A phase i study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer

Steven J. Cohen, Mark M. Zalupski, Manuel R. Modiano, Paul Conkling, Yehuda Z. Patt, Peg Davis, Robert T Dorr, Michelle L. Boytim, Evan M Hersh

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Purpose: Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Methods: Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 min days 1-5, 15- 19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m2 IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 min on days 1, 8, and 15 every 28 days). Results: One hundred five patients received 340 treatment cycles (median 2, range 1-16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. Conclusions: The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)287-294
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number2
DOIs
StatePublished - Jul 2010

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gemcitabine
Pancreatic Neoplasms
Toxicity
Maximum Tolerated Dose
Abdominal Pain
Therapeutics
Pharmacokinetics
Acute Pain
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
Area Under Curve
Half-Life
Diarrhea
Adenocarcinoma
Cells

Keywords

  • Gemcitabine
  • Imexon
  • Pancreatic cancer
  • Phase I clinical trial

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

A phase i study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer. / Cohen, Steven J.; Zalupski, Mark M.; Modiano, Manuel R.; Conkling, Paul; Patt, Yehuda Z.; Davis, Peg; Dorr, Robert T; Boytim, Michelle L.; Hersh, Evan M.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 2, 07.2010, p. 287-294.

Research output: Contribution to journalArticle

Cohen, Steven J. ; Zalupski, Mark M. ; Modiano, Manuel R. ; Conkling, Paul ; Patt, Yehuda Z. ; Davis, Peg ; Dorr, Robert T ; Boytim, Michelle L. ; Hersh, Evan M. / A phase i study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 2. pp. 287-294.
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abstract = "Purpose: Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Methods: Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 min days 1-5, 15- 19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m2 IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 min on days 1, 8, and 15 every 28 days). Results: One hundred five patients received 340 treatment cycles (median 2, range 1-16). Patient characteristics: median age 63, 61{\%} male, ECOG PS 0/1 50{\%}/50{\%}, 93{\%} metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4{\%}, 8.9{\%} unconfirmed PR, and 48.1{\%} with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. Conclusions: The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.",
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AU - Modiano, Manuel R.

AU - Conkling, Paul

AU - Patt, Yehuda Z.

AU - Davis, Peg

AU - Dorr, Robert T

AU - Boytim, Michelle L.

AU - Hersh, Evan M

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