Phase I clinical trial of 7-cyanoquinocarcinol (DX-52-1) in adult patientswith refractory solid malignancies

Purpose: A phase I study of the antitumor antibiotic 7-cyanoquinocarcinol, DX-52-1, was conducted in patients with refractory solid malignancies. This study sought to determine the maximum tolerated dose and principal toxicit ies of this agent and to characterize its pharmacokinetic behavior. Methods : Patients were required to have adequate bone marrow, renal and hepatic fu nction. DX-52-1 was administered by i.v. continuous infusion over a 6-h per iod each week for four consecutive weeks followed by a 2-week rest period, which constituted one cycle of treatment. Results: Initial dose levels were 3, 6, and 10 mg/m(2). An intermediate dose level of 8 mg/m(2) was added af ter acceptable toxicity was observed at the 6 mg/m dose level, but doselimi ting toxicities, including life-threatening ones, were seen at the 10 mg/m( 2) dose level in all three patients. The maximum tolerated dose (MTD) was s ubsequently determined to be 6 mg/m(2). Because a clear pattern of toxiciti es was not initially evident, a larger than usual number of additional pati ents (16) were enrolled at the MTD to better distinguish toxicities due to the study drug from those secondary to the patients' underlying malignancie s. Even at the MTD, the drug was poorly tolerated, with gastrointestinal to xicities (abdominal pain, nausea, vomiting and increased liver function tes ts) predominating and dose-limiting. Pharmacokinetic studies revealed that the mean maximum plasma concentration of DX-52-1 in patients evaluated at t he MTD (138.8 +/- 59.3 ng/ml, n = 19) was considerably lower than the conce ntrations required for cytostatic or cytotoxic activity against sensitive h uman tumor cell lines in vitro. Further, the weekly dose intensity of the m ost efficacious treatment schedule identified during in vivo antitumor effi cacy studies was 60 times greater than the 6 mg/m(2) weekly dose tolerated by cancer patients. None of the 33 patients participating in this study, in cluding the 22 patients evaluated at the MTD, had any response to treatment . Conclusion: Given the poor tolerability, the inability to achieve drug le vels necessary to inhibit in vitro or in vivo tumor growth, and the lack of any responses in our study, DX-52-1, as given by this schedule, does not a ppear to warrant further investigation in phase II studies.