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.
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
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ABSTRACT
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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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INTRODUCTION
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CI-1040 is an oral inhibitor of mitogen-activated extracellular signal regulated kinase kinase (MEK), a key enzyme in the Ras-Raf-MEK- extracellular signal regulated kinase (ERK) kinase pathway known to be involved in key cellular activities including proliferation, differentiation, apoptosis, and angiogenesis.1-5 This pathway is constitutively active in a variety of solid tumor models including lung, colon, pancreatic, and breast.6,7 CI-1040 was recently evaluated in a single phase I clinical study for safety, pharmacokinetics, target (pERK) suppression, and antitumor activity in advanced cancer.8 The most common toxicities were generally grade 1 or 2 in severity and included diarrhea, asthenia, rash, nausea, and vomiting. There were no drug-related grade 4 events. Administration with food increased oral absorption of CI-1040 by three- to five-fold, and continuous dosing of 800 mg bid with food was determined to be safe for phase II testing. One patient in the phase I study with pancreatic cancer achieved a partial response (PR) lasting 12 months, and 19 additional patients with a variety of solid tumors achieved stable disease (SD) lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of pERK expression in tumor by an average of 71% (range, 46% to 100%) was demonstrated by quantitative immunohistochemistry methods. On the basis of these encouraging phase I results, a phase II, multicenter, parallel arm study was carried out in patients with advanced breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer.
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PATIENTS AND METHODS
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Study Population
Patients with histologic or cytologic evidence of metastatic or inoperable breast, colon, NSCLC, or pancreatic cancer with measurable disease were eligible for this study. Prior treatment restrictions were one or no prior chemotherapeutic regimen for NSCLC and colon cancer, two or fewer prior regimens for metastatic breast cancer (excluding adjuvant regimens), and no prior chemotherapy for pancreatic cancer. Additional requirements included age 18 years or older; Eastern Cooperative Group performance status of 2 or less; adequate bone marrow, renal, and hepatic function; 4 or more weeks from prior chemotherapy; 3 or more weeks from prior radiation therapy; and 2 weeks from prior hormonal, immunologic, or biologic therapies. Patients were ineligible if they had untreated brain metastases, concurrent serious infection, life-threatening illness (unrelated to tumor), or a diagnosis of another malignancy within 5 years of study enrollment (except adequately treated carcinoma-in-situ of the cervix or nonmelanomatous skin cancer). Pregnant or lactating women were also excluded. Institutional review boards at each participating site approved the protocol and informed consent document; consent was obtained from all patients.
Pretreatment evaluation included a history and physical examination, CBC, differential and platelet count, serum chemistries and coagulation profile, lesion measurement, multiple-gaited acquisition scan or echocardiogram, and ECG. Follow-up studies included physical examinations, CBC with differential and platelet count, serum chemistries, and imaging procedures every 8 weeks for disease assessment. A steady-state ECG was secured on cycle 1, day 15, and ejection fraction testing with either multiple-gaited acquisition scan or echocardiogram was to be repeated after cycle 3 and again at the end of treatment. In addition, blood samples for pharmacokinetic assessments were collected at baseline, 2 and 4 hours after dose on day 1, and 4 hours after dose on day 15 of cycle 1. Thereafter, a single steady-state blood sample was collected on day 1 of each cycle of treatment at a random time point after the morning dose of CI-1040.
Original diagnostic tumor specimens or other more recent tumor tissue biopsy material, if available, were collected either as paraffin-embedded tissue or unstained slides. These materials were assessed for levels of pERK, pAkt, and Ki-67 by quantitative immunohistochemistry methods.
Experimental Treatment
CI-1040 was supplied as 200-mg capsules by Pfizer Global Research and Development, Michigan Laboratories (Ann Arbor, MI). This study was initiated with an intermittent dosing schedule of CI-1040, which consisted of 21 days of treatment repeated every 28 days. When phase I results confirmed the safety of continuous dosing, the phase II oral dose schedule was amended to 800 mg bid given continuously. Before this amendment took effect, nine patients received a total of 20 intermittent courses of treatment. On the basis of phase I results that revealed significantly enhanced absorption of CI-1040 when administered with food, CI-1040 was dosed with meals. The starting dose was 800 mg bid, and reductions were made in 200-mg decrements for toxicities of grade 2 or greater severity (eg, 800 mg bid to 600 mg bid, and so on).
Response and Toxicity Criteria
Response Evaluation Criteria in Solid Tumors criteria9 were used to evaluate antitumor response, and the first planned assessment occurred after completion of three cycles of treatment to coincide with the definition of SD ( 3 months without objective evidence of disease progression) and every two cycles thereafter. Toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
Study Design and Statistical Methods
This open-label, multicenter study independently screened four different tumor types for single-agent response to CI-1040 using a modified Simon two-stage design.10 The classic Simon design was modified to advance enrollment based on two coprimary end points, either objective response (OR; OR = complete response [CR] + PR) or clinical benefit response (CBR; CBR = CR + PR + SD). To begin, two classic Simon designs were created based on the assumptions in Table 1.
The sample sizes for each stage in the modified design were driven by the parameter that had the larger sample size at each stage. Thresholds for stage advancement criteria were back-calculated based on these sample sizes. Simulations were performed to demonstrate that the overall (ie, for the modified design) type I error was controlled in this algorithm at a level of 10%, which is consistent with the Bonferroni argument. A common set of efficacy no-interest and interest levels (P0 and P1, respectively) and false-positive and false-negative error rates for the four tumor types yielded a common set of sample size estimates for each tumor (13 patients for stage 1 and 30 patients for stage 2).
In stage 1, 13 assessable patients were to be assessed in each of the four tumor cohorts. Assessable patients were those who completed one or more treatment cycle and who had one or more posttreatment response assessment. An additional 30 assessable patients were to be enrolled if one or more OR or four or more CBRs were confirmed in stage 1 (Fig 1). Excess patients enrolled would be counted as part of stage 2, if it opened; however, antitumor outcomes in only the first 13 assessable stage 1 patients would determine whether stage 2 opened or not. On completion of stage 2, the observation of at least six ORs or 13 CBRs would be sufficient to reject the null hypothesis of CI-1040 effect on OR and/or CBR in favor of the alternative hypothesis, that a CI-1040 effect exists on OR and/or CBR.
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Fig 1. Study schema based on two-stage Simon design. (*), Response Evaluation Criteria in Solid Tumors criterion used to assess response; SD = 12 weeks of nonprogression. NSCLC, non-small-cell lung cancer; CBR, clinical benefit responder (CRB = CR + PR + SD); CR, complete response; PR, partial response; SD, stable disease.
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Plasma CI-1040 Concentration Monitoring
Blood samples were drawn on day 1 of cycle 1 before treatment and 2 and 4 hours after dose to monitor drug concentrations. Samples were also drawn on day 15, corresponding with steady-state drug levels, and after transition to continuous dosing of CI-1040, blood samples were collected on day 1 of each subsequent cycle. The dates and times of each blood drawing relative to the most recent dose of CI-1040 were recorded, thus allowing for the assessment of compliance with the CI-1040 dosing regimen. Whole blood specimens were mailed overnight to Pfizer Global Research and Development Laboratories in Ann Arbor.
Concentrations of CI-1040 and its active metabolite, PD 0184264, were measured in plasma using a validated liquid chromatograph/mass spectrometer/mass spectrometer (LC/MS/MS) assay. [13C6]CI-1040 and PD 0184264 internal standard were added to 200 µL of the biologic sample. Samples were deproteinated with acetonitrile and centrifuged, and 5 µL of the extract was injected into the LC/MS/MS system. The isocratic LC system consisted of a BHK SAL Cyano (BHK SAL, Chicago, IL; 100 x 2 mm; 5 µm) analytic column using a mobile phase of acetonitrile (0.5% acetic acid in high-performance liquid chromatography-grade water; 70:30, vol/vol). The mass spectrometer was a Sciex API 3000 (Applied Biosystems, Concord Ontario, Canada) using turbo ion spray/negative ion mode.
Assay sensitivity for the plasma assay was 1.0 ng/mL for CI-1040 and 20.0 ng/mL for PD 0184264. The accuracy of the plasma assay ranged from –5.46% to –3.00% for CI-1040 and –2.97% to 10.9% for PD 0184264, whereas the precision was  10.6% and 8.88% for CI-1040 and PD 0184264, respectively.
Assessment of pERK in Archived Tumor Specimens
Tissues.
Archival tumor specimens (site not specified), fixed and processed according to institutional protocol, were collected either as tissue blocks embedded in paraffin or as unstained tissue sections mounted on charged slides. Microscopic sections were baked at 60°C for 2 hours before analysis. Hematoxylin and eosin staining was used to identify tumor cells.
The antibodies used are listed in Table 2. One of two methods, as indicated in Table 2, was used for immunohistochemical analyses. Slides were first deparaffinized in xylenes and rehydrated through graded alcohols; then they were quenched with 3% hydrogen peroxide in triethanolamine-buffered saline (TBS) to eliminate endogenous peroxidase activity. After washing in water and TBS, sections were subjected to heat-induced epitope retrieval using the buffer indicated in Table 2. Nonspecific binding was blocked by incubation in 10% normal goat serum in TBS. Primary antibodies were diluted using antibody diluent (Ventana Medical Systems, Inc, Tucson, AZ), and incubations were carried out overnight at 4°C. Sections stained for pERK were then rinsed and developed on a DAKO autostainer using the LSAB2 system (DAKO Cytomation, Carpinteria, CA), which uses a mixture of biotinylated antimouse and antirabbit secondary antibodies followed by a streptavidin-peroxidase link. Localization of antibody binding was affected with diaminobenzidine. Specimens stained for Ki-67 and pAkt used NexES automated stainers and the I-View Detection Chemistry (Ventana Medical Systems), which uses specific antimouse and antirabbit secondary antibodies, a streptavidin-peroxidase link, and Ventana Medical Systems formulation of diaminobenzidine.
Image analysis.
Quantification of staining intensity was carried out using an AccuMed AcCell system (AccuMed International, Inc., Chicago, IL)11 and software that analyzes user-defined fields to establish the optical density (OD) of peroxidase-stained regions. Markers that were quantified in terms of proportion of positive nuclear area were analyzed on a CAS 200 Image Analyzer (Becton Dickinson Corp., San Jose, CA).12 Percent nuclear area was determined for Ki-67, and OD was scored for pAkt. For pERK, the product of percent nuclear area and OD was scored as an index; staining was predominantly nuclear. A threshold value of 100 was used for constitutive activation of pERK. This was determined on the basis of 10% of cells staining at an OD of 10, the laboratory confidence point for positive staining.
For scoring, generally 10 random fields were selected for analysis that contained tumor elements, but the size of tumor biopsies did not allow this in all cases. The selection of fields involved prescreening of sections to ensure that representative sections were to be quantified. Efforts were made to analyze similar areas on each section for each stain. The AU-565 cell line treated with epidermal growth factor served as the positive control. A negative control, comprising a section processed in parallel but without primary antibody, was used to set the OD value of zero for each set of samples that were stained and quantified together. In the case of ODs determined on the AcCell, after selection of fields for each slide, slides were automatically loaded on the microscope stage, and pixel density was determined. Image analysis results were reviewed by medical and scientific laboratory directors.
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RESULTS
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Patients
Sixty-seven patients entered the study between January and July of 2002, including 14 patients with breast cancer, 20 with colon cancer, 18 with NSCLC, and 15 with pancreatic cancer (Table 3). Rapid accrual of patients with colon and lung cancer in this multicenter study accounted for overenrollment in these two cohorts. However, stage 1 evaluation for each tumor type was based on response outcomes in the first 13 assessable patients with each tumor type. Ninety percent of patients had an Eastern Cooperative Oncology Group performance status of 1 or less, and 75% of patients had received one or no prior chemotherapeutic regimen. Overall, a total of 194 cycles of CI-1040 were administered, with a median of two cycles per patient (range, one to 14 cycles).
Toxicities
Adverse events that were deemed at least possibly related to CI-1040 by investigators are described. No patient experienced drug-associated toxicity of grade 4 severity, and only 13 patients (19%) experienced toxicities of grade 3 severity. The frequency and severity of the most common toxicities occurring in 10% of patients are listed in Table 4. The common toxicities were generally mild or moderate in severity and, in descending order of incidence, included diarrhea, nausea, asthenia, rash, edema, vomiting, abdominal pain, anorexia, and facial edema. Two patients withdrew from treatment because of adverse events deemed at least possibly related to CI-1040 (abdominal cramping and stroke). Except for deaths caused by disease progression, no patient died either while receiving CI-1040 or within 30 days of their last dose.
The potential for CI-1040 to cause a delay in cardiac repolarization was assessed by evaluating the QTc interval at baseline and on day 15 (steady-state). The data did not reveal significant QTc prolongation associated with either the steady-state exposures of CI-1040 or metabolite in the 38 patients in whom paired assessments of QTc were available. In addition, serial measurement of left ventricular ejection fraction (LVEF) after three cycles of treatment was performed in 28 patients. Seven patients experienced asymptomatic decreases of 10% in LVEF. However, the significance of these results and their relationship to CI-1040 remains unclear because of the lack of a control group. One additional patient experienced a symptomatic decrease in LVEF from 60% at baseline to 15%. It was felt that CI-1040 did not contribute to the decline in left ventricle function because the second evaluation was performed while the patient was undergoing treatment for sepsis in an intensive-care setting.
Visual changes characterized by transient blurring and altered light perception were reported by six patients. One of these patients had an abnormal retinal examination that subsequently returned to normal. The visual changes generally resolved within 1 day, except in one patient whose vision returned to normal after approximately 2 weeks. All patients resumed treatment without recurrence of visual symptoms. In addition to visual disturbances, transient periorbital edema was observed in nine patients. This toxicity has been described with other tyrosine kinase inhibitors.13
Dose Reductions
CI-1040–related toxicities in nine patients (13%) required dose reductions in 17 treatment courses (9%). Toxicities requiring dose reductions included increased bilirubin (two patients), increased lactate dehydrogenase, fatigue, intermittent heart palpitations, blurred vision, abdominal cramping with diarrhea, anemia, and transient ataxia of 1-day duration.
Antitumor Activity
No patient achieved a CR or PR. Eight patients achieved SD confirmed by computed tomography after completion of three cycles of treatment (one patient with breast cancer, two with colon cancer, two with pancreatic cancers, and three with NSCLC). The median duration of SD was 4.4 months (range, 4 to 18 months). The longest SD occurred in a 57-year-old male with NSCLC who had failed prior carboplatin and gemcitabine therapy. This patient was subsequently re-treated with CI-1040 after it was determined that his removal from the study because of disease progression was premature. His disease continued to remain stable while he received an additional 6 months of CI-1040 treatment under a single-patient, compassionate protocol. None of the tumor types studied achieved the prespecified response outcomes required to advance enrollment to stage 2, and thus, the null hypothesis was not rejected.
Plasma CI-1040 Concentration Monitoring
Analysis of CI-1040 plasma concentrations revealed a pattern of steady-state concentrations consistent with those of patients administered 800 mg bid in phase I studies (Fig 2). There was no apparent time-dependent change in steady-state concentrations of CI-1040.
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Fig 2. Plasma CI-1040 concentration by treatment cycle superimposed over the concentration profile generated from the phase I study.
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Biomarkers
A central issue in the development of targeted therapies is the activation status of the targeted pathway. It is expected that, to have a meaningful therapeutic effect, tumor cells must rely on the pathway targeted and, therefore, have evidence of signaling through that pathway. Thus, the presence of activated ERK is theoretically necessary but possibly not sufficient for inhibition of MEK to achieve antitumor effects. In addition, it is reasonable to surmise that the more highly activated the pathway, the more likely that the tumor relies on it and, therefore, the more likely that tumor may respond to inhibition with a single agent. Therefore, we determined the levels of activated ERK (pERK) in patients' archived pathology samples. The index level of 100 was specified in this study as the threshold level of pERK expression corresponding with constitutive activity (see Patients and Methods). As shown in Figure 3, immunohistochemical assessment of archived tumor specimens revealed that pERK expression was generally elevated in all four tumor types studied. Although less so, baseline pAkt levels were also generally elevated, and Ki-67 levels were variable. A logistic regression analysis on the probability of achieving SD showed a mildly predictive association with pERK expression (P < .055) in archived tumor specimens.
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Fig 3. Baseline pERK, pAkt, and Ki-67 expression by tumor type based on immunohistochemical assessment of archived, diagnostic tumor specimens collected for each patient. The index level specified for pERK as the minimum threshold for constitutive activity was 100 (102). (*), Baseline expression levels could not be assessed in one patient with colon cancer who achieved stable disease (SD).
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DISCUSSION
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This report describes the first efficacy results of an oral MEK inhibitor, CI-1040, in breast, colon, pancreatic, and NSCLC cancers, tumors in which constitutive pERK expression has been demonstrated and would be expected to play a role in tumor progression.7 OR was not observed in this study, and only eight patients achieved SD. Although plasma concentrations of CI-1040 were similar in both studies, the rate of SD achieved in this phase II study was less than that observed in the phase I study (12% v 28%, respectively). Moreover, among phase I patients with the same tumor types as those studied in phase II, nine (21%) of 42 patients achieved SD8 or PR.1 Although not statistically significant, this difference between response rates favoring the responses achieved in the more heavily pretreated phase I patients is anecdotally noteworthy and without explanation.
The antitumor response observed in this staged, phase II study was insufficient to advance enrollment to stage 2 for any of the four tumors studied. One might question whether the degree of pERK inhibition achieved in these patients was simply insufficient. In the phase I study, tumor pERK suppression of 50% or greater was observed in seven of 10 tumor specimens with constitutive pERK expression at baseline. Demonstration of target suppression at this level satisfied prespecified proof-of-mechanism criteria and supported further clinical development. However, pERK suppression by more than 90% was achieved in only three patients, thus raising the possibility that the degree of MEK inhibition achieved by CI-1040 may have been insufficient to achieve meaningful antitumor effects. Unfortunately, this phase II study was not designed to assess posttreatment changes in tumor pERK, and consequently, clinical outcome relative to the magnitude of pERK suppression cannot be assessed.
The safety profile of CI-1040 was well predicted by the phase I study. The 800-mg bid dose was well tolerated and appropriate based on the approximate 10% rate of dosage reductions required in this phase II study. Occasional dosing interruptions followed by dose adjustments were necessary for a variety of primarily nonhematologic toxicities. Continuous CI-1040 treatment exceeding 1 year was also well tolerated in this study without occurrence of cumulative toxicities.
Baseline tumor biopsies were not obtained for testing of pERK expression in this study. Instead, archived tumor specimens available from either an original diagnostic or, preferably, a more recent biopsy were assessed. Expression levels of pERK, pAkt, and Ki-67 were assessed in these specimens for investigation of possible associations with antitumor activity. Although inhibiting phosphatase activity is important when assessing fresh tumor specimens for pERK expression, the processing of these specimens predated this study by months to years. Therefore, it is possible that the assessment of pERK expression in the archived tumor specimens may underreport the true level of constitutive expression present at the time of original biopsy.
The archived tissue pERK levels for the majority of patients in each tumor type, except colon cancer, were generally above the threshold for constitutive activity specified in this study. Correlative analyses suggested an association between high pERK expression and the achievement of SD, which is consistent with the hypothesis that tumors in which the MEK pathway is more highly activated are more likely to respond to inhibition. Tumor pERK expression will be assessed in both archived and fresh tumor biopsy specimens with PD 0325901 to investigate how well the expression levels agree. Ki-67 and pAkt levels in archived tissues were not as commonly elevated, and they were not associated with achievement of SD.
In summary, although these phase II results with CI-1040 do not meet prespecified criteria to advance single-agent development, optimism remains concerning the antitumor potential of targeting kinases within the Ras-Raf-MEK-ERK mitogen-activated protein kinase pathway. Clinical development is currently underway with a second-generation MEK inhibitor, PD 0325901. This compound has markedly superior pharmacologic and biopharmaceutical properties, including a more than 50-fold increased potency against MEK, much improved oral bioavailability, and longer duration of target suppression. A phase I to II study is ongoing, with design elements that emphasize collection of pre- and posttreatment target levels relative to not only traditional pharmacokinetic parameters but also antitumor outcomes.
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Authors' Disclosures of Potential Conflicts of Interest
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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Oday Hamid, Pfizer; Mary Varterasian, Pfizer; Peggy Asbury, Pfizer; Eric P. Kaldjian, Pfizer; Stephen Gulyas, Pfizer; David Y. Mitchell, Pfizer; Roman Herrera, Pfizer; Judith S. Sebolt-Leopold, Pfizer; Mark B. Meyer, Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: Oday Hamid, Pfizer; Mary Varterasian, Pfizer; Peggy Asbury, Pfizer; Eric P. Kaldjian, Pfizer; Stephen Gulyas, Pfizer; David Y. Mitchell, Pfizer; Roman Herrera, Pfizer; Judith S. Sebolt-Leopold, Pfizer; Mark B. Meyer, Pfizer.
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Acknowledgment
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We thank the nurses for patient care and the data managers for study coordination.
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NOTES
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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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Submitted January 30, 2004;
accepted August 5, 2004.
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KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection
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March 1, 2009;
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[Abstract]
[Full Text]
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W. W. Ma and A. A. Adjei
Novel Agents on the Horizon for Cancer Therapy
CA Cancer J Clin,
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[Abstract]
[Full Text]
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O. K. Mirzoeva, D. Das, L. M. Heiser, S. Bhattacharya, D. Siwak, R. Gendelman, N. Bayani, N. J. Wang, R. M. Neve, Y. Guan, et al.
Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition
Cancer Res.,
January 15, 2009;
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[Abstract]
[Full Text]
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S. A. Danovi, H. H. Wong, and N. R. Lemoine
Targeted therapies for pancreatic cancer
Br. Med. Bull.,
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[Abstract]
[Full Text]
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M. A. Park, G. Zhang, C. Mitchell, M. Rahmani, H. Hamed, M. P. Hagan, A. Yacoub, D. T. Curiel, P. B. Fisher, S. Grant, et al.
Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
Mol. Cancer Ther.,
September 1, 2008;
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[Abstract]
[Full Text]
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K. S.M. Smalley, M. Lioni, M. D. Palma, M. Xiao, B. Desai, S. Egyhazi, J. Hansson, H. Wu, A. J. King, P. Van Belle, et al.
Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas
Mol. Cancer Ther.,
September 1, 2008;
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[Abstract]
[Full Text]
[PDF]
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J. Leyton, G. Smith, M. Lees, M. Perumal, Q.-d. Nguyen, F. I. Aigbirhio, O. Golovko, Q. He, P. Workman, and E. O. Aboagye
Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901
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September 1, 2008;
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[Abstract]
[Full Text]
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S. Wang, J. Jiang, Q. Guan, H. Wang, C. Y. C. Nguan, A. M. Jevnikar, and C. Du
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling
Am J Physiol Renal Physiol,
September 1, 2008;
295(3):
F672 - F679.
[Abstract]
[Full Text]
[PDF]
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M. Case, E. Matheson, L. Minto, R. Hassan, C. J. Harrison, N. Bown, S. Bailey, J. Vormoor, A. G. Hall, and J. A.E. Irving
Mutation of Genes Affecting the RAS Pathway Is Common in Childhood Acute Lymphoblastic Leukemia
Cancer Res.,
August 15, 2008;
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[Abstract]
[Full Text]
[PDF]
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J. S. Sebolt-Leopold
Advances in the Development of Cancer Therapeutics Directed against the RAS-Mitogen-Activated Protein Kinase Pathway
Clin. Cancer Res.,
June 15, 2008;
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[Abstract]
[Full Text]
[PDF]
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A. A. Adjei, R. B. Cohen, W. Franklin, C. Morris, D. Wilson, J. R. Molina, L. J. Hanson, L. Gore, L. Chow, S. Leong, et al.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers
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May 1, 2008;
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[Abstract]
[Full Text]
[PDF]
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T. Thalhamer, M. A. McGrath, and M. M. Harnett
MAPKs and their relevance to arthritis and inflammation
Rheumatology,
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47(4):
409 - 414.
[Abstract]
[Full Text]
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R. H. El-Maraghi and E. A. Eisenhauer
Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III
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March 10, 2008;
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1346 - 1354.
[Abstract]
[Full Text]
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H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al.
Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo
Mol. Cancer Ther.,
March 1, 2008;
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[Abstract]
[Full Text]
[PDF]
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A. Ocana and A. Pandiella
Identifying Breast Cancer Druggable Oncogenic Alterations: Lessons Learned and Future Targeted Options
Clin. Cancer Res.,
February 15, 2008;
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[Abstract]
[Full Text]
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B. B. Friday and A. A. Adjei
Advances in Targeting the Ras/Raf/MEK/Erk Mitogen-Activated Protein Kinase Cascade with MEK Inhibitors for Cancer Therapy
Clin. Cancer Res.,
January 15, 2008;
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[Abstract]
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M. Xing
BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications
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[Abstract]
[Full Text]
[PDF]
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M.-E. Legrier, C.-P. H. Yang, H.-G. Yan, L. Lopez-Barcons, S. M. Keller, R. Perez-Soler, S. B. Horwitz, and H. M. McDaid
Targeting Protein Translation in Human Non Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression
Cancer Res.,
December 1, 2007;
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[Abstract]
[Full Text]
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D. Liu, Z. Liu, D. Jiang, A. P. Dackiw, and M. Xing
Inhibitory Effects of the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 on the Proliferation and Tumor Growth of Thyroid Cancer Cells with BRAF or RAS Mutations
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[Abstract]
[Full Text]
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Y. Liu, J. Lagowski, A. Sundholm, A. Sundberg, and M. Kulesz-Martin
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November 15, 2007;
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[Abstract]
[Full Text]
[PDF]
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H. Hao, V. M. Muniz-Medina, H. Mehta, N. E. Thomas, V. Khazak, C. J. Der, and J. M. Shields
Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth
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August 1, 2007;
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[Abstract]
[Full Text]
[PDF]
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H. Ji, Z. Wang, S. A. Perera, D. Li, M.-C. Liang, S. Zaghlul, K. McNamara, L. Chen, M. Albert, Y. Sun, et al.
Mutations in BRAF and KRAS Converge on Activation of the Mitogen-Activated Protein Kinase Pathway in Lung Cancer Mouse Models
Cancer Res.,
May 15, 2007;
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4933 - 4939.
[Abstract]
[Full Text]
[PDF]
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A. Jimeno, B. Rubio-Viqueira, M. L. Amador, V. Grunwald, A. Maitra, C. Iacobuzio-Donahue, and M. Hidalgo
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March 1, 2007;
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[Abstract]
[Full Text]
[PDF]
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T. C. Yeh, V. Marsh, B. A. Bernat, J. Ballard, H. Colwell, R. J. Evans, J. Parry, D. Smith, B. J. Brandhuber, S. Gross, et al.
Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor
Clin. Cancer Res.,
March 1, 2007;
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[Abstract]
[Full Text]
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K. M. Haigis, I. I. Wistuba, and J. M. Kurie
Lung premalignancy induced by mutant B-Raf, what is thy fate? To senesce or not to senesce, that is the question
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[Full Text]
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G. F. Weber, F. C. Gaertner, W. Erl, K.-P. Janssen, B. Blechert, B. Holzmann, H. Weighardt, and M. Essler
IL-22-Mediated Tumor Growth Reduction Correlates with Inhibition of ERK1/2 and AKT Phosphorylation and Induction of Cell Cycle Arrest in the G2-M Phase
J. Immunol.,
December 1, 2006;
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[Abstract]
[Full Text]
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L. Chin, L. A. Garraway, and D. E. Fisher
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[Abstract]
[Full Text]
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B. Rubio-Viqueira, A. Jimeno, G. Cusatis, X. Zhang, C. Iacobuzio-Donahue, C. Karikari, C. Shi, K. Danenberg, P. V. Danenberg, H. Kuramochi, et al.
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J. P. Calvet
MEK Inhibition Holds Promise for Polycystic Kidney Disease
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K. S.M. Smalley, N. K. Haass, P. A. Brafford, M. Lioni, K. T. Flaherty, and M. Herlyn
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Y. Newbatt, S. Burns, R. Hayward, S. Whittaker, R. Kirk, C. Marshall, C. Springer, E. Mcdonald, Cancer Genome Project, R. Marais, et al.
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[Abstract]
[PDF]
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A. A. Adjei and M. Hidalgo
Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy
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[Abstract]
[Full Text]
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S. J. Cohen, R. B. Cohen, and N. J. Meropol
Targeting Signal Transduction Pathways in Colorectal Cancer--More Than Skin Deep
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[Abstract]
[Full Text]
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P. M. LoRusso, A. A. Adjei, M. Varterasian, S. Gadgeel, J. Reid, D. Y. Mitchell, L. Hanson, P. DeLuca, L. Bruzek, J. Piens, et al.
Phase I and Pharmacodynamic Study of the Oral MEK Inhibitor CI-1040 in Patients With Advanced Malignancies
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W. S. El-Deiry
Meeting Report: The International Conference on Tumor Progression and Therapeutic Resistance
Cancer Res.,
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[Abstract]
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I. M. Ghobrial, T. E. Witzig, and A. A. Adjei
Targeting Apoptosis Pathways in Cancer Therapy
CA Cancer J Clin,
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[Abstract]
[Full Text]
[PDF]
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H. M. McDaid, L. Lopez-Barcons, A. Grossman, M. Lia, S. Keller, R. Perez-Soler, and S. Band Horwitz
Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants
Cancer Res.,
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S. S. Sridhar, D. Hedley, and L. L. Siu
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M. J. Ratain and S. G. Eckhardt
Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST
J. Clin. Oncol.,
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[Full Text]
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TOP
ABSTRACT
INTRODUCTION
