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

Evanthia Galanis, Jan Craig Buckner, Matthew J. Maurer, Joel M Reid, Mary J. Kuffel, Matthew M. Ames, Bernd W. Scheithauer, Julie E. Hammack, George Pipoly, Steven A. Kuross

Research output: Contribution to journalArticle

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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: 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.

Original languageEnglish (US)
Pages (from-to)495-503
Number of pages9
JournalInvestigational New Drugs
Volume23
Issue number5
DOIs
StatePublished - Oct 2005

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NSC 366140
Carboplatin
Glioma
Neoplasms
Anticonvulsants
Therapeutics
Area Under Curve

Keywords

  • Carboplatin
  • Gliomas
  • Pharmacokinetics
  • Pyrazoloacridine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma : A North Central Cancer Treatment Group trial. / Galanis, Evanthia; Buckner, Jan Craig; Maurer, Matthew J.; Reid, Joel M; Kuffel, Mary J.; Ames, Matthew M.; Scheithauer, Bernd W.; Hammack, Julie E.; Pipoly, George; Kuross, Steven A.

In: Investigational New Drugs, Vol. 23, No. 5, 10.2005, p. 495-503.

Research output: Contribution to journalArticle

Galanis, Evanthia ; Buckner, Jan Craig ; Maurer, Matthew J. ; Reid, Joel M ; Kuffel, Mary J. ; Ames, Matthew M. ; Scheithauer, Bernd W. ; Hammack, Julie E. ; Pipoly, George ; Kuross, Steven A. / Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma : A North Central Cancer Treatment Group trial. In: Investigational New Drugs. 2005 ; Vol. 23, No. 5. pp. 495-503.
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title = "Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: A North Central Cancer Treatment Group trial",
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: 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.",
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author = "Evanthia Galanis and Buckner, {Jan Craig} and Maurer, {Matthew J.} and Reid, {Joel M} and Kuffel, {Mary J.} and Ames, {Matthew M.} and Scheithauer, {Bernd W.} and Hammack, {Julie E.} and George Pipoly and Kuross, {Steven A.}",
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TY - JOUR

T1 - Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma

T2 - A North Central Cancer Treatment Group trial

AU - Galanis, Evanthia

AU - Buckner, Jan Craig

AU - Maurer, Matthew J.

AU - Reid, Joel M

AU - Kuffel, Mary J.

AU - Ames, Matthew M.

AU - Scheithauer, Bernd W.

AU - Hammack, Julie E.

AU - Pipoly, George

AU - Kuross, Steven A.

PY - 2005/10

Y1 - 2005/10

N2 - 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: 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.

AB - 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: 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.

KW - Carboplatin

KW - Gliomas

KW - Pharmacokinetics

KW - Pyrazoloacridine

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