nsc-366140 and Leukopenia

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.. Both carboplatin and pyrazoloacridine were administered intravenously every 28 days. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal.. 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.. 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.

Topics: Acridines; Adult; Aged; Anticonvulsants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Cytochrome P-450 Enzyme System; Female; Glioma; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Pyrazoles; Treatment Outcome

Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted.. PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA.. Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity.. PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Topics: Acridines; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Pyrazoles; Thrombocytopenia; Treatment Outcome

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Nausea; Neoplasms; Pyrazoles; Vomiting