Phase I trial of imexon in patients with advanced malignancy

Tomislav Dragovich, Michael Gordon, David Mendelson, Lucas Wong, Manuel Modiano, Hsiao-Hui Chow, Betty Samulitis, Steven O'Day, Kathryn Grenier, Evan M Hersh, Robert T Dorr

Research output: Contribution to journalArticle

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Abstract

Purpose: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results: There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m 2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d. Conclusion: The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

Original languageEnglish (US)
Pages (from-to)1779-1784
Number of pages6
JournalJournal of Clinical Oncology
Volume25
Issue number13
DOIs
StatePublished - May 1 2007

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Sulfhydryl Compounds
Neoplasms
Maximum Tolerated Dose
Reactive Oxygen Species
Pharmacokinetics
Cystine
Constipation
Neutropenia
Non-Hodgkin's Lymphoma
Nausea
Abdominal Pain
Area Under Curve
Vomiting
Fatigue
Half-Life
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
High Pressure Liquid Chromatography
Apoptosis
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of imexon in patients with advanced malignancy. / Dragovich, Tomislav; Gordon, Michael; Mendelson, David; Wong, Lucas; Modiano, Manuel; Chow, Hsiao-Hui; Samulitis, Betty; O'Day, Steven; Grenier, Kathryn; Hersh, Evan M; Dorr, Robert T.

In: Journal of Clinical Oncology, Vol. 25, No. 13, 01.05.2007, p. 1779-1784.

Research output: Contribution to journalArticle

Dragovich, T, Gordon, M, Mendelson, D, Wong, L, Modiano, M, Chow, H-H, Samulitis, B, O'Day, S, Grenier, K, Hersh, EM & Dorr, RT 2007, 'Phase I trial of imexon in patients with advanced malignancy', Journal of Clinical Oncology, vol. 25, no. 13, pp. 1779-1784. https://doi.org/10.1200/JCO.2006.08.9672
Dragovich T, Gordon M, Mendelson D, Wong L, Modiano M, Chow H-H et al. Phase I trial of imexon in patients with advanced malignancy. Journal of Clinical Oncology. 2007 May 1;25(13):1779-1784. https://doi.org/10.1200/JCO.2006.08.9672
Dragovich, Tomislav ; Gordon, Michael ; Mendelson, David ; Wong, Lucas ; Modiano, Manuel ; Chow, Hsiao-Hui ; Samulitis, Betty ; O'Day, Steven ; Grenier, Kathryn ; Hersh, Evan M ; Dorr, Robert T. / Phase I trial of imexon in patients with advanced malignancy. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 13. pp. 1779-1784.
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AU - Gordon, Michael

AU - Mendelson, David

AU - Wong, Lucas

AU - Modiano, Manuel

AU - Chow, Hsiao-Hui

AU - Samulitis, Betty

AU - O'Day, Steven

AU - Grenier, Kathryn

AU - Hersh, Evan M

AU - Dorr, Robert T

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N2 - Purpose: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results: There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m 2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at ≥ 750 mg/m2/d. Conclusion: The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.

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