SUN-348 Cabozantinib in Advanced Adrenocortical Carcinoma: Rationale and Protocol of Two Phase II Clinical Trials

BACKGROUND: Median overall survival (OS) in advanced adrenocortical (ACC) is only 12-15 months. Mitotane and chemotherapy are the backbones of current treatment but prolonged disease stabilization is rare. Cabozantinib (CABO) is an oral multi-kinase inhibitor (MKI) of c-MET, VEGFR2, AXL, and RET. OBJECTIVE: To report the rationale and design of phase II clinical trials of CABO in advanced ACC RESULTS: Inactivation of the HGF/c-MET axis decreased proliferation of ACC cells in vitro and in mouse xenografts. VEGFR2 inhibition with sunitinib decreased ACC cell proliferation and impaired steroidogenesis in vitro. CABO target molecules c-MET and VEGFR2 and their ligands HGF and VEGF, respectively are overexpressed in ACC tissue. Unsatisfactory efficacy of tyrosine kinase inhibitors in previous clinical trials was caused in part by drug interaction with mitotane, a strong CYP3A4 inducer. In 12 patients treated with CABO off label there were 2 partial responses and we observed progression-free survival at 4 months (PFS4) in 4/12 patients. Two parallel single center phase II trials of CABO in advanced ACC are recruiting in the U.S. (NCT03370718) and Germany (NCT03612232) and will accrue 18 and 37 patients, respectively. Mitotane discontinuation and plasma concentrations <2&nbsp;mg/L prior study treatment are mandatory. The primary endpoint is PFS4. Secondary endpoints include overall survival, best objective response rate, adverse events and quality of life. Markers of treatment response, immune modulation and pharmacokinetics will be studied. CONCLUSION: Two parallel trials will clarify if CABO is a promising therapeutic approach in advanced ACC while controlling for drug interaction with mitotane.