Demetri, G. D., Heinrich, M. C., Fletcher, J. A., Fletcher, C. D., 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. (September 2009) Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. Clin Cancer Res, 15 (18). pp. 5902-9. ISSN 1078-0432 (Print)1078-0432 (Linking)
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 [18F]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 > or =6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adult Aged Benzamides Cell Proliferation/drug effects Dose-Response Relationship, Drug Drug Administration Schedule Female Fluorodeoxyglucose F18 Gastrointestinal Stromal Tumors/*diagnosis/*drug therapy/secondary Humans Imatinib Mesylate Indoles/*administration & dosage/pharmacology/*therapeutic use Male Middle Aged Piperazines/administration & dosage/pharmacology/*therapeutic use *Positron-Emission Tomography Proto-Oncogene Proteins c-kit/antagonists & inhibitors Pyrimidines/administration & dosage/pharmacology/*therapeutic use Pyrroles/*administration & dosage/pharmacology/*therapeutic use Treatment Failure |
| Subjects: | diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | 15 September 2009 |
| Date Deposited: | 25 Oct 2016 20:22 |
| Last Modified: | 25 Oct 2016 20:22 |
| PMCID: | PMC3417101 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33696 |
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