Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies

Patricia M. LoRusso, Alex Adjei, Mary Varterasian, Shirish Gadgeel, Joel M Reid, David Y. Mitchell, Lorelei Hanson, Pamela DeLuca, Laura Bruzek, Jill Piens, Peggy Asbury, Keri Van Becelaere, Roman Herrera, Judith Sebolt-Leopold, Mark B. Meyer

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Abstract

Purpose: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase)-1 and MEK2, in patients with advanced malignancy. Patients and Methods CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. Results Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients. Conclusion CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.

Original languageEnglish (US)
Pages (from-to)5281-5293
Number of pages13
JournalJournal of Clinical Oncology
Volume23
Issue number23
DOIs
StatePublished - 2005

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Mitogen-Activated Protein Kinase Kinases
Neoplasms
Asthenia
Food
Maximum Tolerated Dose
MAP Kinase Kinase Kinase 1
Phosphotransferases
Pharmacokinetics
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
Exanthema
Drug-Related Side Effects and Adverse Reactions
Pancreatic Neoplasms
Nausea
Vomiting
Meals
Diarrhea
Fats
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. / LoRusso, Patricia M.; Adjei, Alex; Varterasian, Mary; Gadgeel, Shirish; Reid, Joel M; Mitchell, David Y.; Hanson, Lorelei; DeLuca, Pamela; Bruzek, Laura; Piens, Jill; Asbury, Peggy; Van Becelaere, Keri; Herrera, Roman; Sebolt-Leopold, Judith; Meyer, Mark B.

In: Journal of Clinical Oncology, Vol. 23, No. 23, 2005, p. 5281-5293.

Research output: Contribution to journalArticle

LoRusso, PM, Adjei, A, Varterasian, M, Gadgeel, S, Reid, JM, Mitchell, DY, Hanson, L, DeLuca, P, Bruzek, L, Piens, J, Asbury, P, Van Becelaere, K, Herrera, R, Sebolt-Leopold, J & Meyer, MB 2005, 'Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies', Journal of Clinical Oncology, vol. 23, no. 23, pp. 5281-5293. https://doi.org/10.1200/JCO.2005.14.415
LoRusso, Patricia M. ; Adjei, Alex ; Varterasian, Mary ; Gadgeel, Shirish ; Reid, Joel M ; Mitchell, David Y. ; Hanson, Lorelei ; DeLuca, Pamela ; Bruzek, Laura ; Piens, Jill ; Asbury, Peggy ; Van Becelaere, Keri ; Herrera, Roman ; Sebolt-Leopold, Judith ; Meyer, Mark B. / Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 23. pp. 5281-5293.
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title = "Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies",
abstract = "Purpose: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase)-1 and MEK2, in patients with advanced malignancy. Patients and Methods CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. Results Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28{\%}) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73{\%}; range, 46{\%} to 100{\%}) was demonstrated in 10 patients. Conclusion CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.",
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T1 - Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies

AU - LoRusso, Patricia M.

AU - Adjei, Alex

AU - Varterasian, Mary

AU - Gadgeel, Shirish

AU - Reid, Joel M

AU - Mitchell, David Y.

AU - Hanson, Lorelei

AU - DeLuca, Pamela

AU - Bruzek, Laura

AU - Piens, Jill

AU - Asbury, Peggy

AU - Van Becelaere, Keri

AU - Herrera, Roman

AU - Sebolt-Leopold, Judith

AU - Meyer, Mark B.

PY - 2005

Y1 - 2005

N2 - Purpose: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase)-1 and MEK2, in patients with advanced malignancy. Patients and Methods CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. Results Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients. Conclusion CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.

AB - Purpose: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase)-1 and MEK2, in patients with advanced malignancy. Patients and Methods CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. Results Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients. Conclusion CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.

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