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 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

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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.

Original languageEnglish (US)
Pages (from-to)4456-4462
Number of pages7
JournalJournal of Clinical Oncology
Volume22
Issue number22
DOIs
StatePublished - Dec 1 2004

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Mitogen-Activated Protein Kinase Kinases
Pancreatic Neoplasms
Non-Small Cell Lung Carcinoma
Colonic Neoplasms
Breast Neoplasms
Neoplasms
Colon
Breast
MAP Kinase Kinase Kinases
Asthenia
Mouth Neoplasms
Extracellular Signal-Regulated MAP Kinases
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
Exanthema
Mitogens
Nausea
Pancreas
Diarrhea
Therapeutics
Bone Marrow

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Rinehart, John; Adjei, Alex; LoRusso, Patricia M.; Waterhouse, David; Hecht, J. Randolph; Natale, Ronald B.; Hamid, Oday; Varterasian, Mary; Asbury, Peggy; Kaldjian, Eric P.; Gulyas, Stephen; Mitchell, David Y.; Herrera, Roman; Sebolt-Leopold, Judith S.; Meyer, Mark B.

In: Journal of Clinical Oncology, Vol. 22, No. 22, 01.12.2004, p. 4456-4462.

Research output: Contribution to journalArticle

Rinehart, J, Adjei, A, LoRusso, PM, Waterhouse, D, Hecht, JR, Natale, RB, Hamid, O, Varterasian, M, Asbury, P, Kaldjian, EP, Gulyas, S, Mitchell, DY, Herrera, R, Sebolt-Leopold, JS & Meyer, MB 2004, 'Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer', Journal of Clinical Oncology, vol. 22, no. 22, pp. 4456-4462. https://doi.org/10.1200/JCO.2004.01.185
Rinehart, John ; Adjei, Alex ; LoRusso, Patricia M. ; Waterhouse, David ; Hecht, J. Randolph ; Natale, Ronald B. ; Hamid, Oday ; Varterasian, Mary ; Asbury, Peggy ; Kaldjian, Eric P. ; Gulyas, Stephen ; Mitchell, David Y. ; Herrera, Roman ; Sebolt-Leopold, Judith S. ; Meyer, Mark B. / Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 22. pp. 4456-4462.
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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.",
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T1 - Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer

AU - Rinehart, John

AU - Adjei, Alex

AU - LoRusso, Patricia M.

AU - Waterhouse, David

AU - Hecht, J. Randolph

AU - Natale, Ronald B.

AU - Hamid, Oday

AU - Varterasian, Mary

AU - Asbury, Peggy

AU - Kaldjian, Eric P.

AU - Gulyas, Stephen

AU - Mitchell, David Y.

AU - Herrera, Roman

AU - Sebolt-Leopold, Judith S.

AU - Meyer, Mark B.

PY - 2004/12/1

Y1 - 2004/12/1

N2 - 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.

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