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Alisertib Shows Activity With Irinotecan/Temozolomide in Relapsed or Refractory Neuroblastoma

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Key Points

  • In a phase I dose-escalation trial of patients with relapsed or refractory neuroblastoma, the maximum tolerated dose of alisertib was 60 mg/m2, with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea.
  • The objective response rate was 32%, and the 2-year progression-free survival was 52%.

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.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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