“A Phase III, double blind, randomized, placebo-controlled trial of sorafenib in desmoid tumors or aggressive fibromatosis (DT/DF).”

First year of two-year project for correlative research to define novel biomarkers of response in desmoid tumors treated with sorafenib. Desmoid tumors (DT/DF) are clonal connective tissue malignancies of fibroblastic origin. DT/DF lack metastatic potential however, can cause significant morbidity, loss of function and pain through mass effects. Mortality from DT/DF results from local infiltration of vital structures. There is no standard of care for the treatment of DT/DF. Surgery is curative however associated with high recurrences. In unresectable patients, systemic therapies range from anti-estrogens to cytotoxic chemotherapies. DT/DF over express c-KIT and PDGFR and a Phase II study of imatinib showed a partial response (PR) of 6%. Sorafenib is a multi-target kinase inhibitor of b-Raf, PDGFR and VEGFR and available through an expanded access program. We treated an index patient with recurrent, unresectable DT/DF with sorafenib. A PR and clinical benefit prompted us to evaluate our experience of sorafenib in 26 patients. We noted a 25% PR by RECIST 1.1 and improvement of symptoms in 70% of patients. We noted a 30% decrease in the MRI T2 signal in 90% of patients with extra-abdominal disease. We hypothesize that sorafenib will lead to improved response rates, symptoms and progression free survival (PFS) in DT/DF patients. This is a multicenter, Phase III, randomized, double-blind, placebo-controlled trial of sorafenib in DT/DF patients. The primary endpoint is to evaluate overall response rates (ORR) for patients treated with sorafenib versus those treated with placebo. This study will enroll 126 patients over 2 years and will have a 90% power to detect a 22% increase in response rates (1-sided a=0.05). The secondary endpoints are 1) PFS and 2) pain palliation by the Brief Pain Inventory scale (BPI). Patients on placebo will cross over to sorafenib. Explorative studies include pre- and post-treatment biopsies in responding patients to determine biomarkers of response and mechanism of action of sorafenib. Decrease in MRI T2 signal may be an early marker of RECIST response and may be a more sensitive imaging marker for clinical benefit than RECIST response. We will conduct an explorative study a novel imaging biomarker by correlating changes in T2 signal to RECIST response and clinical benefit by pain palliation.