FDA Places Partial Holds on 3 Trials for Solid Tumor Treatment, Azenosertib

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06/28/2024

Two deaths due to presumed sepsis in patients treated in the DENALI trial led to the clinical holds on the advanced solid tumor treatment.

The FDA has placed partial clinical holds on the phase 1 ZN-c3-001 study (NCT04158336), phase 2 DENALI trial (NCT05128825), and phase 2 TETON trial (NCT04814108) assessing efficacy of azenosertib (ZN-c3) in patients with solid tumors, platinum-resistant ovarian cancer, and uterine serious carcinoma, respectively, according to a news release from the developer, Zentalis Pharmaceuticals, Inc.1

Two fatalities due to presumed sepsis within the phase 2 DENALI trial led to the clinical holds, impacting further development of the treatment.

“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 at Zentalis, said in the press release.1 “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 [patients with platinum-resistant ovarian cancer and uterine serous carcinoma]. 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 undergoing evaluation as a monotherapy and in combination regimens as a potentially first-in-class WEE1 inhibitor for advanced solid tumors and hematologic cancers.

Phase 1 ZN-c3-001 Trial

The phase 1 open-label, multicenter ZN-c3-001 study is evaluating azenosertib monotherapy in patients with solid tumors.2 Data reported for patients with heavily pretreated platinum-resistant ovarian cancer and uterine serous carcinoma (n = 19) show that azenosertib produced an objective response rate (ORR) of 36.8% and a median progression-free survival (PFS) of 6.5 months (95% CI, 2.79-6.87), as well as a superior safety and tolerability profile compared with other anti-cancer agents.3

Primary end points for this trial include the safety and tolerability of azenosertib, including identification of the maximum tolerated dose and recommended phase 2 dose, as well as the incidence and severity of adverse effects (AEs) and dose-limiting toxicities (DLTs), dose escalation time, pharmacokinetics (PK), and dose expansion.2 The secondary end points are ORR, electrocardiogram intervals (QTc Interval), duration of response (DOR), PFS, and clinical benefit rate (CBR).

Inclusion criteria included adults with an ECOG performance status of 2 or less with adequate hematologic and organ function, with female patients of childbearing potential and male patients agreeing to use effective contraception for 6 months and 90 days, respectively, after the last dose of azenosertib. Additionally, for the dose escalation phase, patients with solid tumors and advanced or metastatic disease were selected. Furthermore, for the dose expansion phase, patients with recurrent or persistent uterine serous carcinoma or locally advanced or metastatic malignancy with 1 or more relevant biomarkers related to DNA damage pathways were selected.

Phase 2 DENALI Trial

The phase 2 open-label, multicenter DENALI study is evaluating the efficacy and safety of azenosertib in patients with high-grade serious ovarian, fallopian tube, or primary peritoneal cancer.4 Primary end points for the study include frequency and severity of treatment emergent AEs (TEAEs), incidence of dose modifications, and ORR. Secondary end points include DOR, PFS, CBR, and time to response.

Inclusion criteria for the study included adult patients with platinum-resistant ovarian cancer, fewer than 5 lines of therapy, prior bevacizumab (Avastin) treatment, and adequate hematologic and organ function.

Phase 2 TETON Trial

The phase 2 open-label, multicenter TETON study is evaluating the efficacy and safety of azenosertib in patients with recurrent or persistent uterine serous carcinoma.5 Primary end points include frequency and severity of TEAEs, incidence of dose modifications, and ORR. Secondary end points include DOR, PFS, CBR, and time to response.

Inclusion criteria include adult female patients with histologically confirmed recurrent or persistent uterine serous carcinoma—including those with endometrial carcinoma of mixed histology where the serous component comprised at least 5% of the tumor—prior treatment with a platinum-based chemotherapy regimen, PD-L1 inhibitor, and at least 1 HER2-targeted therapy for known HER2-positive tumors; and adequate hematologic and organ function.

Adverse Effects

Common any-grade and grade 3 or higher treatment-related AEs (TRAEs) in a multicenter trial (NCT04516447) evaluating the efficacy of azenosertib/chemotherapy included neutropenia (54.9%, 25.5%), thrombocytopenia (47.1%, 27.5%), anemia (49.0%, 15.7%) nausea (43.1%, 3.9%), vomiting (17.6%, 3.9%), diarrhea (37.3%, 2.0%), and fatigue (41.2%, 9.8%).3

References

  1. Zentalis Pharmaceuticals provides update on azenosertib clinical development program. News release. Zentalis Pharmaceuticals. June 18, 2024. Accessed June 21, 2024. https://tinyurl.com/47krvv3c
  2. A study of ZN-c3 in participants with solid tumors. ClinicalTrials.gov. Updated February 1, 2023. Accessed June 21, 2024. https://clinicaltrials.gov/study/NCT04158336
  3. Zentalis corporate presentation. June 3, 2024. https://tinyurl.com/4jmt76m8
  4. 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 21, 2024. https://clinicaltrials.gov/study/NCT05128825
  5. A study of ZN-c3 in women with recurrent or persistent uterine serous carcinoma. ClinicalTrials.gov. Updated May 3, 2024. Accessed June 21, 2024. https://clinicaltrials.gov/study/NCT04814108

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