Phase II study of dovitinib (TKI258) in patients with progressive metastatic adenoid cystic carcinoma.

Abstract

6021 Background: Adenoid cystic carcinoma (ACC) is an uncommon malignancy of secretory glands for which there is no standard systemic therapy. At least 90% of ACC tumors carry a t(6;9)(q22–23;p23–24) chromosome translocation that results in overexpression of the MYB oncogene that in turn upregulates FGF2 and other growth factors. Dovitinib is a multiple receptor kinase inhibitor that could potentially block autocrine activation of the FGFR and VEGFR-mediated angiogenesis. In a mouse model, dovitinib suppressed the growth of low passage ACC xenografts. Methods: In this open-label, single-arm trial, patients (n=21) with metastatic ACC that progressed in the last 6 months were treated with dovitinib 500 mg/d, 5-days on/2-days off. The primary endpoint was objective response rate using a two-stage design to test a null and alternative rate of 1% and 18%, respectively, with 90% power and type I error <5%. Secondary endpoints were progression-free survival, safety, quality of life, biomarker studies, and change in tumor growth rate. Results: All 21 patients (median age 54.3, range 29-74) had previous treatment with chemotherapy, radiotherapy or targeted agents. Median duration of treatment to date is 5.7 months (range 2-10 months) and is ongoing in 11 patients. Nine of 21 patients required dose reductions. Grade 3/4 drug-related adverse events included thromboembolism (4), hematuria (1), dehydration (1), pneumonia (2), hypertriglyceridemia (3), diarrhea (2), stomach pain (2), anxiety (1), transaminitis (3) and cytopenias (4). One death occurred unrelated to study drug. Among 19 evaluable patients, 2 had partial responses by RECIST criteria (1 with lung metastases and 1 with tracheal recurrence and stable bone metastases). Both experienced improvements in pain ratings and are free of disease progression at 8+ and 5+ months. Stable disease >6 months was observed in 9 patients while 6 others with shorter follow-up have not progressed. Four patients progressed early (<4 months) and two are too early to assess. Conclusions: Dovitinib produces objective partial responses and prolonged tumor stabilization with acceptable toxicity in patients with progressive ACC. Clinical trial information: NCT01524692.