Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial

Abstract

Purpose Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. Patients and Methods Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m2 per day on days 1 to 7 along with irinotecan 50 mg/m2 intravenously and temozolomide 100 mg/m2 orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. Results Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. Conclusion Alisertib 60 mg/m2 per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

“…Here we have characterized the complex with Aurora-A in which N-Myc is trapped in an ordered conformation. The interaction can be disrupted by targeting the ATP-binding site of Aurora-A to induce a conformation that is incompatible with the binding of N-Myc, and early clinical trial data suggest these compounds may provide patient benefit when combined with chemotherapy (20,22,28). However, this approach also would target the main function of Aurora-A in the proper assembly and the function of the mitotic spindle, and it is too early to know whether the potential benefit of this in targeting dividing cancer cells offsets the accompanying damage to normal tissue.…”

Overview and recent advances in the treatment of neuroblastoma

“…Smallmolecule inhibitors of this kinase block proliferation and soft agar colony formation of neuroblastoma tumor cells and increase sensitivity to chemotherapy [126]. Subsequent phase I trials in children with relapsed tumors demonstrated some evidence of efficacy of the Aurora A kinase inhibitor MLN8237 (alisertib) both alone and in combination with irinotecan and temozolomide in children with relapsed neuroblastoma [128,129], suggesting a potential role for Aurora A kinase inhibitors in future neuroblastoma therapy.…”

Malignant rhabdoid tumors of soft tissues in children. Literature review

“…Выявлено, что использова-ние ингибитора Aurora A тирозинкиназы повышает радиочувствительность ЗРО, что может являться пер-спективным в использовании данного ингибитора в составе комбинированной или комплексной те-рапии [119]. Препараты данной группы находятся в I-II фазах клинических испытаний у взрослых и детей с различными нозологическими формами заболева-ний, включая ЗРО [120][121][122].…”