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Published on: July 20, 2019
PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study
H J Groen1, E G de Vries, W Wynendaele
1Department of Pulmonary Diseases, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. h.j.m.groen@int.azg.nl
Abstract:
Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score
Insights
The maximum tolerated dose of PNU-145156E in solid tumor patients was 1050 mg/m(2). This novel agent did not significantly impact basic fibroblast growth factor levels but showed potential for disease stabilization.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- PNU-145156E, a distamycin A derivative, inhibits angiogenesis and shows preclinical antitumor activity.
- Phase I trials are crucial for determining the safety and dosage of new cancer therapeutics.
Purpose of the Study:
- To determine the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacokinetics of PNU-145156E in patients with solid tumors.
- To evaluate the effect of PNU-145156E on serum basic fibroblast growth factor (bFGF) levels.
Main Methods:
- A Phase I clinical trial involving 29 patients with solid tumors.
- PNU-145156E was administered intravenously every 6 weeks, with dose escalation from 100 to 1050 mg/m(2).
- Toxicity, pharmacokinetics, and serum bFGF levels were assessed using standardized criteria and assays.
Main Results:
- The maximum tolerated dose (MTD) of PNU-145156E was established at 1050 mg/m(2).
- Dose-limiting toxicities included thrombophlebitis, pulmonary embolism, and grade 3 dyspnea.
- PNU-145156E exhibited a long terminal half-life of approximately 1 month; no significant change in serum bFGF was observed.
- Disease stabilization was observed in four patients, but no objective tumor responses were noted.
Conclusions:
- PNU-145156E is a novel sulfonated distamycin A derivative with an MTD of 1050 mg/m(2) in patients with solid tumors.
- The drug's pharmacokinetic profile is characterized by a prolonged terminal half-life.
- PNU-145156E did not significantly affect serum bFGF levels and showed limited efficacy in terms of objective tumor response, although disease stabilization was achieved in some patients.
