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

Authors' Affiliations: ¹ Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, Oregon; ² Helsinki University Central Hospital, Helsinki, Finland; ³ Harvard Medical School and Dana-Farber Cancer Institute; ⁴ Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts; ⁵ Hammersmith Hospital and Imperial College School of Medicine, London, United Kingdom; ⁶ Centre Hospitalier de l'Univesité de Montréal, Montreal, Canada; ⁷ Institute for Pathology; ⁸ Novartis Pharma AG; ⁹ University Hospital, Basel, Switzerland; ¹⁰ Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia; ¹¹ Peter MacCallum Cancer Institute, East Melbourne, Australia; and ¹² UZ Gasthuisberg Dienst Oncology, Leuven, Belgium

Requests for reprints: Michael C. Heinrich, Department of Hematology and Medical Oncology, Portland VA Medical Center, R&D-19, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239-3098. Phone: 503-220-3405; Fax: 503-273-5158; E-mail: heinrich{at}ohsu.edu.

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.

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