Axitinib in Combination with Radiotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial

Abstract

Background: Axitinib is a selective vascular endothelial growth factor receptors 1–3 inhibitor approved for second-line treatment of advanced renal cell carcinoma. In a randomized, placebo-controlled phase II trial for patients with locally advanced or metastatic hepatocellular carcinoma (HCC), axitinib improved progression-free survival and showed overall response rate of 9.7%. This phase I study aimed at evaluating maximum tolerated dose (MTD) of axitinib in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC).

Methods: This phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT.

Results: Total nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months.

Conclusions: Axitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort.

Trial registration: ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461