title: A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies.
abstract: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model.
  
  
  
  To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed.
  
  
  
  BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed.
  
  
  
  Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmaxand AUC0-24over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmaxand AUC0-24on day 28 and decreased clearance to 13.41 L/hr.
  
  
  
  The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug-drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Trisha M
authors.initials: TM
authors.lastname: Wise-Draper
authors.affiliation: Division of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Moorthy
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.|Division of Hematology-Oncology, Department of Medicine, West Virginia University Cancer Institute, Morgantown, WV, 26506, USA.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Salkeni
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Nagla Abdel
authors.initials: NA
authors.lastname: Karim
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Hala Elnakat
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mercer
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.|Division of Hematology-Oncology, University of Texas Southwestern, Dallas, TX, 75390, USA.
authors.forename: M Shalaan
authors.initials: MS
authors.lastname: Beg
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: O'Gara
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Olugbenga
authors.initials: O
authors.lastname: Olowokure
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Hassana
authors.initials: H
authors.lastname: Fathallah
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.|Institut Català d'Oncologia i Institut d'Investigació Biomèdica de Bellvitge, Laboratory of Cancer Metabolism, Hospital Duran i Reynals, 08908, Barcelona, Spain.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.|Institut Català d'Oncologia i Institut d'Investigació Biomèdica de Bellvitge, Laboratory of Cancer Metabolism, Hospital Duran i Reynals, 08908, Barcelona, Spain.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA.|Division of Hematology-Oncology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, 87106, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.affiliation: Division of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, OH, 45267, USA. pankaj.desai@uc.edu.|The James L. Winkle College of Pharmacy, University of Cincinnati, 3225 Eden Avenue, Cincinnati, OH, 45267-0004, USA. pankaj.desai@uc.edu.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Desai
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA. morri2j7@ucmail.uc.edu.|Division of Hematology-Oncology, University of Cincinnati, Vontz Center for Molecular Studies, 3125 Eden Avenue, ML 0562, Cincinnati, OH, 45267-0562, USA. morri2j7@ucmail.uc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D000068338:Everolimus / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015275:Tumor Lysis Syndrome / Q000209:etiology
chemical_list: D000068338:Everolimus; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib