Κυριακή, 20 Μαρτίου 2016

AURORA A KINASE INHIBITORS FOR NEUROBLASTOMA TREATMENT

The oral Aurora A kinase inhibitor alisertib was active in combination with irinotecan/temozolomide in patients with relapsed or refractory neuroblastoma, in a phase I dose-escalation trial reported in the Journal of Clinical Oncology by DuBois et al. The maximum tolerated dose of alisertib was 60 mg/m2.
Study Details
The study included 22 evaluable patients with relapsed or refractory neuroblastoma aged 4 to 23 years (median = 7 years) who received alisertib at 45, 60, or 80 mg/m2/d on days 1 to 7 with irinotecan at 50 mg/m2 and temozolomide at 100 mg/m2 on days 1 to 5 every 21 days.
Toxicity
Patients received a total of 244 courses (median = 8, range = 2–32). The alisertib maximum tolerated dose was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea.
Thrombocytopenia and neutropenia of any grade occurred in 84% and 69% of courses, respectively; grade 4 thrombocytopenia (3%–35%) and neutropenia (9%–35%) were dose-related. Diarrhea and nausea were the most common nonhematologic toxicities, occurring in 55% and 54% of courses, respectively; diarrhea occurred in 76% of courses (7% grade 3) before and 48% of courses (2% grade 3) after institution of mandatory diarrhea prophylaxis.  No evidence of a drug-drug interaction between irinotecan and alisertib was found in pharmacokinetics evaluation.
Response Rate
The overall objective response rate was 31.8%, with a complete response rate of 22.7%. Response occurred in three (two complete responses) of six patients at the maximum tolerated dose. All responses occurred in irinotecan-naive patients (6 of 17 = 41.2%). Progression-free survival at 2 years was 52.4%. The investigators noted that these findings compare well with data from patients receiving irinotecan/temozolomide alone.
The investigators concluded: “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.”
The study was supported by the National Cancer Institute and Millennium Pharmaceuticals.


Steven G. DuBois, MD, of Dana-Farber Cancer Institute, Boston, is the corresponding author of the Journal of Clinical Oncology article.

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