Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma

Ann Oncol. 2016 Oct;27(10):1855-60. doi: 10.1093/annonc/mdw281. Epub 2016 Aug 8.


Background: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.

Patients and methods: This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.

Results: Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).

Conclusions: Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.

Trial registration id: NCT01653028.

Keywords: aurora kinase inhibitors; bone sarcoma; phase II clinical trials; soft tissue sarcoma.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / genetics
  • Azepines / administration & dosage*
  • Azepines / adverse effects
  • Disease-Free Survival
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Female
  • Humans
  • Leiomyosarcoma / drug therapy*
  • Leiomyosarcoma / genetics
  • Leiomyosarcoma / pathology
  • Liposarcoma / drug therapy*
  • Liposarcoma / genetics
  • Liposarcoma / pathology
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors / administration & dosage
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects


  • Azepines
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Aurora Kinase A

Associated data