title: Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer.
abstract: We assessed the tolerability, safety, pharmacokinetics and dose-limiting toxicity (DLT) of the recombinant humanized IgG4 anti-vascular endothelial growth factor (VEGF) monoclonal antibody, HuMV833, in patients with advanced cancer. Cohorts of patients with progressive solid tumours received escalating doses of HuMV833 as a 1-h intravenous (I.V.) infusion on days 1, 15, 22, and 29. Twenty patients (median Eastern Cooperative Oncology Group (ECOG) score 1) were accrued. HuMV833 infusions were well tolerated and there were no grade III or IV toxicities definitely related to the antibody. Grade I or II toxicities probably related to the antibody included fatigue, dyspnoea and rash. There were two episodes of asymptomatic hypocalcaemia, one at grade III and one grade IV, which were recorded in early follow-up. There were eight grade I episodes of asymptomatic elevation of activated partial thromboplastin time (APTT) and two grade III events; one in a patient receiving 1 mg/kg and the other receiving extended doses of 10 mg/kg. Pharmacokinetic analysis revealed a non-linear kinetic and an elimination half-life of between 8.2 (0.3 mg/kg) and 18.7 (10 mg/kg) days. One patient with ovarian cancer experienced a partial response (PR) of 9 months duration and eight had disease stabilisation (SD) including one patient with colorectal carcinoma whose disease was stable for 14 months. In 13 of the 14 samples taken from 12 patients, the plasma concentration of hepatocyte growth factor (HGF) was reduced 24 h after drug administration. HuMV833 is safe and lacked DLT at doses up to 10 mg/kg on this schedule. Multiple doses were well tolerated, despite occasional asymptomatic elevations in APTT. By combining pharmacokinetic, pharmacodynamic and toxicity data, we can identify doses of 1 and 3mg/kg for further investigation. HuMV833 appears to possess some clinical activity.
authors.affiliation: Department of Medical Oncology, Cancer Research UK, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. gordon.jayson@christie-tr.nwest.nhs.uk
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.forename: Clive
authors.initials: C
authors.lastname: Mulatero
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Jamal
authors.initials: J
authors.lastname: Zweit
authors.forename: Alan
authors.initials: A
authors.lastname: Jackson
authors.forename: Lynn
authors.initials: L
authors.lastname: Broughton
authors.forename: John
authors.initials: J
authors.lastname: Wagstaff
authors.forename: Leif
authors.initials: L
authors.lastname: Hakansson
authors.forename: Gerard
authors.initials: G
authors.lastname: Groenewegen
authors.forename: Jeremy
authors.initials: J
authors.lastname: Lawrance
authors.forename: Meina
authors.initials: M
authors.lastname: Tang
authors.forename: Linda
authors.initials: L
authors.lastname: Wauk
authors.forename: Dan
authors.initials: D
authors.lastname: Levitt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marreaud
authors.forename: Frederic F
authors.initials: FF
authors.lastname: Lehmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Herold
authors.forename: Heinz
authors.initials: H
authors.lastname: Zwierzina
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C466953:MV833 monoclonal antibody, human; D011994:Recombinant Proteins