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

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/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) 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/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 2 Pg. 287-94 (Jul 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19855966 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Hexanones
• Sulfhydryl Compounds
• Deoxycytidine
• Cystine
• 4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, pathology)
• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Cohort Studies
• Cystine (blood)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Hexanones (administration & dosage)
• Humans
• Male
• Middle Aged
• Pancreatic Neoplasms (drug therapy, pathology)
• Sulfhydryl Compounds (metabolism)
• Tomography, X-Ray Computed
• Gemcitabine