title: First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014.
abstract: OBJECTIVE
  AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models.
  
  
  METHODS
  A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry.
  
  
  RESULTS
  A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively.
  
  
  CONCLUSIONS
  The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses.
authors: The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Bristi
authors: B
authors: Basu
authors: University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors: Emma
authors: E
authors: Dean
authors: The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Martina
authors: M
authors: Puglisi
authors: University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors: Alastair
authors: A
authors: Greystoke
authors: The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Michael
authors: M
authors: Ong
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Wendy
authors: W
authors: Burke
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Maria
authors: M
authors: Cavallin
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Graham
authors: G
authors: Bigley
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Christopher
authors: C
authors: Womack
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Elizabeth A
authors: EA
authors: Harrington
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Stephen
authors: S
authors: Green
authors: AstraZeneca, Macclesfield, United Kingdom.
authors: Elisabeth
authors: E
authors: Oelmann
authors: The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Johann S
authors: JS
authors: de Bono
authors: University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors: Malcolm
authors: M
authors: Ranson
authors: The Institute of Cancer Research and The Royal Marsden, London, United Kingdom. udai.banerji@icr.ac.uk.
authors: Udai
authors: U
authors: Banerji
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; 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* / Q000473:pathology; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D009025:Morpholines; D046912:Multiprotein Complexes; D011743:Pyrimidines; C585537:vistusertib; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases