Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer.

Abstract

PURPOSE:

This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer.

PATIENTS AND METHODS:

Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry.

RESULTS:

Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed.

CONCLUSION:

CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

• Authors: John Rinehart, Alex A Adjei, Patricia M Lorusso, David Waterhouse, J Randolph Hecht, Ronald B Natale, Oday Hamid, Mary Varterasian, Peggy Asbury, Eric P Kaldjian, Stephen Gulyas, David Y Mitchell, Roman Herrera, Judith S Sebolt-Leopold, Mark B Meyer
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 22 Issue 22 Pg. 4456-62 (Nov 15 2004) ISSN: 0732-183X [Print] United States
• PMID: 15483017 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Benzamides

Topics

• Administration, Oral
• Aged
• Benzamides (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Colonic Neoplasms (drug therapy)
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Pancreatic Neoplasms (drug therapy)
• Treatment Outcome