [Table: see text]