FDA Lifts Partial Clinical Hold on Trials Evaluating Azenosertib in Advanced Solid Tumors

FDA

The FDA has lifted the partial clinical hold previously placed on studies evaluating the WEE1 inhibitor azenosertib in patients with advanced solid tumors.¹

In June 2024, the regulatory agency issued the partial clinical hold on the phase 1 ZN-c3-001 trial (NCT04158336) for patients with advanced solid tumors, the phase 2 DENALI trial (NCT05128825) for patients with platinum-resistant ovarian cancer, and the phase 2 TETON trial (NCT04814108) for patients with uterine serous carcinoma.² The decision stemmed from 2 deaths due to presumed sepsis reported in patients being treated in the DENALI trial.

After reviewing the complete response package from Zentalis Pharmaceuticals, the developer of azenosertib, the FDA cleared the studies to resume enrollment in all ongoing studies of the agent without any changes to the clinical development plan.¹

"We are grateful to the FDA for their collaboration and review of our complete response package, which included a comprehensive safety assessment of the azenosertib program,” Kimberly Blackwell, MD, chief executive officer of Zentalis Pharmaceuticals, stated in a news release. “We are extremely pleased with the successful resolution of the partial clinical hold. Our confidence in the therapeutic index of azenosertib has been unwavering, and we continue to believe in the potential for this treatment to address unmet medical needs faced by people living with gynecologic malignancies.”

By inhibiting WEE1, azenosertib is intended to enable cell cycle progression to facilitate the accumulation of DNA damage, leading to mitotic catastrophe and cancer cell death.

The agent is being investigated as both monotherapy and in combination therapy. Additional data for azenosertib are anticipated in the fourth quarter of 2024.

ZN-c3-001

ZN-c3-001 is a phase 1, open-label, multicenter, dose-escalation and -expansion study investigating azenosertib as monotherapy for the treatment of patients with advanced solid tumors.³ Prior data demonstrated that patients with platinum-resistant or refractory ovarian cancer and uterine serous carcinoma (n = 19) experienced an objective response rate (ORR) of 37% and a median progression-free survival (PFS) of 6.5 months.⁴

The study is enrolling patients at least 18 years of age with an ECOG performance status of 0 to 2 and adequate hematologic and organ function.³ Participants were required to have advanced or metastatic solid tumors with measurable or evaluable disease per RECIST 1.1 criteria refractory to standard therapy or had no standard therapy available to be eligible for the dose-escalation portion of the trial. In dose expansion, patients need to have recurrent or persistent uterine serous carcinoma, or a locally advanced or metastatic malignancy with one or more relevant biomarkers related to DNA damage pathways.

Identifying the maximum tolerated dose and recommended phase 2 dose, based on the rates of adverse effects (AEs) and dose-limiting toxicities, served as the primary end point in dose escalation. In dose expansion, ORR was the primary end point.

DENALI

The phase 2, open-label, multicenter DENALI study is including patients at least 18 years of age with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer that is platinum resistant. One to 4 prior lines of therapy that include a bevacizumab (Avastin)-containing regimen are required. In part 1b of the study, 1 to 5 prior lines of therapy are permitted allowed. Measurable disease per RECIST 1.1 criteria and adequate hematologic and organ function are also necessary.⁵

The frequency and severity of treatment-emergent AEs; incidence of dose modifications; and ORR per RECIST 1.1 criteria as assessed by an independent review committee are the trial. Secondary end points included duration of response, PFS, clinical benefit rate, and time to response.

TETON

The open-label, multicenter study is evaluating azenosertib in patients at least 18 years of age with histologically confirmed recurrent or persistent uterine serous carcinoma without available effective therapies or intolerance to available standard-of-care treatments. Patients with endometrial carcinoma of mixed histology are allowed to participate if the serous component comprises at least 5% of the tumor. Those with carcinosarcomas are not eligible, even in the presence of a serous component.⁶

Prior treatment requirements include a platinum-based chemotherapy regimen and a PD-1 or PD-L1 inhibitor. At least 1 HER2-targeted therapy is required for patients with HER2-positive tumors. Other key inclusion criteria included measurable disease per RECIST 1.1 criteria and adequate hematologic and organ function.

The end points for TETON mirror the DENALI objectives.

References

1. Zentalis Pharmaceuticals announces FDA has lifted partial clinical hold on azenosertib studies. News release. Zentalis Pharmaceuticals. September 16, 2024. Accessed September 16, 2024. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-announces-fda-has-lifted-partial
2. Zentalis Pharmaceuticals provides update on azenosertib clinical development program. News release. Zentalis Pharmaceuticals. June 18, 2024. Accessed September 16, 2024. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-provides-update-azenosertib-clinical
3. A study of ZN-c3 in participants with solid tumors. ClinicalTrials.gov. Updated February 1, 2023. Accessed September 16, 2024. https://clinicaltrials.gov/study/NCT04158336
4. Zentalis Pharmaceuticals reports third quarter 2023 financial results and operational updates. News release. Zentalis Pharmaceuticals. November 6, 2023. Accessed September 16, 2024. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-reports-third-quarter-2023-financial
5. A study of ZN-c3 in subjects with high-grade serous ovarian, fallopian tube or primary peritoneal cancer. ClinicalTrials.gov. Updated June 25, 2024. Accessed September 16, 2024. https://clinicaltrials.gov/study/NCT05128825
6. A study of ZN-c3 in women with recurrent or persistent uterine serous carcinoma. ClinicalTrials.gov. Updated June 25, 2024. Accessed September 16, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04814