Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure Journal Article
| Authors: | Demetri, G. D.; Heinrich, M. C.; Fletcher, J. A.; Fletcher, C. D. M.; Van Den Abbeele, A. D.; Corless, C. L.; Antonescu, C. R.; George, S.; Morgan, J. A.; Chen, M. H.; Bello, C. L.; Huang, X.; Cohen, D. P.; Baum, C. M.; Maki, R. G. |
| Article Title: | Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure |
| Abstract: | Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/ intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [<sup>18</sup>F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [<sup>18</sup>F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. © 2009 American Association for Cancer Research. |
| Keywords: | adult; cancer chemotherapy; human tissue; protein phosphorylation; treatment response; aged; middle aged; treatment failure; major clinical study; clinical trial; drug activity; fatigue; paresthesia; sunitinib; diarrhea; drug dose comparison; drug safety; drug withdrawal; hypertension; recommended drug dose; side effect; treatment duration; cancer patient; nuclear magnetic resonance imaging; positron emission tomography; anorexia; cell proliferation; gastrointestinal stromal tumor; imatinib; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; metastasis; computer assisted tomography; multiple cycle treatment; neutrophil count; phase 2 clinical trial; anemia; nausea; stomatitis; vomiting; drug administration schedule; creatinine blood level; hemoglobin blood level; tumor biopsy; antineoplastic activity; dose-response relationship, drug; diagnostic imaging; pyrimidines; abdominal pain; drug dose escalation; hair color; drug fatality; thorax pain; heart infarction; pancreatitis; fluorodeoxyglucose f 18; fluorodeoxyglucose f18; positron-emission tomography; clinical evaluation; tumor cell; taste disorder; limb pain; open study; skin discoloration; dermatitis; headache; phase 3 clinical trial; drug blood level; leukocyte count; phase 1 clinical trial; piperazines; hypothyroidism; indoles; pyrroles; antithyroid agent; amylase blood level; drug dose regimen; drug treatment failure; dyspepsia; flatulence; glossodynia; hand foot syndrome; heart left ventricle ejection fraction; st segment; triacylglycerol lipase blood level |
| Journal Title: | Clinical Cancer Research |
| Volume: | 15 |
| Issue: | 18 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-09-15 |
| Start Page: | 5902 |
| End Page: | 5909 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-09-0482 |
| PUBMED: | 19737946 |
| PROVIDER: | scopus |
| PMCID: | PMC3417101 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus" |
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