FDA Places Partial Clinical Holds on 3 Trials Evaluating Azenosertib in Advanced Solid Tumors

The FDA has placed partial clinical holds on trials evaluating azenosertib (ZN-c3), including 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.¹

The clinical holds were initiated following 2 deaths due to presumed sepsis reported in patients being treated in the DENALI trial.

“Patient safety is our top priority and any deaths that occur in the setting of clinical trials are unfortunate. We are working closely with the FDA to resolve this partial clinical hold as quickly as possible,” Kimberly Blackwell, MD, chief executive officer of Zentalis Pharmaceuticals, stated in a news release.

“Over 500 patients have been treated with azenosertib monotherapy to date, and we believe that our data indicate a favorable therapeutic index that could potentially offer meaningful benefits to women facing platinum-resistant ovarian cancer and uterine serous carcinoma,” Blackwell continued. “We have completed enrollment for cohort 1b of the DENALI study, where we’ve enrolled more than a hundred patients, further demonstrating the support we’ve seen for having a novel oral therapy like azenosertib. We look forward to sharing these results along with overall efficacy and safety data from DENALI cohort 1b later this year.”

Azenosertib is a potentially first-in-class and best-in-class, small molecule WEE1 inhibitor. Inhibiting WEE1 pushes cancer cells into mitosis without the ability to repair damaged DNA, leading to cell death.²

ZN-c3-001

The phase 1, open-label, multicenter, dose-escalation and -expansion study is evaluating azenosertib monotherapy in patients with advanced solid tumors.3 Previously reported data for patients with platinum-resistant or refractory ovarian cancer and uterine serous carcinoma (n = 19) showed that azenosertib elicited an objective response rate (ORR) of 37% and a median progression-free survival (PFS) of 6.5 months. Safety data showed that the agent’s toxicity and tolerability profile was similar to or better than approved ovarian cancer treatments.⁴

The study was enrolling patients at least 18 years of age with an ECOG performance status of 0 to 2, as well as adequate hematologic and organ function.3 During dose escalation, patients were required to have advanced or metastatic solid tumors that were refractory to standard therapy or had no standard therapy available. Measurable or evaluable disease per RECIST 1.1 criteria was also necessary for enrollment.

In the dose expansion phase, investigators were enrolling patients with recurrent or persistent uterine serous carcinoma, or a locally advanced or metastatic malignancy with one or more relevant biomarkers related to DNA damage pathways. These patients needed to have measurable disease per RECIST 1.1 criteria.

Exclusion criteria for all patients included prior treatment with azenosertib or any WEE1 inhibitor; any serious illness or medical conditions; and any unresolved grade 2 or higher toxicities from prior therapies other than grade 2 or lower neuropathy, alopecia, or skin pigmentation.

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

DENALI

The phase 2, open-label, multicenter DENALI study was enrolling patients at least 18 years of age with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had platinum-resistant disease and received 1 to 4 prior lines of therapy that included a bevacizumab (Avastin)-containing regimen. In part 1b of the trial, 1 to 5 prior lines of therapy was allowed. Patients also needed to have measurable disease per RECIST 1.1 criteria and adequate hematologic and organ function.⁵

Patients were excluded from the study if they received major surgery within 28 days of enrollment; any chemotherapy or targeted therapy within 14 days or 5 half-lives of enrollment; radiation therapy within 21 days of enrollment; autologous or allogeneic stem cell transplant within 3 months of enrollment; or any other investigational drug therapy within 28 days or 5 half-lives of enrollment. Prior treatment with azenosertib or any other WEE1 inhibitor, an ATR inhibitor, or a CHK1/2 inhibitor was not allowed.

The primary end points of the study were 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. Secondary end points included duration of response, PFS, clinical benefit rate, and time to response.

TETON

The open-label, multicenter study was enrolling patients at least 18 years of age with histologically confirmed recurrent or persistent uterine serous carcinoma who had no other effective therapies available, or who refused or were intolerant to any available standard-of-care treatments. Notably, the study included patients with endometrial carcinoma of mixed histology if the serous component comprised at least 5% of the tumor, and patients with carcinosarcomas were not eligible even if a serous component was present.⁶

Prior treatment requirements included a platinum-based chemotherapy regimen and a PD-1 or PD-L1 inhibitor. Patients with HER2-positive tumors also needed to have prior treatment with at least 1 HER2-targeted therapy. Other key inclusion criteria included measurable disease per RECIST 1.1 criteria, as well as adequate hematologic and organ function.

The key exclusion criteria for TETON mirrored the DENALI exclusion criteria regarding prior treatments leading up to enrollment, as did the trial’s primary and secondary end points.

References

1. Zentalis Pharmaceuticals provides update on azenosertib clinical development program. News release. Zentalis Pharmaceuticals. June 18, 2024. Accessed June 19, 2024. https://ir.zentalis.com/news-releases/news-release-details/zentalis-pharmaceuticals-provides-update-azenosertib-clinical
2. Our pipeline. Zentalis Pharmaceuticals. Accessed June 19, 2024. https://www.zentalis.com/pipeline/pipeline#azenosertib
3. 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 June 19, 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 18, 2024. Accessed June 19, 2024. https://clinicaltrials.gov/study/NCT05128825
6. A study of ZN-c3 in women with recurrent or persistent uterine serous carcinoma. ClinicalTrials.gov. Updated May 3, 2024. Accessed June 19, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04814108