A phase II trial of 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP) in patients with metastatic breast cancer

Abstract

864 Background: 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine), a potent inhibitor of ribonucleotide reductase, demonstrates both in vitro and in vivo antitumor activity. This cytotoxic effect seems to be maximized by chronic, intermittent enzymatic inhibition. Methods: Patients(Pts) with measurable metastatic breast cancer(MBC) refractory to at least one regimen were eligible for enrollment. Pts were required to have an ECOG PS of 0–1, adequate organ function, no active brain metastases. Treatment: 2-hour IV infusion of 3-AP daily × 5 days every other week at an initial dose of 96 mg/m2/d. Four courses were considered 1 cycle of treatment. Based on interval and residual toxicities, dose modifications to 84mg/m2 or 72mg/m2 were employed. Dose escalation to 105mg/m2 was also permitted. Full staging to be completed every 8 weeks. Results: 9 pts with a median age of 58 were enrolled (range 36–68). Median # of prior chemotherapy regimens was 6 (range 4–10) and 44% of pts (4/9) were refractory to 6 or more chemotherapy regimens. Three of nine pts demonstrated stable disease and the remainder had progression of disease (2/9) or discontinued treatment (4/9) before restaging was required/performed. A total of 42 courses were administered and all pts completed at least 2 courses of treatment (range 2–12). Seven of nine (77%) pts required a cycle 2 dose reduction of 84mg/m2 and an additional two required a cycle 3 dose reduction to 72mg/m2. Dominant toxicity was hematologic with thirty Grade 3 or 4 toxicities documented. All pts experienced Grade 4 neutropenia (4/9 hospitalized with nadir fevers) and 3/9 had Grade 4 thrombocytopenia. Conclusions: Thirty-three percent of pts achieved stable disease following administration of 3-AP(Triapine®) on a daily for five days schedule. Hematological toxicity was significant and managed with dose reductions. Future studies are planned with a more convenient dosing schedule. No significant financial relationships to disclose.