Final results: A phase I study of sorafenib and palliative radiation in patients with malignancy in the thorax, abdomen, or pelvis.

Abstract

e13602 Background: The combination of VEGF-directed therapy with radiotherapy (RT) has shown preclinical promise but data of potential toxicities are limited. We initiated a phase I study combining sorafenib (S) with palliative radiotherapy in patients with primary or metastatic malignancy in the thorax, abdomen or pelvis. Methods: Cohorts of 3-6 patients with measureable tumor lesions in the chest, abdomen or pelvis were treated with S (dose levels: 1 - 200 od; 2 - 200 mg bid; 3 - 400 mg bid) for 4 weeks and RT (30 Gy in 10 daily fractions) in weeks 2 and 3. Each anatomic cohort escalated S dose independently. Primary endpoint: maximum tolerated dose of S (MTD) - the dose level below that resulting in ≥ 2/6 patients with dose limiting, acute, in-field toxicities (≥Gr 3 and attributable to RT). Results: From May 2007 to Nov 2010, 34 patients were entered on study (thorax/abdomen/pelvis - 14/16/4). The thoracic, abdominal and pelvic cohorts reached dose levels 3, 3 and 1, respectively. Significant S dose modifications occurred in 6/10 patients on dose level 3 due to S systemic toxicities. DLTs were noted in each cohort: thorax dose level 2 – Gr 3 esophagitis; abdomen dose level 3: Gr 3 ALT elevation; pelvis dose level 1 – Gr 5 perforation of tumor-involved bowel. No other high grade, RT-related toxicities were observed. Grade 2 acute RT skin toxicity was observed in 7/8 patients who completed both 4 weeks of S on dose level 2 or 3, and had RT plans using only 2 or 3 beams implying a minimum drug/RT dose threshold for this phenomenon. Conclusions: MTD was not defined for any anatomic cohort. The trial was terminated as systemic toxicity of sorafenib resulted in dose reductions and discontinuations at 400 mg bid precluding efficient evaluation of RT-related toxicity combined with this dose of sorafenib. Gr 2 RT dermatitis was consistently seen in patients receiving 4 weeks of uninterrupted sorafenib 200 or 400 mg bid. The severity and prevalence of Gr 2 dermatitis was greater than expected for 30 Gy in 10 fraction RT. One patient developed Gr 3 esophagitis following esophageal RT. It is likely that sorafenib in conjunction with higher dose RT may require drug dose or schedule modification to mitigate acute cutaneous or mucosal reactions.