| General information |
| Database: | DB00128 |
| Objective: | To determine the maximum tolerated dose (MTD) of the oral mTOR inhibitor everolimus in advanced hepatocellular carcinoma patients |
| Authors: | Shiah HS, et al |
| Title: | Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. |
| Journal: | Aliment Pharmacol Ther |
| Year: | 2013 |
| PMID: | 23134470 |
| Trial Design |
| Clinical Trial Id: | NCT00390195 |
| Agent: | everolimus
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | liver cancer |
| Cancer Subtype: | advanced hepatocellular carcinoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | an openlabelphase I study |
| Key Patients Feature: | Patients with locally advanced or metastatic hepatocellular carcinoma (ChildPugh class A or B) |
| Biomarker: | serum hepatitis B virus (HBV) DNA levels were quantified. |
| Biomark Analysis: | NA |
| Control Group Info: | daily and weekly cohorts |
| Treatment Info: | daily (2.510 mg) or weekly (2070 mg) everolimus in a standard 3 + 3 doseescalation design |
| Primary End Point: | MTD was based on the rate of doselimiting toxicities (DLTs). |
| Secondary End Point: | Secondary endpoints included safety, pharmacokinetics and tumour response. |
| Patients Number: | 39 |
| Trial Results |
| DLT_MTD: | DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. |
| Objective Response Rate: | NA |
| Disease Control Rate: | Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Grade 3/4 adverse events with a more than and equal to 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 HBsAgseropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). |
| Conclusions: | The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic antiviral therapy should be mandatory for HBsAgseropositive patients |