Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma

Summary Background Deregulation of mammalian target of rapamycin ( mTOR ) signalling is common in human hepatocellular carcinoma ( HCC ). Aim To determine the maximum tolerated dose ( MTD ) of the oral mTOR inhibitor everolimus in advanced HCC patients. Methods Patients with locally advanced or metastatic HCC (Child‐Pugh class A or B) were enrolled in an open‐label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose‐escalation design. MTD was based on the rate of dose‐limiting toxicities ( DLT s). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus ( HBV ) DNA levels were quantified. Results Thirty‐nine patients were enrolled. DLT s occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTD s were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase ( ALT ) elevation. In four hepatitis B surface antigen (HBsAg)‐seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg‐seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively ( P  <   0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively. Conclusions The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti‐viral therapy should be mandatory for HB sAg‐seropositive patients ( ClinicalTrials.gov NCT00390195).