Phase 2 Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma

Purpose: In phase 1 testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. The current study sought to: confirm activity of this regimen; evaluate an alisertib oral solution (OS); and evaluate biomarkers of clinical outcomes. Methods: We conducted a two-stage phase 2 trial of alisertib tablets (60 mg/m2/dose x 7 days), irinotecan (50 mg/m2/dose IV x 5 days), and temozolomide (100 mg/m2/dose orally x 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/m2 using OS instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase 1, phase 2, and OS cohorts. Results: Twenty and 12 eligible patients were treated in the phase 2 and OS cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase 2, 4 partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the OS cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib OS at 45 mg/m2 had significantly higher median Cmax and exposure compared to tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, while MYCN amplification was associated with inferior PFS. Conclusion:This combination shows antitumor activity, particularly in patients with MYCN non-amplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

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