A phase I study of DMS612, a novel bifunctional alkylating agent

Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule. Experimental Design: Patients with advanced solid malignancies were eligible. Enrollment followed a 33 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by g-H2AX immunofluorescence. Results: A total of 31 patients, including those with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers, were enrolled. Six dose levels were studied, from 1.5 mgm² to 12 mg/m². DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mgm². The MTD was determined to be 9 mgm² with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9mgm² dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. g-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs. Conclusions: The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mgm². DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent PD signals and two partial responses at the MTD support further evaluation of DMS612 in phase II trials.