NEW YORK – Zenith Epigenetics and Bristol Myers Squibb on Tuesday said they've dosed the first patient in a Phase I/Ib trial evaluating ZEN-3694 plus BMS' checkpoint inhibitors Opdivo (nivolumab) and Yervoy (ipilimumab) in solid tumors that are resistant to other therapies.
Once dosing of the combination regimens have been identified, the trial will expand to enroll ovarian cancer patients who have progressed on platinum-based chemotherapy. In the trial, researchers will also evaluate how ZEN-3694 affects the tumor microenvironment and explore predictors of response and resistance to therapy.
The companies will measure several response and resistance biomarkers in patients over the course of the study. They will use whole-exome sequencing to evaluate patients' CCNE1, MYC, and BRD4 status; microsatellite instability status and tumor mutational burden; deficiencies in B2M and MHC1; and alterations in DNA damage repair pathways. They will use RNA sequencing to measure functional CCNE1, MYC, BRD4 gene expression status and assess immune markers and signatures. They will also test patients' immune and tumor cells for PD-L1 expression.
Haider Mahdi, a principal investigator in the trial and a medical oncologist at University of Pittsburgh Medical Center, said in a statement that researchers expect the triple combination to be effective in MYC- and BRD4-amplified ovarian cancer. ZEN-3694, a BET inhibitor, has also shown in preclinical studies to enhance the activity of checkpoint inhibitors, Mahdi noted.
Zenith, based in Calgary, Alberta, is also studying ZEN-3694 in combination with Astellas and Pfizer's Xtandi (enzalutamide) in metastatic castration-resistant prostate cancer, in combination with Pfizer's PARP inhibitor Talzenna (talazoparib) in triple-negative breast cancer, and in combination with Xtandi and Merck's Keytruda (pembrolizumab) in prostate cancer.