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A phase I study with oral SU5416 in patients with advanced solid tumors: a drug inducing its clearance

Marc Salzberg1, Miklos Pless, Christoph Rochlitz

  • 1University Hospital Basel, Switzerland.

Investigational New Drugs
|October 21, 2005
PubMed

Insights

This study evaluated a new Nanocrystal Colloidal Dispersion (NCD) formulation of SU5416 for cancer treatment. While well-tolerated, the oral NCD SU5416 formulation did not achieve effective drug serum levels in patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Development

Background:

  • Vascular endothelial growth factor (VEGF) drives angiogenesis, crucial for tumor growth.
  • SU5416 is a tyrosine kinase inhibitor targeting VEGF-mediated signaling, showing anti-tumor activity.
  • Current intravenous SU5416 dosing is suboptimal for long-term cancer therapy.

Purpose of the Study:

  • To assess the safety, tolerability, and pharmacokinetics of an oral Nanocrystal Colloidal Dispersion (NCD) formulation of SU5416 in cancer patients.
  • To compare the pharmacokinetic profile of oral NCD SU5416 with intravenous administration.
  • To understand the Absorption, Distribution, Metabolism, and Excretion (ADME) properties of indoline compounds.

Main Methods:

  • Phase I clinical trial involving patients with advanced solid organ tumors.
  • Administration of various SU5416 regimens in NCD formulation.
  • Evaluation of safety, tolerability, and pharmacokinetic parameters.

Main Results:

  • Oral NCD SU5416 demonstrated induced clearance in humans, exceeding that of i.v. administration.
  • SU5416 was confirmed as a high clearance compound, even in the oral NCD formulation.
  • The NCD formulation was well tolerated, but failed to achieve effective therapeutic drug serum levels.

Conclusions:

  • The oral NCD SU5416 formulation, despite good tolerability, is not suitable for achieving effective drug concentrations in cancer patients.
  • Findings provide insights into the ADME properties of indoline chemical class compounds.
  • Lessons learned will inform the development of future indoline-based anti-angiogenic and anti-tumor agents.

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