Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors

Clin Cancer Res. 2020 Sep 1;26(17):4633-4642. doi: 10.1158/1078-0432.CCR-19-3498. Epub 2020 May 15.


Purpose: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.

Experimental design: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).

Results: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.

Conclusions: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / metabolism
  • Azepines / administration & dosage*
  • Azepines / adverse effects
  • Benzoxazoles / administration & dosage*
  • Benzoxazoles / adverse effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Xenograft Model Antitumor Assays


  • Azepines
  • Benzoxazoles
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • AURKA protein, human
  • Aurora Kinase A
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • sapanisertib