EVALUATION OF CL-973, A PLATINUM ANALOG, IN REFRACTORY OR RELAPSED ACUTE-LEUKEMIA

The purpose of the study was to define the maximally tolerated dose (M TD), major toxicities, and possible antitumor activity of Cl-973 a new platinum analogue, in patients with refractory or relapsed acute leuk emia, Cl-973 was given as a 5-day continuous infusion every 3 to 4 wee ks to patients with refractory or relapsed acute leukemia, at doses ra nging from 150 mg/m(2) to 1350 mg/m(2) per course. Thirty-six patients were treated including 18 patients with acute myelogenous leukemia (A ML), four with acute lymphocytic leukemia (ALL) and 14 with chronic my elogenous leukemia in blastic phase (CML-BP). Severe gastrointestinal and renal side-effects were the dose-limiting toxicities occurring in four of five patients treated with Cl-973 1200 to 1350 mg/m(2) per cou rse. At the MTD of 1000 mg/m(2) per course, three of 13 patients treat ed (23%) had moderate to severe nausea and vomiting, three (23%) had m oderate diarrhea and one had moderate mucositis. Among 21 patients tre ated at greater than or equal to 1000 mg/m(2) (15 AML, 6 CML-BP) no ob jective complete or partial responses were observed. Twelve of 18 pati ents (66%) with evaluable marrows on day 14 showed significant suppres sion of marrow blasts percentage and marrow leukemic infiltrate percen tage. Tests for measurement of DNA adduct formation in leukemic cells in vivo after Cl-973 therapy, and in vitro following exposure of leuke mic cells to Cl-973 were developed. This study defined the MTD of Cl-9 73 to be 1000 mg/m(2) by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Gastroin testinal and renal side-effects were dose-limiting. No objective respo nses were noted in this heavily resistant population. Correlations bet ween Cl-973-induced DNA adduct formation and individual patient respon se to Cl-973 will help to define its role in leukemia subsets.