The FDA has lifted the partial clinical hold on studies evaluating azenosertib, a WEE1 inhibitor developed by Zentalis Pharmaceuticals, in patients with advanced solid tumors. This decision allows the phase 1 ZN-c3-001 trial, the phase 2 DENALI trial for platinum-resistant ovarian cancer, and the phase 2 TETON trial for uterine serous carcinoma to resume enrollment.
The partial clinical hold was initially implemented in June 2024 following two reported deaths due to presumed sepsis in patients participating in the DENALI trial. After a thorough review of Zentalis Pharmaceuticals' complete response package, the FDA cleared the studies to proceed without any modifications to the clinical development plan.
Azenosertib's Mechanism and Clinical Development
Azenosertib functions by inhibiting WEE1, a kinase that regulates the cell cycle. By blocking WEE1, azenosertib promotes cell cycle progression, leading to the accumulation of DNA damage, mitotic catastrophe, and ultimately, cancer cell death. The drug is under investigation as both a monotherapy and in combination with other agents.
Kimberly Blackwell, MD, CEO of Zentalis Pharmaceuticals, expressed gratitude for the FDA's collaboration and review, stating, "We are extremely pleased with the successful resolution of the partial clinical hold...we continue to believe in the potential for this treatment to address unmet medical needs faced by people living with gynecologic malignancies."
Trial Details
ZN-c3-001: This phase 1 trial is an open-label, multicenter study evaluating azenosertib monotherapy in advanced solid tumors. Prior data showed a 37% objective response rate (ORR) and a median progression-free survival (PFS) of 6.5 months in patients with platinum-resistant or refractory ovarian cancer and uterine serous carcinoma (n = 19).
DENALI: The phase 2 DENALI trial is an open-label, multicenter study involving patients with platinum-resistant high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Participants must have received one to four prior lines of therapy, including a bevacizumab-containing regimen. The trial's primary end point is ORR as assessed by an independent review committee.
TETON: The TETON trial is an open-label, multicenter study assessing azenosertib in patients with recurrent or persistent uterine serous carcinoma who lack effective therapies or cannot tolerate standard-of-care treatments. Prior treatment must include a platinum-based chemotherapy regimen and a PD-1 or PD-L1 inhibitor, with HER2-targeted therapy required for HER2-positive tumors. The primary and secondary endpoints mirror those of the DENALI trial.
