Abstract | PURPOSE: Novel therapeutic agents in the treatment of recurrent gliomas are urgently needed. Pyrazoloacridine (PZA), a rationally synthesized acridine derivative, has shown promising antitumor activity against glioma lines in combination with platinum compounds. This phase I/II trial of the PZA/ carboplatin combination in recurrent glioma patients consisted of two phase I studies (studies 1 and 2) and a phase II trial (study 3). The objectives of studies 1 and 2 were to (a) assess the safety and toxicity and to establish the phase II dose of the pyrazoloacridine/ carboplatin combination for recurrent glioma patients on P450 inducing anticonvulsants, and (b) to confirm the phase II dose for patients not on P450 inducing anticonvulsants. The primary objectives of study 3 were to determine the efficacy of the pyrazoloacridine/ carboplatin combination in patients with recurrent gliomas, to further assess the toxicity of the combination, and to evaluate the impact of enzyme-inducing anticonvulsants on the pyrazoloacridine metabolism. EXPERIMENTAL DESIGN: Both carboplatin and pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. RESULTS: 14 patients were treated in the two phase I studies and 32 patients in the phase II trial. The phase II dose of the combination was PZA 400 mg/m(2) and carboplatin AUC of 5 every 28 days. Neutropenia (4 patients) and dyspnea (1 patient) was the dose limiting toxicity in the phase I studies. In the phase II trial, the most frequent toxicity was myelosuppression with grade 3 and 4 hematologic adverse events being observed in 22 and 19% of the patients, respectively. The antitumor activity of this regimen was limited; the response rate in the phase II trial was 0%, (95% CI:0-11%) while 12 of the 32 patients (38%) had stable disease with a median duration of 2 months. The percentage of phase II patients who were progression free at three months was 22% and at six months was 16%. Median survival from study entry was 5.0 months for phase I patients and 5.8 months for phase II patients. Pharmacokinetic analysis performed in 8 phase I patients demonstrated no significant impact of the enzyme-inducing anticonvulsants on the pharmacokinetics of pyrazoloacridine. CONCLUSIONS:
|
Authors | Evanthia Galanis, Jan C Buckner, Matthew J Maurer, Joel M Reid, Mary J Kuffel, Matthew M Ames, Bernd W Scheithauer, Julie E Hammack, George Pipoly, Steven A Kuross |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 23
Issue 5
Pg. 495-503
(Oct 2005)
ISSN: 0167-6997 [Print] United States |
PMID | 16133802
(Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article)
|
Chemical References |
- Acridines
- Anticonvulsants
- Antineoplastic Agents
- Pyrazoles
- Cytochrome P-450 Enzyme System
- Carboplatin
- NSC 366140
|
Topics |
- Acridines
(administration & dosage, adverse effects, pharmacokinetics)
- Adult
- Aged
- Anticonvulsants
(pharmacology)
- Antineoplastic Agents
(administration & dosage, adverse effects, pharmacokinetics)
- Antineoplastic Combined Chemotherapy Protocols
(adverse effects, pharmacokinetics, therapeutic use)
- Brain Neoplasms
(drug therapy, metabolism)
- Carboplatin
(administration & dosage, adverse effects, pharmacokinetics)
- Cytochrome P-450 Enzyme System
- Female
- Glioma
(drug therapy, metabolism)
- Humans
- Leukopenia
(chemically induced)
- Male
- Middle Aged
- Neutropenia
(chemically induced)
- Pyrazoles
(administration & dosage, adverse effects, pharmacokinetics)
- Treatment Outcome
|