Open label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: The Greko II study.

Abstract

5577 Background: Granulosa-cell tumors (GCT) of the ovary are a rare entity characterized by presenting a punctual mutation at the FOXL2 gene 402C→G (C134W). Such mutation leads to a disregulation and overstimulation of the steroidogenic pathway and, ultimately, hormone overproduction. A prior trial by our group (GREKO I trial-GETHI 2011-03; NCT01584297) showed promising activity of ketoconazole, a CYP17 inhibitor used to control steroidogenesis in several conditions. Thus, we aimed to assess the activity of Orteronel (TAK700), a selective inhibitor of 17, 20-lyase, in GCT. Methods: An open-label phase II single arm clinical trial was designed for women with metastatic or locally advanced non-resectable GCT who harbored the somatic mutation FOXL2 402C→G (C134W) and who had not received prior treatment with any CYP17 inhibitor. Treatment consisted on Orteronel 300mg BID, given orally, continuously in a 28-day treatment cycle. The primary objective was clinical benefit rate; secondary objectives were response rate, progression free and overall survival, assessment of the impact of Orteronel in reducing hormonal overproduction and toxicity. Sample size calculation was based on a two stage Simon´s design. A power of 80% was set to differentiate between a 5% and a 25% clinical benefit rate. 20% of losses had been assumed thus 20 patients were scheduled to be enrolled. Results: Since 30/06/2014 to 11/01/2017 10 patients have been included in 9 participating institutions members of Spanish Group for Research in Orphan and Unfrequent Tumors (GETHI). Due to a low recrutiment rate the study was terminated early. Median PFS was 3 months 95%CI (0-12) with 3 patients achieving disease stabilization longer than 12 months. 2 patients remain on treatment after 16 and 14 months. Clinical benefit rate (CR + PR + SD) was 50%, 95%CI (19%-81%). Seven patients have progressed and 2 have died. Only 6 suspected unresected adverse reactions (SUSARs) have been communicated so far (chest pain, fever, febrile neutropenia, eosinophila, neutropenia and anemia). Conclusions: Orteronel achieved a significant clinical benefit in advanced GCT with an favorable toxicity profile. Clinical trial information: NCT02101684.