Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: a North Central Cancer Treatment Group trial.
OBJECTIVE
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.


METHODS
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
The phase II dose of the pyrazoloacridine/carboplatin combination is pyrazoloacridine 400 mg/m(2) in combination with carboplatin AUC of 5. Antitumor activity in patients with recurrent gliomas was limited. Initial disease stabilization occurred in approximately 38% of the patients, with median duration of 2 months. Enzyme-inducing anticonvulsants did not affect the pyrazoloacridine metabolism.
Galanis
Evanthia
E
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. galanis.evanthia@mayo.edu
Buckner
Jan C
JC
Maurer
Matthew J
MJ
Reid
Joel M
JM
Kuffel
Mary J
MJ
Ames
Matthew M
MM
Scheithauer
Bernd W
BW
Hammack
Julie E
JE
Pipoly
George
G
Kuross
Steven A
SA
D000166:Acridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000166:Acridines; D000927:Anticonvulsants; D000970:Antineoplastic Agents; D011720:Pyrazoles; D003577:Cytochrome P-450 Enzyme System; D016190:Carboplatin; C064541:NSC 366140