Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

Neuro Oncol. 2008 Jun;10(3):320-9. doi: 10.1215/15228517-2008-012. Epub 2008 Apr 10.


The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses <or=100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Brain Neoplasms / drug therapy*
  • ErbB Receptors / antagonists & inhibitors*
  • Exotoxins / administration & dosage*
  • Exotoxins / adverse effects
  • Humans
  • Immunotoxins / administration & dosage*
  • Injections, Intraventricular
  • Magnetic Resonance Imaging
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Tomography, Emission-Computed, Single-Photon
  • Transforming Growth Factor alpha / administration & dosage*
  • Transforming Growth Factor alpha / adverse effects


  • Antineoplastic Agents
  • Exotoxins
  • Immunotoxins
  • Transforming Growth Factor alpha
  • transforming growth factor(alpha)-Pseudomonas aeruginosa exotoxin (38)
  • ErbB Receptors