title: Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. anaing@mdanderson.org
authors.forename: A
authors.initials: A
authors.lastname: Naing
authors.forename: C
authors.initials: C
authors.lastname: Aghajanian
authors.forename: E
authors.initials: E
authors.lastname: Raymond
authors.forename: D
authors.initials: D
authors.lastname: Olmos
authors.forename: G
authors.initials: G
authors.lastname: Schwartz
authors.forename: E
authors.initials: E
authors.lastname: Oelmann
authors.forename: L
authors.initials: L
authors.lastname: Grinsted
authors.forename: W
authors.initials: W
authors.lastname: Burke
authors.forename: R
authors.initials: R
authors.lastname: Taylor
authors.forename: S
authors.initials: S
authors.lastname: Kaye
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
authors.forename: U
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D009025:Morpholines; D046912:Multiprotein Complexes; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases