title: First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).
  
  
  METHODS
  Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.
  
  
  RESULTS
  Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·μmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.
  
  
  CONCLUSIONS
  Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ≥100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Debashis
authors.initials: D
authors.lastname: Sarker
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Joo Ern
authors.initials: JE
authors.lastname: Ang
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Baird
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Krunal
authors.initials: K
authors.lastname: Shah
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Gallia
authors.initials: G
authors.lastname: Levy
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mazina
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Ray
authors.initials: R
authors.lastname: Lin
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wu
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Fredrickson
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Genentech Inc., South San Francisco, California, United States of America.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Derynck
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: The Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey, United Kingdom.|The Institute of Cancer Research, London, United Kingdom.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood
chemical_list: D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C482119:BRAF protein, human