Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases

Abstract

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 z15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinibsensitive 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 imatinibsensitive 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.

Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation

“…1 Only few c-Kit mutations have been reported to clinically respond to imatinib therapy (eg, p.Asp816Thr, p.Lys509Ile, p.Phe522Cys, p.Val560Gly, p.Asp419del). [18][19][20][21][22] KIT mutation analysis in our patient yielded not only a somatic p.Asp419del mutation but also a novel germ line p.Ser840Asn substitution in the intracellular kinase domain of the receptor. The boy had inherited the mutation from his father; his siblings were not affected.…”

Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma

“…This drug is approved for the treatment of chronic myelogenous leukemia and GIST, and is being evaluated in clinical trials for the treatment of melanomas harboring KIT mutations (16)(17)(18)(19)(20)(21)(22). KIT is a validated therapeutic target in GIST, with a large percentage of patients bearing KIT mutant tumors benefiting from imatinib and second-generation KIT inhibitors (16,17).…”

The use of imatinib in the treatment of inoperable dermatofibrosarcoma protuberans in the area of the shoulder joint

“…A median overall survival was not reached. Translocation (17:22) [(q22:q13)] or its gene product was present in almost all patients who responded to treatment with imatinib [9][10][11][12].…”