A phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer

Background: 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). Patients and methods: 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. Results: 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. Conclusion: The combination of PZA and CBDCA was well tolerated and may have utility in some tumor types.