Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases
| Autor: | Michael Heinrich, Denis Soulières, Zariana Nikolova, Jonathan A. Fletcher, Stephan Dirnhofer, and Grant McArthur, Shane G. Supple, Ajia Town, John F. Seymour, Heikki Joensuu, Allan T. van Oosterom, George D. Demetri, Jane F. Apperley, Amy Harlow, Arin McKinley, Lilla Di Scala, Christopher L. Corless, Richard Herrmann |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Receptor Platelet-Derived Growth Factor alpha Antineoplastic Agents Kaplan-Meier Estimate Piperazines Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences 0302 clinical medicine Myeloproliferative Disorders Neoplasms medicine Dermatofibrosarcoma protuberans Humans Systemic mastocytosis 030304 developmental biology 0303 health sciences Hypereosinophilic syndrome business.industry Imatinib Protein-Tyrosine Kinases medicine.disease 3. Good health Proto-Oncogene Proteins c-kit Pyrimidines Imatinib mesylate Oncology Hematologic Neoplasms 030220 oncology & carcinogenesis Benzamides Mutation Immunology Aggressive fibromatosis Imatinib Mesylate Cancer research business Tyrosine kinase medicine.drug |
| Zdroj: | Clinical Cancer Research. 14:2717-2725 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-07-4575 |
| Popis: | Purpose: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases. Experimental Design: This was a phase II, open-label, single arm study. Patients ≥15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point. Results: One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response. Conclusion: Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment. |
| Databáze: | OpenAIRE |
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