Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study

Invest New Drugs. 2013 Jun;31(3):677-84. doi: 10.1007/s10637-012-9860-4. Epub 2012 Jul 28.


Background: This is the first phase I, dose-finding study of AZD8055, a first-in-class dual mTORC1/2 inhibitor, in Japanese patients with advanced solid tumors.

Patients and methods: Patients received a single oral dose of AZD8055, followed by twice-daily (BID) dosing. The starting dose was 10 mg with dose escalations in subsequent cohorts to a maximum of 90 mg BID or a non-tolerated dose.

Results: Seventeen patients were dosed: 10 mg (n=3), 40 mg (n=4), 60 mg (n=3), 90 mg (n=7). In the 90 mg cohort, one dose limiting toxicity (n=1) of increased aspartate aminotransferase and increased alanine aminotransferase was observed in the 90 mg BID cohort (n=1). Four patients, all in the 90 mg BID cohort, experienced a serious adverse event considered to be related to AZD8055: increased alanine aminotransferase (n=3), increased aspartate aminotransferase (n=3), increased gamma-glutamyltransferase (n=2). The 90 mg BID dose was considered as tolerated in Japanese patients but higher doses were not investigated as this dose was also the maximum tolerated dose in Western patients. AZD8055 was rapidly absorbed with greater-than-proportional increases in exposure with increasing dose. No responses were reported, but two patients had stable disease. Mean pAKT and p4EBP1 levels decreased in most cohorts. Conclusion The tolerability and pharmacokinetic profiles of AZD8055 in Japanese patients were similar to those reported in Western patients.

Trial registration: NCT00973076.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Female
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Middle Aged
  • Morpholines / administration & dosage*
  • Morpholines / adverse effects
  • Morpholines / pharmacokinetics
  • Multiprotein Complexes / antagonists & inhibitors
  • Neoplasms / blood
  • Neoplasms / diagnostic imaging
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Radiography
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Treatment Outcome


  • Antineoplastic Agents
  • Morpholines
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2

Associated data