nsc-366140 and Neutropenia

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

The Gynecologic Oncology Group performed a phase II study to determine the response rate to pyrazoloacridine (PZA) in patients with advanced, persistent or recurrent squamous carcinoma of the cervix.. PZA was administered intravenously over 3 h every 3 weeks. A dose of 760 mg/m(2) was given to the first 11 patients and was reduced to 560 mg/m(2) for subsequent patients. The dose reduction was undertaken because of unexpected severe neutropenia among the initial patients.. Among 24 evaluable patients, 21 of whom had prior chemotherapy, there was one, brief, complete response (4.2%) and no partial responses. The major toxicity was neutropenia.. PZA at the dose and schedule employed, has insignificant activity in this population.

Topics: Acridines; Adult; Aged; Carcinoma, Squamous Cell; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Infusions, Intravenous; Intercalating Agents; Middle Aged; Neutropenia; Nucleic Acid Synthesis Inhibitors; Pyrazoles; Remission Induction; Salvage Therapy; Treatment Outcome; Uterine Cervical Neoplasms; Vomiting

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. We previously demonstrated cytotoxic synergy between combinations of PZA and platinum compounds. Subsequent studies revealed that PZA inhibits removal of platinum-DNA adducts in cultured A549 cells. Based on these results, we undertook a phase I study of the combination of PZA and carboplatin (CBDCA).. Twenty-eight patients received 76 28-day courses (median 2.5, range 1-6) of CBDCA (30-minute infusion) followed by PZA (3-hour infusion), through six dose levels [PZA/CBDCA] (200/AUC 3, 400/AUC 3, 400/AUC 4, 400/AUC 5, 500/AUC 5, 600/AUC 5 mg/m2/AUC). Pharmacokinetic analyses were performed to evaluate the disposition of PZA. Retention of platinum-DNA adducts in peripheral blood mononuclear cells of patients was also evaluated.. The most common and dose-limiting toxicity was myelosuppression, consisting of neutropenia and leukopenia. Non-hematologic toxicities of anorexia, nausea and stomatitis were mild to moderate. In six patients evaluated at the MTD, CBDCA did not appear to affect the pharmacokinetics of PZA. One patient with malignant melanoma had a partial response. Disease stabilization for greater than 4 courses of treatment occurred in 4 patients.. The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.

Topics: Acridines; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; DNA Adducts; Drug Interactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Platinum; Pyrazoles

To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy.. PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed.. No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1-6). Toxicity included neutropenia and neurologic side-effects, which were > or = grade III in 73% and 14%, respectively. High plasma concentrations of PZA (Cmax) correlated with low neutrophil counts (P = 0.04).. PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Colonic Neoplasms; Female; Humans; Intercalating Agents; Male; Middle Aged; Neoplasm Metastasis; Nervous System Diseases; Neutropenia; Pyrazoles; Rectal Neoplasms

To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers.. Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data.. On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed by a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m2 and the clearance was 300 mL/min/m2. There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose.. PZA administered as 1- or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose for phase II studies is 640 mg/m2.

Topics: Acridines; Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Neoplasms; Neutropenia; Pyrazoles; Thrombocytopenia

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

To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple-dosing schedules.. PZA was administered on a single-dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively.. On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity.. Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single- and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

Topics: Acridines; Adult; Aged; Antineoplastic Agents; Central Nervous System; Colorectal Neoplasms; DNA, Neoplasm; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Intercalating Agents; Male; Middle Aged; Neutropenia; Ovarian Neoplasms; Pyrazoles; Remission Induction; Uterine Cervical Neoplasms