Abstract
INTRODUCTION: Selective internal radiation therapy (SIRT) and sorafenib are used for patients with liver metastases from uveal melanoma. We conducted a phase I study to determine the optimal timing of administration of sorafenib in combination with radioembolisation. METHODS: Patients received radioembolisation plus sorafenib initiated 14, 11, or 3 days after or 7 days before radioembolisation. The primary endpoint was safety. Secondary endpoints included efficacy and evaluation of circulating angiogenic factors. Sorafenib plasma levels were quantified retrospectively. RESULTS: Ten patients received radioembolisation plus sorafenib. The most common grade 2-4 adverse events included rash, abdominal pain, fatigue and lymphocytopenia. Best response was partial response (30%) and stable disease (70%). Median progression-free and overall survival were 6.2 (4.8-not reached) and 11.7 months (9.4-not reached), respectively. Circulating angiogenic factors showed transient elevation at Day 10 post-SIRT when sorafenib was started 11-14 days after SIRT, but not when sorafenib was started before or just after SIRT. Most steady-state sorafenib plasma concentrations were in the upper percentiles relative to reference curves for single-agent sorafenib. CONCLUSIONS: SIRT plus sorafenib was feasible, but appeared more toxic than sorafenib alone, presumably due to altered pharmacokinetics. Sorafenib may hinder the angiogenic response when initiated before or shortly after SIRT. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, NCT01893099.