title: Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer.
abstract: OBJECTIVE
  ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed.
  
  
  RESULTS
  The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS.
  
  
  CONCLUSIONS
  Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, David H. Koch Cancer Research Building 2, 1550 Orleans St, Rm 544, Baltimore, MD 21231, USA. rudin@jhmi.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Ann
authors.initials: A
authors.lastname: Mauer
authors.forename: Martin
authors.initials: M
authors.lastname: Smakal
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Juergens
authors.forename: Stanislav
authors.initials: S
authors.lastname: Spelda
authors.forename: Michael
authors.initials: M
authors.lastname: Wertheim
authors.forename: Andrew
authors.initials: A
authors.lastname: Coates
authors.forename: Evelyn
authors.initials: E
authors.lastname: McKeegan
authors.forename: Peter
authors.initials: P
authors.lastname: Ansell
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhou
authors.forename: Jane
authors.initials: J
authors.lastname: Qian
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Barry
authors.initials: B
authors.lastname: Dowell
authors.forename: Andrew
authors.initials: A
authors.lastname: Krivoshik
authors.forename: Gary
authors.initials: G
authors.lastname: Gordon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D018153:Czech Republic; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: C490492:ABT751; D014408:Biomarkers, Tumor; D005971:Glutamates; D013449:Sulfonamides; D000068437:Pemetrexed; D006147:Guanine