title: Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies.
abstract: OBJECTIVE
  To determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies.
  
  
  METHODS
  Patients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously.
  
  
  RESULTS
  Thirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004).
  
  
  CONCLUSIONS
  ABT-869 by continuous once-daily dosing was tolerable at doses </= 0.25 mg/kg/d. Biomarker evidence of antiangiogenic activity and DCE-MRI evidence of tumor antiangiogenesis were observed together with promising clinical activity.
authors.affiliation: Department of Hematology-Oncology, National University Hospital, National University of Singapore, Singapore 119074.
authors.forename: Chiung-Ing
authors.initials: CI
authors.lastname: Wong
authors.forename: Tong-San
authors.initials: TS
authors.lastname: Koh
authors.forename: Ross
authors.initials: R
authors.lastname: Soo
authors.forename: Septian
authors.initials: S
authors.lastname: Hartono
authors.forename: Choon-Hua
authors.initials: CH
authors.lastname: Thng
authors.forename: Evelyn
authors.initials: E
authors.lastname: McKeegan
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Lim
authors.forename: Norita
authors.initials: N
authors.lastname: Sukri
authors.forename: Siew-Eng
authors.initials: SE
authors.lastname: Lim
authors.forename: Ai-Bee
authors.initials: AB
authors.lastname: Ong
authors.forename: Joyce
authors.initials: J
authors.lastname: Steinberg
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Rod
authors.initials: R
authors.lastname: Humerickhouse
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007191:Indazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D007191:Indazoles; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases