TY - JOUR
T1 - A phase I study of DMS612, a novel bifunctional alkylating agent
AU - Appleman, Leonard J.
AU - Balasubramaniam, Sanjeeve
AU - Parise, Robert A.
AU - Bryla, Christine
AU - Redon, Christophe E.
AU - Nakamura, Asako J.
AU - Bonner, William M.
AU - Wright, John J.
AU - Piekarz, Richard
AU - Kohler, David R.
AU - Jiang, Yixing
AU - Belani, Chandra P.
AU - Eiseman, Julie
AU - Chu, Edward
AU - Beumer, Jan H.
AU - Bates, Susan E.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-14-1333
DO - 10.1158/1078-0432.CCR-14-1333
M3 - Article
C2 - 25467180
AN - SCOPUS:84923166042
SN - 1078-0432
VL - 21
SP - 721
EP - 729
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -
