A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium.

Abstract

Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA^- vs. ARID1A⁺; 33% vs. 12%, <i>P</i> = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with <i>PI3KCA</i> wild-type versus <i>PI3KCA</i>-mutated group was 5 versus 3.7 months (<i>P</i> = 0.049). Molecular profiling showed variants in <i>PI3KCA</i> (27%), <i>ARID1A</i> (26%), and <i>TP53</i> (7%). The patient with the longest treatment duration (22 months) was <i>PTEN</i> wild-type, diploid PTEN with putative biallelic inactivation of <i>ARID1A</i>. Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.