A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies

Br J Cancer. 2016 Apr 12;114(8):889-96. doi: 10.1038/bjc.2016.59. Epub 2016 Mar 22.


Background: The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted.

Methods: Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics.

Results: One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients.

Conclusions: OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use*
  • Leukocytes, Mononuclear / drug effects
  • Male
  • Maximum Tolerated Dose
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Middle Aged
  • Multiprotein Complexes / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Triazines / pharmacokinetics
  • Triazines / therapeutic use*
  • Young Adult


  • Imidazoles
  • Multiprotein Complexes
  • OSI 027
  • Protein Kinase Inhibitors
  • Triazines
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2