title: Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors.
abstract: OBJECTIVE
  Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors.
  
  
  METHODS
  Patients enrolled to intermittent dosing cohorts received navitoclax on day -3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring.
  
  
  RESULTS
  Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume.
  
  
  CONCLUSIONS
  Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA. Leena_Gandhi@dfci.harvard.edu
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Moacyr
authors.initials: M
authors.lastname: Ribeiro de Oliveira
authors.forename: Philip
authors.initials: P
authors.lastname: Bonomi
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.forename: Divis
authors.initials: D
authors.lastname: Khaira
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Litvinovich
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hemken
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Sari H
authors.initials: SH
authors.lastname: Enschede
authors.forename: Cathy
authors.initials: C
authors.lastname: Nolan
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.forename: Todd
authors.initials: T
authors.lastname: Busman
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Krivoshik
authors.forename: Rod
authors.initials: R
authors.lastname: Humerickhouse
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D018570:Risk Assessment; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D013449:Sulfonamides; C528561:navitoclax