Phase 1/1b Trial Evaluating the Safety and Efficacy of BET Inhibitor, ZEN003694 with PD-1 Inhibitor, Nivolumab with or without CTLA-A Inhibitor, Ipilimumab in Platinum Resistant Ovarian Cancer
Abstract
Chemoresistance is a major cause of high mortality in patients with high-grade serous ovarian carcinoma (HGSOC). These tumors initially respond to platinum-based chemotherapy, but often relapse with decreased chemotherapeutic sensitivity. Cancer stem-like cells (CSCs) have been shown to contribute to chemotherapy resistance. Epithelial ovarian cancer (EOC) CSCs are characterized by increased aldehyde dehydrogenase (ALDH) activity due to upregulation of the ALDH1A1 gene. Preclinical work showed that suppression of ALDH activity by ALDH1A1 knock-down sensitizes EOC cells to chemotherapy, demonstrating the functional importance of ALDH activity in EOC chemoresistance. We have also shown that BRD4 (BET) inhibition reduces ALDH activity, thereby eradicating CSCs. The mechanism of suppression of ALDH activity is through downregulation of the ALDH1A1 super-enhancer associated non-coding enhancer RNAs (eRNAs).Notably, BRD4 genomic locus 19p13.12 is often amplified in HGSOC (tilde 20 percent), and amplification/overexpression correlates with poor prognosis. Therefore, we hypothesize that BRD4/BET inhibition may overcome chemotherapy resistance and plan a phase I clinical trial to evaluate combination of BET inhibitor INCB57643 (Incyte, Inc.) with carboplatin to establish MTD, tolerability, and preliminary efficacy of the combination. We propose embedded correlative science to identify populations most likely to respond to therapy. Our central hypothesis is that platinum resistance can be overcome by eliminating ALDH positive CSCs by targeting BRD4 through BET inhibition. The goals of the proposal are: 1) To conduct a Phase I clinical trial of combined BET inhibitor (INCB57643) and carboplatin in patients with platinum-resistant HGSOC. 2) To identify companion biomarkers that correlate with response to combination therapy in HGSOC patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1223417
Entities
People
- Alessandro Gardini
- Rugang Zhang
Organizations
- University of Pennsylvania