A phase i study of DMS612, a novel bifunctional alkylating agent.

Abstract

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 3+3 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by γ-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 mg/m(2) to 12 mg/m(2). DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m(2). The MTD was determined to be 9 mg/m(2) with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9 mg/m(2) dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. γ-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 mg/m(2). 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.

• Authors: Leonard J Appleman, Sanjeeve Balasubramaniam, Robert A Parise, Christine Bryla, Christophe E Redon, Asako J Nakamura, William M Bonner, John J Wright, Richard Piekarz, David R Kohler, Yixing Jiang, Chandra P Belani, Julie Eiseman, Edward Chu, Jan H Beumer, Susan E Bates
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 4 Pg. 721-9 (Feb 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25467180 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Benzaldehydes
• NSC281612

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzaldehydes (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)