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

Purpose:

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.

Patients and Methods:

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.

Results:

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%, P = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with PI3KCA wild-type versus PI3KCA-mutated group was 5 versus 3.7 months (P = 0.049). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), and TP53 (7%). The patient with the longest treatment duration (22 months) was PTEN wild-type, diploid PTEN with putative biallelic inactivation of ARID1A.

Conclusions:

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.

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