title: A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.
abstract: 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.
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Mateo
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.|Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven B-3000, Belgium.
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL 60201, USA.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL 60201, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Samberg
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL 60201, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Barr
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL 60201, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Van Tornout
authors.affiliation: Astellas Pharma Global Development, Northbrook, IL 60201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Jie
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
authors.forename: Shahneen
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Yale University, New Haven, CT 06520, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Drug Development Unit; The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London SM2 5PT, UK.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven B-3000, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D007093:Imidazoles; D046912:Multiprotein Complexes; C568605:OSI 027; D047428:Protein Kinase Inhibitors; D014227:Triazines; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases