title: Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors.
  
  
  METHODS
  Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations.
  
  
  RESULTS
  The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity.
  
  
  CONCLUSIONS
  SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease.
authors.affiliation: Authors' Affiliations: South Texas Accelerated Research Therapeutics, San Antonio, Texas; Memorial Sloan-Kettering Cancer Center, Memorial Hospital, New York, New York; Sanofi, Cambridge, Massachusetts; Exelixis Inc., South San Francisco, California; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain; Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia; and Sanofi, Vitry-sur-Seine, France.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Ben
authors.initials: B
authors.lastname: Markman
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Weiliang
authors.initials: W
authors.lastname: Shi
authors.forename: Coumaran
authors.initials: C
authors.lastname: Egile
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Ruiz-Soto
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: Dale
authors.initials: D
authors.lastname: Miles
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D058570:TOR Serine-Threonine Kinases