Efficacy and Safety Evaluation of Azenosertib (ZN-c3) in Recurrent or Persistent Uterine Serous Carcinoma: A Phase 2 Open-Label Multicenter Study
- Trial ID
- 2023-507324-23-00
- Protocol
- ZN‑c3-004
- Sponsor
- K-Group Beta Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 open-label, multicenter study is to evaluate the **safety** and **tolerability** of ZN-c3 in adult women with recurrent or persistent uterine serous carcinoma (USC). This is clinically relevant as it aims to establish the safety profile of ZN-c3, which is crucial for determining its potential as a therapeutic option for this patient population. Additionally, the study seeks to investigate the **antitumor activity** of ZN-c3, which is essential for assessing its efficacy in treating USC.
Secondary objectives include:
- Part 1b: To investigate the antitumor activity of ZN-c3 at different doses/schedules and to evaluate the plasma pharmacokinetics (PK) of ZN-c3.
- Part 2: To further investigate the antitumor activity, safety, and tolerability of ZN-c3, to explore the association of key biomarkers with clinical outcomes, and to evaluate the plasma PK of ZN-c3.
Participants
The clinical trial involves a total of **50 participants** who are exclusively **female** and aged **18 years and older**. The study population consists of individuals diagnosed with **recurrent or persistent uterine serous carcinoma** (USC), a condition for which no other proven effective treatment options are available, or where standard therapies were not tolerated or refused. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of USC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and measurable disease per RECIST 1.1 criteria. The trial does not include males and focuses on a vulnerable population. Participants are required to have adequate hematologic and organ function and must agree to use effective contraception if of childbearing potential. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have undergone prior therapy for endometrial cancer, including a platinum-based chemotherapy regimen and a PD-(L)1 inhibitor, unless clinically ineligible or unavailable in their region.
Plans and Procedures
The clinical trial is designed as a **Phase 2 open-label** study to evaluate the efficacy and safety of **ZN-c3** in adult women with recurrent or persistent uterine serous carcinoma. The trial is structured to include two parts: Part 1b focuses on determining the safety and tolerability of ZN-c3, while Part 2 investigates its antitumor activity. The study is expected to commence recruitment on May 31, 2024, and conclude by May 31, 2025. Participants will be involved for a maximum treatment period of 21 days, with the possibility of early termination if adverse events necessitate discontinuation or if the participant withdraws consent.
The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed uterine serous carcinoma, measurable disease per RECIST 1.1 criteria, and adequate hematologic and organ function. Following the screening, participants will undergo regular follow-up visits to monitor safety, tolerability, and efficacy outcomes. The end-of-study visit will assess the overall response rate (ORR) and other secondary endpoints such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Participants will receive ZN-c3 orally, with the dosage and administration tailored to individual needs and tolerability. The study will employ rigorous monitoring of treatment-emergent adverse events (TEAEs) and laboratory abnormalities, graded according to the NCI-CTCAE v5.0. The trial's primary endpoints include the frequency and severity of TEAEs and the incidence of dose modifications due to ZN-c3-related adverse events. Secondary endpoints will explore additional efficacy measures and the association of key biomarkers with clinical outcomes.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The primary experimental medication is **azenosertib**, also known as ZN-c3, which is provided in the form of a film-coated tablet. The maximum daily dose is 400 mg, with a total maximum dose of 6000 mg over a treatment period of 21 days. The route of administration is oral. Compliance with the dosing schedule is monitored throughout the trial.
**Aprepitant** is used as an auxiliary treatment in the trial. It is administered as a hard capsule with a maximum daily dose of 125 mg and a total maximum dose of 855 mg over 21 days. The administration route is oral.
**Granisetron** is another auxiliary treatment, provided as a film-coated tablet. The maximum daily dose is 2 mg, with a total maximum dose of 30 mg over 21 days. It is administered orally.
**Dexamethasone** is included as an auxiliary treatment in the form of a film-coated tablet. The maximum daily dose is 12 mg, with a total maximum dose of 36 mg over a shorter treatment period of 4 days. The route of administration is oral.
**Akynzeo**, containing **palonosetron** and **netupitant**, is used as an auxiliary treatment. It is provided in hard capsule form, with a maximum daily dose of 300 mg and a total maximum dose of 900 mg over 21 days. The administration route is oral.
**Ondansetron** is administered as an auxiliary treatment in the form of a coated tablet. The maximum daily dose is 8 mg, with a total maximum dose of 120 mg over 21 days. The route of administration is oral.
**Olanzapine** is included as an auxiliary treatment, provided as a coated tablet. The maximum daily dose is 10 mg, with a total maximum dose of 150 mg over 21 days. It is administered orally.
All medications are of chemical origin and are administered orally. The trial ensures participant compliance through regular monitoring and adherence to the specified dosing schedules. The study aims to evaluate the efficacy and safety of these treatments in adult women with recurrent or persistent uterine serous carcinoma.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for Part 2 of the trial is the Objective Response Rate (ORR) as defined by the revised RECIST v1.1 criteria, assessed by Independent Central Review (ICR). Secondary endpoints include Duration of Response (DOR), Progression-Free Survival (PFS), Clinical Benefit Rate (CBR), and Time to Response (TTR), all defined by RECIST v1.1 and assessed by ICR. Additionally, Overall Survival (OS) and the frequency and severity of Treatment-Emergent Adverse Events (TEAEs) will be evaluated. Plasma pharmacokinetic (PK) concentrations of **ZN-c3** will also be measured to assess the association of key biomarkers with clinical outcomes.
The efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific attention to the revised RECIST v1.1 criteria for tumor response evaluation. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection. The schedule for these assessments will be aligned with the trial's protocol to ensure consistency and adherence to regulatory standards.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Provision of signed informed consent prior to initiation of any study related procedures 2. Females ≥18 years old 3. Histologically confirmed recurrent or persistent USC for which no other proven effective treatment options are available or any available standard of care therapy was not tolerated or was refused by the subject • Endometrial carcinoma of mixed histology where the serous component ≥ 5% of the tumor • Carcinosarcomas (even with a serous component) are not eligible 4. ECOG PS 0 or 1
- Measurable disease per RECIST 1.1 criteria that has not been previously irradiated or has progressed following radiation therapy 6. Required prior therapy for endometrial cancer: • platinum-based chemotherapy regimen • PD-(L)1 inhibitor, except for subjects who are not clinically eligible in the opinion of the Investigator, or in regions where it is unavailable. • Known HER2-positive tumors: Treatment with at least 1 HER2-targeted therapy, except for subjects who are not clinically eligible in the opinion of the Investigator, or in regions where it is unavailable 7. FFPE tumor tissue block collected within 3 years prior to ICF
- Adequate hematologic and organ function during the Screening period, as defined: • ANC ≥1.5 × 109/L • Hgb ≥9.0 g/dL without PRBC transfusion in the prior 14 days • Platelet count ≥100 × 109/L • ALT and aspartate aminotransferase AST ≤3 × ULN;AST and ALT ≤5 × ULN if abnormalities are due to liver metaseses • Total serum bilirubin ≤1.5 × ULN or ≤3 × ULN in the case of Gilbert’s Syndrome • CrCl ≥30 mL/min based on Cockcroft-Gault method 9. Females of childbearing potential must agree to use an effective method of contraception prior to the first dose and for at least 6 months after the last dose of ZN c3. For determination of effective methods of contraception, refer to Section 12.1 10. Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
Exclusion Criteria
- Any of the following treatment interventions within the specified time frame prior to C1D1: • Major surgery within 28 days and any preplanned major surgery during the study treatment period. • Any chemotherapy or targeted tumor therapy within 14 days or 5 half-lives (whichever is shorter). • Radiation within 21 days. • Autologous or allogeneic stem cell transplant within 3 months. • Current use of any other investigational drug therapy <28 days or 5 half-lives (whichever is shorter) • Inability to discontinue treatment with drugs, or to discontinue food and herbal supplements, that are strong or moderate CYP3A inhibitors and inducers, or P-gp inhibitors at least 14 days prior to start of study drug treatment. Mandatory anti-emetics that may be CYP3A inhibitors are an exception to this criterion 2. Prior therapy with ZN-c3 or any other WEE1 inhibitor, ATR inhibitor, or CHK1/2 inhibitor 3. Known hypersensitivity to ZN-c3 or any of the inactive ingredients in ZN-c3
- A serious illness or medical condition(s) including, but not limited to, the following: • Brain metastases that require immediate treatment or are clinically or radiologically unstable • Leptomeningeal disease that requires or is anticipated to require immediate treatment • Myocardial impairment of any cause resulting in heart failure by New York Heart Association Criteria (Class III or IV) • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the subject inappropriate for entry into this study • Significant gastrointestinal abnormalities, considered to be clinically significant in the judgrior to C1D1, rement of the Investigator, or prior surgical procedures affecting absorption • Active, uncontrolled systemic infection. • Any evidence of bowel obstruction , recent hospitalization for bowel obstruction within 3 months prior to C1D1, or paracentesis/ thoracentesis within 3 weeks pcurrent paracentesis or thoracentesis within 6 weeks prior to C1D1 5, or paracentesis/thoracentesis anticipated during C1. Unresolved toxicity of Grade >1 attributed to any prior therapies
- Pregnant or lactating females or females of childbearing potential who have a positive serum pregnancy test within 14 days prior to C1D1 7. History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease free. 8. Individuals who are judged by the Investigator to be unsuitable as study subjects
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 31 May 2024 | 18 |
 Italy | Not Recruiting | 31 May 2024 | 30 |
 Spain | Not Recruiting | 31 May 2024 | 22 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
APREPITANT | Other | — | ORAL USE | 125 | 21 | SUB20017 |
GRANISETRON | Other | — | ORAL USE | 2 | 21 | SUB07964MIG |
DEXAMETHASONE | Other | — | ORAL USE | 12 | 4 | SUB07017MIG |
Akynzeo 300 mg/0.5 mg hard capsules | Other | HARD CAPSULES | ORAL USE | 300 | 21 | PRD2825038 |
azenosertib, also known as ZN-c3 | Test | FILM-COATED TABLET | ORAL USE | 400 | 21 | PRD9495924 |
ONDANSETRON | Other | — | ORAL USE | 8 | 21 | SUB09445MIG |
azenosertib, also known as ZN-c3 | Test | FILM-COATED TABLET | ORAL USE | 400 | 21 | PRD9495923 |
Akynzeo 300 mg/0.5 mg hard capsules | Other | HARD CAPSULES | ORAL USE | 300 | 21 | PRD6893730 |
OLANZAPINE | Other | — | ORAL USE | 10 | 21 | SUB09426MIG |