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

Abstract

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.

Inhibition of placenta growth factor with TB-403: a novel antiangiogenic cancer therapy

“…No objective responses were observed. Six patients had stable disease ‡ 8 weeks, including two patients (pancreatic adenocarcinoma and esophageal squamous carcinoma) treated with TB-403 5 mg/kg for approximately 12 months [79]. Pharmacokinetic parameters supported findings in healthy males with a T½ of 9 --14 days.…”

Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study

“…6 In humans, aflibercept (VEGF Trap) and the anti-PlGF antibody TB-403, can be new antiangiogenic and antiatherogenic drugs that antagonize PlGF signaling with already well established safety and tolerability. 37,38 Further interventional trials of these agents are required to determine whether reducing serum PlGF levels provides cardioprotective effects in patients with CKD.…”

Placental Growth Factor (PlGF)–Specific Uptake in Tumor Microenvironment of 89Zr-Labeled PlGF Antibody RO5323441

“…It is as of yet unclear how the antibody dose affects the efficacy (9). In the clinical phase I dose-escalation studies with RO5323441, no dose-limiting toxicities were found with doses of up to 30 mg/kg (10,11). It is possible that the maximum effective dose was already reached with optimal target saturation of its target.…”

“…No dose-limiting toxicities were observed with doses of up to 30 mg/kg administered once every 3 wk. Because no maximum-tolerated dose could be defined (11), determination of the optimal dose for phase II studies was hampered. Rational dosing might be obtained when tumor and normal tissue uptake of the antibody is defined with 89 Zr-RO5323441 PET.…”