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Originally published as JCO Early Release 10.1200/JCO.2004.01.185 on October 13 2004

Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4456-4462
© 2004 American Society of Clinical Oncology.
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Multicenter Phase II Study of the Oral MEK Inhibitor, CI-1040, in Patients With Advanced Non-Small-Cell Lung, Breast, Colon, and Pancreatic Cancer

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

From the University of Alabama at Birmingham, Birmingham, AL; The Mayo Clinic, Rochester, MN; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Oncology/Hematology Care, Inc, Cincinnati, OH; University of California Los Angeles Medical Center; and Cedars-Sinai Medical Center at Los Angeles, Los Angeles, CA

Address reprint requests to John Rinehart, MD, University of Alabama at Birmingham, 263 Wallace Tumor Institute, 1824 6th Ave S, Birmingham, AL 35294; e-mail: john.rinehart{at}ccc.uab.edu

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.

Supported by Pfizer Global Research and Development, Department of Clinical Oncology, Ann Arbor, MI.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


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