title: Phase I and pharmacokinetic study of CT-322 (BMS-844203), a targeted Adnectin inhibitor of VEGFR-2 based on a domain of human fibronectin.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.
  
  
  RESULTS
  Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.
  
  
  CONCLUSIONS
  CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas 78229, USA. atolcher@start.stoh.com
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.forename: Kyri
authors.initials: K
authors.lastname: Papadopoulos
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Elena G
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Kamalesh
authors.initials: K
authors.lastname: Sankhala
authors.forename: Eric
authors.initials: E
authors.lastname: Furfine
authors.forename: Jochem
authors.initials: J
authors.lastname: Gokemeijer
authors.forename: Lisa
authors.initials: L
authors.lastname: Iacono
authors.forename: Cheryl
authors.initials: C
authors.lastname: Eaton
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Silver
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
mesh_terms: D000328:Adult; D000368:Aged; D000917:Antibody Formation; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005353:Fibronectins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D010446:Peptide Fragments / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C549678:CT-322; D005353:Fibronectins; D010446:Peptide Fragments; D040301:Vascular Endothelial Growth Factor Receptor-2