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

Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.

Patients And Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m/dose × 7 days), irinotecan (50 mg/m/dose i.v. × 5 days), and temozolomide (100 mg/m/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m using 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). Alisertib oral solution at 45 mg/m had significantly higher median and exposure compared with tablets at 60 mg/m. Higher alisertib trough concentration was associated with first cycle DLT, whereas amplification was associated with inferior PFS.

Conclusions: This combination shows antitumor activity, particularly in patients with nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.