A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma

Jeffrey S. Weber, Wolfram E. Samlowski, Rene Gonzalez, Antoni Ribas, Joe Stephenson, Steven O'Day, Takami Sato, Robert T Dorr, Kathryn Grenier, Evan M Hersh

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.

Original languageEnglish (US)
Pages (from-to)3683-3691
Number of pages9
JournalCancer
Volume116
Issue number15
DOIs
StatePublished - Aug 1 2010

Fingerprint

Dacarbazine
Melanoma
Maximum Tolerated Dose
Pharmacokinetics
Survival
Mitochondrial Membranes
Anorexia
Pulmonary Edema
Constipation
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
L-Lactate Dehydrogenase
Thrombocytopenia
Disease-Free Survival
Vomiting
Anemia
Diarrhea
Reactive Oxygen Species
Fever
Apoptosis
Drug Therapy

Keywords

  • Chemotherapy
  • Dacarbazine
  • Imexon
  • Malignant melanoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Weber, J. S., Samlowski, W. E., Gonzalez, R., Ribas, A., Stephenson, J., O'Day, S., ... Hersh, E. M. (2010). A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. Cancer, 116(15), 3683-3691. https://doi.org/10.1002/cncr.25119

A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. / Weber, Jeffrey S.; Samlowski, Wolfram E.; Gonzalez, Rene; Ribas, Antoni; Stephenson, Joe; O'Day, Steven; Sato, Takami; Dorr, Robert T; Grenier, Kathryn; Hersh, Evan M.

In: Cancer, Vol. 116, No. 15, 01.08.2010, p. 3683-3691.

Research output: Contribution to journalArticle

Weber, JS, Samlowski, WE, Gonzalez, R, Ribas, A, Stephenson, J, O'Day, S, Sato, T, Dorr, RT, Grenier, K & Hersh, EM 2010, 'A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma', Cancer, vol. 116, no. 15, pp. 3683-3691. https://doi.org/10.1002/cncr.25119
Weber JS, Samlowski WE, Gonzalez R, Ribas A, Stephenson J, O'Day S et al. A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. Cancer. 2010 Aug 1;116(15):3683-3691. https://doi.org/10.1002/cncr.25119
Weber, Jeffrey S. ; Samlowski, Wolfram E. ; Gonzalez, Rene ; Ribas, Antoni ; Stephenson, Joe ; O'Day, Steven ; Sato, Takami ; Dorr, Robert T ; Grenier, Kathryn ; Hersh, Evan M. / A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. In: Cancer. 2010 ; Vol. 116, No. 15. pp. 3683-3691.
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abstract = "BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9{\%} and 25{\%} for all subjects and 2{\%} and 30{\%} for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.",
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AU - Samlowski, Wolfram E.

AU - Gonzalez, Rene

AU - Ribas, Antoni

AU - Stephenson, Joe

AU - O'Day, Steven

AU - Sato, Takami

AU - Dorr, Robert T

AU - Grenier, Kathryn

AU - Hersh, Evan M

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N2 - BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.

AB - BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.

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