TY - JOUR

T1 - A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours

AU - Lassen, U

AU - Nielsen, D L

AU - Sørensen, M

AU - Winstedt, L

AU - Niskanen, T

AU - Stenberg, Y

AU - Pakola, S

AU - Stassen, J-M

AU - Glazer, S

PY - 2012/2/14

Y1 - 2012/2/14

N2 - BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid tumours.METHODS: Patients in sequential dose groups received either weekly doses of 1.25, 5.0, or 10 mg kg(-1) or doses of 20 or 30 mg kg(-1) every third week.RESULTS: Twenty-three patients were enrolled and received TB-403. The most common adverse events (AEs) were fatigue, constipation, pyrexia, dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg(-1) weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg(-1) weekly, remained stable for 12 months.CONCLUSION: TB-403 treatment in this patient population is well tolerated, with a safety profile distinct from that of vascular endothelial growth factor-axis inhibitors.

AB - BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid tumours.METHODS: Patients in sequential dose groups received either weekly doses of 1.25, 5.0, or 10 mg kg(-1) or doses of 20 or 30 mg kg(-1) every third week.RESULTS: Twenty-three patients were enrolled and received TB-403. The most common adverse events (AEs) were fatigue, constipation, pyrexia, dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg(-1) weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg(-1) weekly, remained stable for 12 months.CONCLUSION: TB-403 treatment in this patient population is well tolerated, with a safety profile distinct from that of vascular endothelial growth factor-axis inhibitors.

KW - Adult

KW - Aged

KW - Angiogenesis Inhibitors

KW - Antibodies, Monoclonal

KW - Antibodies, Monoclonal, Humanized

KW - Drug Administration Schedule

KW - Female

KW - Humans

KW - Infusions, Intravenous

KW - Male

KW - Maximum Tolerated Dose

KW - Middle Aged

KW - Neoplasms

KW - Pregnancy Proteins

KW - Clinical Trial, Phase I

KW - Journal Article

KW - Multicenter Study

U2 - 10.1038/bjc.2011.609

DO - 10.1038/bjc.2011.609

M3 - Journal article

C2 - 22333707

VL - 106

SP - 678

EP - 684

JO - The British journal of cancer. Supplement

JF - The British journal of cancer. Supplement

SN - 0007-0920

IS - 4

ER -