title: Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.
abstract: OBJECTIVE
  Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy.
  
  
  METHODS
  Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates.
  
  
  RESULTS
  The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit.
  
  
  CONCLUSIONS
  Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Cancer Research Building 2, Room 544, 1550 Orleans Street, Baltimore, MD 21231, USA. rudin@jhmi.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
authors.forename: Moacyr
authors.initials: M
authors.lastname: Ribeiro de Oliveira
authors.forename: Philip D
authors.initials: PD
authors.lastname: Bonomi
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Quincy
authors.initials: Q
authors.lastname: Chu
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Divis
authors.initials: D
authors.lastname: Khaira
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Ranson
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Chyla
authors.forename: Barry L
authors.initials: BL
authors.lastname: Dowell
authors.forename: Arunava
authors.initials: A
authors.lastname: Chakravartty
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Nolan
authors.forename: Niki
authors.initials: N
authors.lastname: Rudersdorf
authors.forename: Todd A
authors.initials: TA
authors.lastname: Busman
authors.forename: Mack H
authors.initials: MH
authors.lastname: Mabry
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Krivoshik
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
mesh_terms: D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012008:Recurrence; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax