A Phase I and Pharmacologic Study of Pyrazoloacridine (NSC 366140) and Carboplatin in Patients with Advanced Cancer.

Background: Pyrazoloacridine (PZA) is thefirst of a new class of rationallysynthesized acridine derivatives to undergoclinical testing as an anticancer agent. We previously demonstrated cytotoxicsynergy between combinations of PZA andplatinum compounds. Subsequent studiesrevealed that PZA inhibits removal ofplatinum-DNA adducts in cultured A549cells. Based on these results, weundertook a phase I study of thecombination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eightpatients received 76 28-day courses (median2.5, range 1–6) of CBDCA (30-minuteinfusion) followed by PZA (3-hourinfusion), through six dose levels [PZA/CBDCA] (200/AUC 3,400/AUC 3, 400/AUC 4,400/AUC 5, 500/AUC 5, 600/AUC5 mg/m²/AUC). Pharmacokineticanalyses were performed to evaluate thedisposition of PZA. Retention ofplatinum-DNA adducts in peripheral bloodmononuclear cells of patients was alsoevaluated. Results: The most common anddose-limiting toxicity wasmyelosuppression, consisting of neutropeniaand leukopenia. Non-hematologic toxicitiesof anorexia, nausea and stomatitis weremild to moderate. In six patientsevaluated at the MTD, CBDCA did not appearto affect the pharmacokinetics of PZA. Onepatient with malignant melanoma had apartial response. Disease stabilizationfor greater than 4 courses of treatmentoccurred in 4 patients. Conclusion: The combination of PZAand CBDCA was well tolerated and may haveutility in some tumor types. [ABSTRACT FROM AUTHOR]