Treatment > Pyrazoloacridine

Meeting Abstract

A phase I/II trial and pharmacokinetic study of pyrazoloacridine in adults with newly diagnosed glioblastoma multiforme

G. J. Lesser, K. Carson, J. Supko, J. Kuhn, R. Priet, B. Nabors, D. Lawson, T. Doyle, S. Grossman

The New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium, Baltimore, MD

Pyrazoloacridine (PZA) is an acridine derivative with broad spectrum preclinical antitumor efficacy that may result from topoisomerase I and II inhibition.
The NABTT CNS consortium is conducting a phase I/II trial of pre-irradiation PZA in patients with newly diagnosed glioblastoma multiforme with measurable disease on postoperative contrast-enhanced brain MRI scans.
The dose is being independently escalated by the CRM method in patients receiving hepatic enzyme-inducing anticonvulsant drugs (EIAD) and in patients not receiving those drugs.
Groups of at least 3 patients were evaluated at each dose level.
The starting dose in both arms was 750 mg/m2 given as a 3 hour intravenous infusion.
A maximum of 4 cycles of PZA, given at 3 week intervals, could be delivered prior to standard radiation therapy.
To date, 15 patients have been enrolled, including 12 on the +EIAD arm in which dose escalation to 1267 mg/m2 has been completed.
A total of 34 cycles of PZA have been delivered and pharmacokinetic sampling was performed in all patients.
Grade 3/4 toxicity has been minimal and limited to 4 episodes of neutropenia.
Four patients have received all 4 planned pre-irradiation cycles of PZA.
The mean +/- SD clearance of PZA in 6 patients in the +EIAD cohort (750 and 871 mg/m2) was 28.2 +/- 17.7 liters/h/m2 which is comparable to previously reported values in patients with extraneural solid tumors.
These preliminary results suggest that the pharmacokinetics of PZA is not markedly affected by EIAD.
Furthermore, our ability to dose escalate in patients receiving EIAD suggests that dose limiting toxicity may be mediated by a metabolite of PZA which interacts with EIAD, rather than the parent drug.
Response, toxicity and pharmacokinetic data will continue to be collected as additional patients are enrolled on this trial.

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