Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma

Purpose: In phase I testing, alisertibtablets with irinotecanand temozolomideshowed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertiboral solution; and evaluate biomarkers of clinical outcomes. Experimental Design: We conducted a two-stage phase II trial of alisertibtablets (60 mg/ m 2/dose × 7 days), irinotecan(50 mg/ m 2/dose i.v. × 5 days), and temozolomide(100 mg/ m 2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertibat 45 mg/ m 2using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertiboral solution at 45 mg/ m 2had significantly higher median C max and exposure compared with tablets at 60 mg/ m 2. Higher alisertibtrough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertiboral solution expand the population able to be treated with this agent. Clin Cancer Res; 24(24); 1–8. ©2018 AACR.