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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)721-729
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number4
DOIs
StatePublished - Feb 15 2015

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NSC281612
Alkylating Agents
Maximum Tolerated Dose
Renal Cell Carcinoma
Fluorescent Antibody Technique
Organ Specificity
Neutropenia
Scalp
Intravenous Infusions
Uterine Cervical Neoplasms
Hair
DNA Damage
Mass Spectrometry
Neoplasms
Appointments and Schedules
Research Design
Pharmacokinetics
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Appleman, L. J., Balasubramaniam, S., Parise, R. A., Bryla, C., Redon, C. E., Nakamura, A. J., ... Bates, S. E. (2015). A phase I study of DMS612, a novel bifunctional alkylating agent. Clinical Cancer Research, 21(4), 721-729. https://doi.org/10.1158/1078-0432.CCR-14-1333
Appleman, Leonard J. ; Balasubramaniam, Sanjeeve ; Parise, Robert A. ; Bryla, Christine ; Redon, Christophe E. ; Nakamura, Asako J. ; Bonner, William M. ; Wright, John J. ; Piekarz, Richard ; Kohler, David R. ; Jiang, Yixing ; Belani, Chandra P. ; Eiseman, Julie ; Chu, Edward ; Beumer, Jan H. ; Bates, Susan E. / A phase I study of DMS612, a novel bifunctional alkylating agent. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 4. pp. 721-729.
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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 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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Appleman, LJ, Balasubramaniam, S, Parise, RA, Bryla, C, Redon, CE, Nakamura, AJ, Bonner, WM, Wright, JJ, Piekarz, R, Kohler, DR, Jiang, Y, Belani, CP, Eiseman, J, Chu, E, Beumer, JH & Bates, SE 2015, 'A phase I study of DMS612, a novel bifunctional alkylating agent', Clinical Cancer Research, vol. 21, no. 4, pp. 721-729. https://doi.org/10.1158/1078-0432.CCR-14-1333

A phase I study of DMS612, a novel bifunctional alkylating agent. / Appleman, Leonard J.; Balasubramaniam, Sanjeeve; Parise, Robert A.; Bryla, Christine; Redon, Christophe E.; Nakamura, Asako J.; Bonner, William M.; Wright, John J.; Piekarz, Richard; Kohler, David R.; Jiang, Yixing; Belani, Chandra P.; Eiseman, Julie; Chu, Edward; Beumer, Jan H.; Bates, Susan E.

In: Clinical Cancer Research, Vol. 21, No. 4, 15.02.2015, p. 721-729.

Research output: Contribution to journalArticle

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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.

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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Appleman LJ, Balasubramaniam S, Parise RA, Bryla C, Redon CE, Nakamura AJ et al. A phase I study of DMS612, a novel bifunctional alkylating agent. Clinical Cancer Research. 2015 Feb 15;21(4):721-729. https://doi.org/10.1158/1078-0432.CCR-14-1333