A phase I trial of the combination of temsirolimus (TEM) and sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).

Abstract

TPS213 Background: The multikinase inhibitor SOR prolongs survival in patients with advanced HCC. Another pathway often active in HCC is mammalian target of rapamycin (mTOR). Preclinical studies suggest that mTOR inhibition impairs HCC tumor growth and angiogenesis. In HCC xenografts, the addition of an mTOR inhibitor to SOR enhances antitumor effect. Phase I studies of an mTOR inhibitor combined with SOR show acceptable toxicity but do not include HCC patients with liver disease. We have developed a 2-site phase I dose escalation trial of the mTOR inhibitor TEM plus SOR in patients with advanced HCC to determine safety and the maximum tolerated dose (MTD) which will be the recommended phase II dose of the combination. Pharmacokinetics (PK) of TEM and its primary metabolite will be performed in 6 patients (pts) at MTD. A future single arm, 2-stage phase II study with exploratory endpoints is planned to measure efficacy. The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support. Methods: Main eligibility criteria: Unresectable HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection and local Tx permitted if ≥1 untreated radiographically measurable site of disease. ECOG performance status ≤2. Child-Pugh score ≤7 points and bilirubin ≤2 mg/dL. Adequate organ and marrow function. Treatment: Starting dose level (DL 1) is TEM 15 mg IVweekly plus SOR 200 mg PO BID in 28-day cycles. Design: 3+3 dose escalation until MTD with dose-limiting toxicity (DLT) window of 28 days. 6 additional pts will be enrolled at MTD as PK cohort. Sample size for phase I: 9-30 pts. Primary endpoints: Safety and MTD. Other endpoints: PK for TEM in 6 pts at MTD. Viral load measurement in pts with viral hepatitis. Exploratory dynamic-contrast enhanced CT imaging, Choi response criteria, biomarkers (AFP, AFP-L3, and DCP), and circulating tumor cell measurements will be performed in PK cohort pts and all pts in ensuing phase II trial. Accrual information: 3 pts have enrolled to DL 1. Updated enrollment information will be provided. Dose level TEM (mg IV weekly) SOR (mg PO) −2 10 200 QD −1 15 200 QD 1 (starting dose) 15 200 BID 2 15 400 BID 3 25 400 BID 4 25 200 BID Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer-Onyx National Comprehensive Cancer Network