title: Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors.
abstract: OBJECTIVE
  Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors.
  
  
  METHODS
  An open-label dose escalation study included an arm evaluating navitoclax combined with erlotinib, which included a dose escalation cohort and a planned safety expansion cohort. Patients with documented cancers for whom erlotinib therapy was appropriate received erlotinib 150 mg orally once daily plus navitoclax 150 mg orally once daily, with navitoclax dose escalation via a continuous reassessment method model.
  
  
  RESULTS
  Eleven patients were enrolled, including six patients with nonsmall cell lung cancer. Dose-limiting toxicities, most commonly diarrhea, were observed in 4 patients. Navitoclax dosing remained at 150 mg/day because the maximum tolerated dose was exceeded at this starting dose. The planned dose escalation did not occur; no recommended phase II dose (RPTD) was identified, and there was no safety expansion cohort. The most common treatment-related adverse events were diarrhea, nausea, vomiting, and decreased appetite. Pharmacokinetic analysis showed no apparent interactions between co-administered navitoclax and erlotinib. No objective responses were observed; the disease control rate was 27 % (95 % CI, 6-61 %).
  
  
  CONCLUSIONS
  At the erlotinib and navitoclax doses administered, RPTD was not reached, but the safety profile of the combination was consistent with data from monotherapy studies. There were no apparent pharmacokinetic interactions between erlotinib and navitoclax. Three patients had stable disease.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Arzt
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Busman
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Guinan
authors.initials: G
authors.lastname: Lian
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Niki S
authors.initials: NS
authors.lastname: Rudersdorf
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Vanderwal
authors.affiliation: AbbVie Biotherapeutics Inc., Redwood City, CA, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Kirschbrown
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.affiliation: Division of Hematology-Oncology, University of California Los Angeles, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA. lrosen@mednet.ucla.edu.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000556:secondary; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000814:Aniline Compounds; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C528561:navitoclax
keywords: Antineoplastic combined chemotherapy protocols; Bcl-2 inhibitor of transcription 1 protein; Erlotinib; Human; Navitoclax; Phase I clinical trials