title: Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors.
abstract: BACKGROUND
  This phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib (SAR245408), an oral pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in combination with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor.
  
  
  METHODS
  In a 3 + 3 dose-escalation study, patients with advanced solid tumors received pilaralisib capsules once daily (21 days per 28-day cycle; 50-600 mg) plus erlotinib tablets once daily (28 days per 28-day cycle; 100 or 150 mg). An MTD expansion cohort of patients with non-small cell lung cancer who had previously received treatment with an EGFR inhibitor was included.
  
  
  RESULTS
  Thirty-five patients were enrolled. Only one patient had an EGFR activating mutation. One dose-limiting toxicity was reported (grade 4 drug reaction or rash with eosinophilia and systemic symptoms). MTD was pilaralisib 400 mg plus erlotinib 150 mg. The most commonly reported treatment-related adverse events were rash (62.9%), diarrhea (42.9%), and fatigue (40.0%). Pilaralisib PK findings were consistent with previous studies, suggesting erlotinib had no effect on pilaralisib pharmacokinetics. Pharmacodynamic analyses indicated moderate inhibition of PI3K, mitogen-activated protein kinase, and EGFR pathways. Of 27 evaluable patients, one had a partial response (3.7%) and 14 (51.9%) had stable disease. There was no association between molecular alterations of PI3K pathway components and clinical activity.
  
  
  CONCLUSIONS
  Pilaralisib plus erlotinib had limited antitumor activity. Safety findings were similar to recent studies of single-agent pilaralisib or other PI3K inhibitors.
authors: Gustave Roussy, Drug Development Department (DITEP), Villejuif, France; jean-charles.soria@igr.fr.
authors: Jean-Charles
authors: JC
authors: Soria
authors: Yale Smilow Cancer Center, New Haven, Connecticut, USA;
authors: Patricia
authors: P
authors: LoRusso
authors: Gustave Roussy, Drug Development Department (DITEP), Villejuif, France;
authors: Ratislav
authors: R
authors: Bahleda
authors: Sanofi, Cambridge, Massachusetts, USA;
authors: Joanne
authors: J
authors: Lager
authors: Sanofi, Bridgewater, New Jersey, USA;
authors: Li
authors: L
authors: Liu
authors: Sanofi, Bridgewater, New Jersey, USA;
authors: Jason
authors: J
authors: Jiang
authors: Exelixis Inc., South San Francisco, California, USA;
authors: Jean-François
authors: JF
authors: Martini
authors: Sanofi, Vitry sur Seine, France;
authors: Sandrine
authors: S
authors: Macé
authors: Sarah Cannon Research Institute, Nashville, Tennessee, USA.
authors: Howard
authors: H
authors: Burris
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D011810:Quinoxalines; D013449:Sulfonamides; C581157:XL147; D000069347:Erlotinib Hydrochloride