nsc-366140 and Vomiting

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

Topics: Acridines; Adult; Aged; Aged, 80 and over; Agranulocytosis; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Evaluation; Humans; Kidney Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Pyrazoles; Thrombocytopenia; Vomiting

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