Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma

J Hepatol. 2013 Dec;59(6):1271-7. doi: 10.1016/j.jhep.2013.07.029. Epub 2013 Aug 6.

Abstract

Background & aims: Sorafenib is the only therapy shown to improve overall survival in advanced hepatocellular carcinoma (HCC). Combination therapy targeting multiple signaling pathways may improve outcomes. This phase I study was designed to determine the maximum tolerated dose (MTD) of everolimus given with sorafenib 400mg twice daily in patients with advanced HCC of Child-Pugh class A liver function who were naive to systemic therapy.

Methods: Everolimus was initiated at 2.5mg once daily and increased per a Bayesian sequential dose-escalation scheme based on the dose-limiting toxicities experienced within the first 28 days of treatment. Adverse events were assessed continuously. Efficacy was evaluated using the best overall response rate per RECIST.

Results: Thirty patients were enrolled; 25 were evaluable for MTD determination. One out of 12 patients treated with everolimus 2.5mg once daily and 6 out of 13 patients treated with everolimus 5.0mg once daily experienced a dose-limiting toxicity, most commonly thrombocytopenia (n=5). All patients experienced 1 adverse event, most commonly diarrhea (66.7%), hand-foot skin reaction (66.7%), and thrombocytopenia (50.0%). Best overall response was stable disease (62.5% and 42.9% in the 2.5-mg and 5.0-mg cohorts, respectively). Median time to progression and overall survival in the 2.5-mg cohort were 4.5 months and 7.4 months, respectively, and 1.8 months and 11.7 months, respectively, in the 5.0-mg cohort.

Conclusions: In patients with advanced HCC, the everolimus MTD in combination with standard-dose sorafenib was 2.5mg once daily. The inability to achieve a biologically effective everolimus concentration at the MTD precluded phase II study of this combination.

Keywords: AE; AST; BCLC; BID; Barcelona Clinic Liver Cancer; C(max); C(min); CI; DCR; DLT; Dose-finding; ECOG; Eastern Cooperative Oncology Group; Everolimus; HBV; HCC; Hepatocellular carcinoma; MTD; Mammalian target of rapamycin; OS; PDGFR; QD; RCC; RDI; RECIST; Response Evaluation Criteria in Solid Tumors; SD; SHAR; Sorafenib; Sorafenib HCC Assessment Randomized Protocol; TTP; ULN; VEGFR; adverse event; aspartate aminotransferase; confidence interval; disease control rate; dose-limiting toxicity; hepatitis B virus; hepatocellular carcinoma; mTOR; mammalian target of rapamycin; maximum blood concentration; maximum tolerated dose; minimum blood concentration; once daily; overall survival; platelet-derived growth factor receptor; relative dose intensity; renal cell carcinoma; standard deviation; time to progression; twice daily; upper limit of normal; vascular endothelial growth factor receptor.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy
  • Everolimus
  • Female
  • Humans
  • Liver Neoplasms / drug therapy*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Niacinamide / administration & dosage
  • Niacinamide / adverse effects
  • Niacinamide / analogs & derivatives*
  • Phenylurea Compounds / administration & dosage*
  • Phenylurea Compounds / adverse effects
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / analogs & derivatives*
  • Sorafenib

Substances

  • Phenylurea Compounds
  • Niacinamide
  • Everolimus
  • Sorafenib
  • Sirolimus