title: First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies.
abstract: OBJECTIVE
  GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors.
  
  
  METHODS
  Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts.
  
  
  RESULTS
  One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant).
  
  
  CONCLUSIONS
  Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.
authors.affiliation: University of California, San Francisco, California. pmunster@medicine.ucsf.edu.
authors.forename: Pamela
authors.initials: P
authors.lastname: Munster
authors.affiliation: University of California, San Francisco, California.
authors.forename: Rahul
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Noll
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Specht
authors.affiliation: Cancer Center University Utrecht, the Netherlands.
authors.forename: Petronella O
authors.initials: PO
authors.lastname: Witteveen
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Werner
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.affiliation: University of California, San Francisco, California.
authors.forename: Emily
authors.initials: E
authors.lastname: Bergsland
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kleha
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Durante
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Laurel
authors.initials: L
authors.lastname: Adams
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lampkin
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Morris
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011724:Pyridazines; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D011724:Pyridazines; D011804:Quinolines; D013449:Sulfonamides; C561454:omipalisib; D000096926:Benzenesulfonamides