Randomized phase II trial of TACE plus everolimus as first-line therapy in localized unresectable hepatocellular carcinoma (HCC): The TRACER trial.

Abstract

TPS4149 Background: Transcatheter Arterial Chemoembolization (TACE) has shown benefit in improving survival and is a widely used treatment for unresectable HCC. However, TACE induces hypoxia leading to up-regulation of HIF-1α and VEGF signaling, and tumor progression. Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR) and its downstream signaling including HIF-1α. Everolimus has also been shown to increase chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9). Combining everolimus with TACE may delay tumor progression. TRACER (Tace with Rad001 in Asian Centers for Evaluation and Research) aims to evaluate the efficacy and safety of everolimus plus TACE in patients with localised unresectable HCC. Methods: TRACER is a multinational, randomized, double-blind, placebo-controlled phase II trial. Patients aged ≥18 years newly diagnosed with localized unresectable Child A HCC; ECOG PS of <2; ≥1 unidimensional lesion measurable according to RECIST; and adequate bone marrow, liver, and renal function. Exclusion criteria include main portal vein invasion and/or extrahepatic spread; prior local or systemic treatment for HCC, or contraindications to TACE. Eligible patients who have successfully undergone the first TACE are randomized 1:1 to oral everolimus 7.5mg or matching placebo daily. TACE is repeated every 10 weeks or so. A short everolimus dose interruption of 48 hours before and after each TACE has been designed to allow recovery from complications of TACE. For standardization, doxorubicin-eluting beads are being used in every TACE. Patients shall exit the trial upon tumor progression, unacceptable toxicity, death, or trial discontinuation. All endpoints will be assessed on an ITT basis. The primary endpoint is time to progression base on Modified RECIST Criteria. Secondary endpoints include objective response rate, overall survival, and incidence of extrahepatic spread, safety and exploratory biomarkers. An independent data monitoring committee has been established to safeguard the trial subjects. Estimated total enrollment is 80, of which 12 subjects have been enrolled. (Clinical Trial Registry Number: NCT01379521.)