title: A phase i study of DMS612, a novel bifunctional alkylating agent.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Prostate Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sanjeeve
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Bryla
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Redon
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Asako J
authors.initials: AJ
authors.lastname: Nakamura
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: William M
authors.initials: WM
authors.lastname: Bonner
authors.affiliation: Investigational Drug Branch, Cancer Treatment Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.affiliation: Investigational Drug Branch, Cancer Treatment Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: Pharmacy Department, Clinical Center, NIH, Bethesda, Maryland.
authors.forename: David R
authors.initials: DR
authors.lastname: Kohler
authors.affiliation: Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Julie
authors.initials: J
authors.lastname: Eiseman
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. batess@helix.nih.gov.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D001547:Benzaldehydes; C492379:NSC281612