Phase II study of dovitinib in first line metastatic or (non resectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.

Abstract

4588 Background: Dovitinib is a novel targeted therapy that inhibits the fibroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical activity in this tumor. Methods: A phase II proof of concept trial was designed. Based on a two-stage Gehan model 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 centrally assessed. Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. A translational substudy looking for biomarkers of efficacy was also scheduled. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) were included. Median age was 53 years (range 26–72); ECOG was 0–1 in 15 patients, 2 in one patient and N/A in one patient. Grade 3–4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%),hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). No toxic death was reported. After a median follow-up of 5.2 months (range 2.27–21) one partial response has been observed. Median PFS was 1.8 months (95%CI [1.35–2.25]), however clinical benefit has been achieved in 30% of patients with long lasting stable disease (>6 months) in 23%. One patient remains on dovitinib 21 months after initiating therapy. We sequenced 409 tumor suppressor genes and oncogenes frequently mutated in cancer (Ion AmpliSeq Comprehensive Cancer Panel) in 9 FFPE tumor samples. Putative variants are currently being validated by Sanger sequencing and will presented at the meeting. Conclusions: Though primary endpoint was not reached, dovitinib showed activity in a subpopulation of ACC patients. The ongoing molecular identification of such subpopulation will be key in order to prompt further investigation. Clinical trial information: NCT01514526.