title: Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors.
abstract: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.
  
  
  
  Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.
  
  
  
  Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas).
  
  
  
  Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874-84. ©2016 AACR.
authors.affiliation: The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Saoirse O
authors.initials: SO
authors.lastname: Dolly
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: The Gastrointestinal Oncology and Mesothelioma Programs, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.affiliation: Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.affiliation: The Gastrointestinal Oncology and Mesothelioma Programs, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
authors.affiliation: Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Marjorie G
authors.initials: MG
authors.lastname: Zauderer
authors.affiliation: The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Department of Medical Oncology, Cancer Institute Rotterdam, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Doris
authors.initials: D
authors.lastname: Apt
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jill O
authors.initials: JO
authors.lastname: Fredrickson
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Lauchle
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. johann.de-bono@icr.ac.uk.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D058570:TOR Serine-Threonine Kinases