title: Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.
abstract: OBJECTIVE
  A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors.
  
  
  METHODS
  In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months.
  
  
  RESULTS
  Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days.
  
  
  CONCLUSIONS
  CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.
authors.affiliation: Cancer Research, UK. Gordon.Jayson@christie-tr.nwest.nhs.uk
authors.forename: Saifee A
authors.initials: SA
authors.lastname: Mullamitha
authors.forename: Nhuan C
authors.initials: NC
authors.lastname: Ton
authors.forename: Geoff J M
authors.initials: GJ
authors.lastname: Parker
authors.forename: Alan
authors.initials: A
authors.lastname: Jackson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Julyan
authors.forename: Caleb
authors.initials: C
authors.lastname: Roberts
authors.forename: Gio A
authors.initials: GA
authors.lastname: Buonaccorsi
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Watson
authors.forename: Karen
authors.initials: K
authors.lastname: Davies
authors.forename: Sue
authors.initials: S
authors.lastname: Cheung
authors.forename: Lynn
authors.initials: L
authors.lastname: Hope
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.forename: John A
authors.initials: JA
authors.lastname: Radford
authors.forename: Jeremy
authors.initials: J
authors.lastname: Lawrance
authors.forename: Mark P
authors.initials: MP
authors.lastname: Saunders
authors.forename: Mihaela C
authors.initials: MC
authors.lastname: Munteanu
authors.forename: Marian T
authors.initials: MT
authors.lastname: Nakada
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nemeth
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiao
authors.forename: Uma
authors.initials: U
authors.lastname: Prabhakar
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Lang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Corringham
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000276:immunology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D039564:Integrin alphaV