A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921)

Yael P. Mosse, Elizabeth Fox, David T. Teachey, Joel M. Reid, Stephanie L. Safgren, Hernan Carol, Richard B. Lock, Peter J. Houghton, Malcolm A. Smith, David Hall, Donald A. Barkauskas, Mark Krailo, Stephan D. Voss, Stacey L. Berg, Susan M. Blaney, Brenda J. Weigel

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centro-someandspindlematuration.Alisertib(MLN8237)isapotent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A128), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 mmol/L, exceeding the 1 mmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.

Original languageEnglish (US)
Pages (from-to)3229-3238
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number11
DOIs
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921)'. Together they form a unique fingerprint.

  • Cite this

    Mosse, Y. P., Fox, E., Teachey, D. T., Reid, J. M., Safgren, S. L., Carol, H., Lock, R. B., Houghton, P. J., Smith, M. A., Hall, D., Barkauskas, D. A., Krailo, M., Voss, S. D., Berg, S. L., Blaney, S. M., & Weigel, B. J. (2019). A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children's Oncology Group Phase I and pilot Consortium (ADVL0921). Clinical Cancer Research, 25(11), 3229-3238. https://doi.org/10.1158/1078-0432.CCR-18-2675