title: A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.
abstract: OBJECTIVE
  To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors.
  
  
  METHODS
  Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax.
  
  
  RESULTS
  Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39).
  
  
  CONCLUSIONS
  The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.forename: Caio Max S Rocha
authors.initials: CM
authors.lastname: Lima
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Montero
authors.forename: Catherine
authors.initials: C
authors.lastname: Franklin
authors.forename: Jianning
authors.initials: J
authors.lastname: Yang
authors.forename: Alison
authors.initials: A
authors.lastname: Graham
authors.forename: Todd
authors.initials: T
authors.lastname: Busman
authors.forename: Mack
authors.initials: M
authors.lastname: Mabry
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Hope
authors.initials: H
authors.lastname: Uronis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000814:Aniline Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D003841:Deoxycytidine; C528561:navitoclax; D000093542:Gemcitabine