Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma

Br J Cancer. 2012 Sep 25;107(7):1093-9. doi: 10.1038/bjc.2012.368. Epub 2012 Aug 30.

Abstract

Background: This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055.

Methods: Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID).

Results: Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median t(max) ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ≥ 4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ≥ 40 mg BID (n=8 at day 35).

Conclusion: The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Lymphoma / drug therapy*
  • Lymphoma / metabolism
  • Male
  • Maximum Tolerated Dose
  • 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 / drug therapy*
  • Neoplasms / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors

Substances

  • Morpholines
  • Multiprotein Complexes
  • (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