Alisertib Combined with Chemotherapy Achieves Response in Neuroblastoma

Chemotherapy with irinotecan and temozolomide is used as a salvage therapy in patients with relapsed or refractory neuroblastoma. The combination has only modest response rates, but is well tolerated, providing the possibility of combining it with new therapies. In preclinical studies, the Aurora A kinase inhibitor alisertib was cytotoxic to neuroblastoma cells, and early clinical studies of alisertib in adult patients have shown it may be combined with chemotherapy. In a phase I dose escalation study, DuBois and colleagues determined the maximum tolerated dose of alisertib with fixed doses of irinotecan and temozolomide in 22 patients with relapsed or refractory neuroblastoma. After the first course of treatment, two patients developed dose-limiting toxicities including neutropenia, and two patients had grade 3 diarrhea, prompting amendment of the protocol to add myeloid growth factor support and cephalosporin diarrhea prophylaxis. The maximum tolerated dose for alisertib was determined to be 60mg/m². The majority of patients exhibited hematologic toxicities, including thromboycytopenia (84%) and neutropenia (69%). Diarrhea and nausea were the most common nonhematologic toxicities. Pharmacokinetic profiles indicated that there were no interactions between alisertib and irinotecan. Across all dose levels, the overall response rate was 31.8%, including a complete response rate of 22.7%, and the progression-free survival rate at two years was 52.4%. None of the five patients who had previously received irinotecan responded, whereas among the irinotecan-naïve patients the response rate was 41.2%. In addition, the response rate was poorer in patients with MYCN-amplified tumors (16.7%) compared to patients with MYCN-nonamplified tumors (35.7%). Overall, the results of this phase I trial demonstrate that alisertib can be combined with irinotecan and temozolomide, and this combination has a promising response rate and progression-free survival rate in patients with relapsed and refractory neuroblastoma. These findings support further investigation of alisertib with irinotecan and temozolomide in larger clinical trials.

DuBois SG, Marachelian A, Fox E, Kudgus RA, Reid JM, Groshen S, et al. 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. J Clin Oncol 2016 Feb 16 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.