Phase I dose escalation study of concurrent palliative radiation therapy with sorafenib in three anatomical cohorts (Thorax, Abdomen, Pelvis): The TAP study

Abstract Background and purpose To evaluate the tolerability and maximum tolerated dose (MTD) of sorafenib administered concurrently with palliative radiotherapy. Material and methods In patients with incurable cancer, sorafenib was escalated independently in three cohorts based on irradiation site: thorax, abdomen or pelvis. Sorafenib was administered days 1–28 and radiotherapy (30Gy in 10 fractions) was delivered days 8–12 and 15–19. Dose-limiting toxicities (DLT) were acute grade 3+ toxicities attributable to radiotherapy. Results For the thorax, abdomen and pelvis cohorts, 14, 16 and 4 patients were recruited, and Dose Levels 3, 3 and 2 were reached, respectively. Sorafenib-related systemic toxicity led to significant sorafenib interruption in 10 patients. There were 3 DLTs in total, one per cohort: grade 3 oesophagitis (thoracic), transaminase elevation (abdominal) and grade 5 bowel perforation (pelvic; patient with tumour invading bowel). Grade 2 radiation dermatitis developed in 12 patients. The trial was terminated early as slow accrual and sorafenib-related systemic toxicity prevented efficient evaluation of RT-related DLTs. Conclusions The MTD of sorafenib when used with 30Gy in 10 fractions was not established due to sorafenib-related systemic toxicity. Severe radiotherapy-related toxicities were also observed. These events suggest this concurrent combination does not warrant further study.