A Phase 1 Study of Nilotinib Plus Radiation in High-Risk Chordoma

Abstract

Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative radiation therapy (RT), progression-free survival and overall survival (OS) remain poor in patients with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib withRT as either preoperative or definitive treatment for patients with high-risk chordoma. We recruited 23 patients with high-risk, nonmetastatic chordoma. High risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable or marginally resectable disease based on locally advanced stage, or declining surgery because of excessive morbidity. Patients were treated with nilotinib and concurrent RT to 50.4Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2Gy RBE or definitively up to 77.4Gy RBE without surgery. On completion of RT, patients were eligible to continue nilotinib until disease progression. In patients receiving nilotinib 200mg twice daily with RT, 3 dose-limiting toxicities (DLT) occurred in 5 patients. One DLT was seen among 6 patients receiving nilotinib 200mg daily with RT. Therefore, 200mg daily was declared the maximum tolerated dose. Eleven additional patients received nilotinib with RT at the maximum tolerated dose, and 1 additional DLT occurred. The objective best response rate was 6% (1 of 18 patients, 95% confidence interval [CI], 0.1%-27%). The median progression-free survival was 58.15months (95% CI, 39.10-∞). The median OS was 61.5months (43.1-∞), and the 2-year OS rate was 95%. Nilotinib 200mg/d with RT is safe and tolerated in patients with high-risk chordoma. Long-term follow-up is needed to understand whether nilotinib combined with RT, with or without surgery, adds greater improvement to progression-free survival or OS than with RT with or without surgery alone in patients with high-risk chordoma.