A Study of Azenosertib (ZN-c3) Versus Investigator's Choice Chemotherapy in Subjects With Platinum-Resistant High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers Positive for Cyclin E1 Protein Expression

Official title

A Randomized, Open-Label Phase 3 Study of Azenosertib Versus Investigator's Choice of Chemotherapy in Platinum-Resistant High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers Positive for Cyclin E1 Protein Expression

Overview

This is a randomized, Phase 3 trial designed to evaluate the efficacy and safety of azenosertib compared to Investigator's choice of chemotherapy in subjects with platinum-resistant ovarian cancer whose tumors are positive for cyclin E1 protein expression.

Detailed description

A Phase 3 study to evaluate the efficacy, safety, and overall clinical benefit of azenosertib (ZN-c3) compared with Investigator's choice of chemotherapy in subjects with Platinum-Resistant, High-Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Azenosertib is a selective and orally bioavailable inhibitor of WEE1. In HGSOC, high Cyclin E1 protein drives replication stress and increases tumor reliance on WEE1-mediated G2/M checkpoint control. Treating tumor cells with azenosertib promotes premature cell cycle progression leading to increased replication stress and accumulation of DNA damage pushing cells to mitotic catastrophe resulting in tumor cell death.

Interventions

• Drug Investigator's choice of Chemotherapy
  The investigator will select the chemotherapy in accordance with the protocol defined requirements. The possible choices as defined by the protocol: * Paclitaxel * Gemcitabine * Pegylated liposomal doxorubicin (PLD) * Topotecan The selected chemotherapy will be administered intravenously
• Drug Azenosertib
  Azenosertib 400 mg will be administered orally.

Primary outcome measures

• Progression free survival (PFS) per RECIST v1.1 as assessed by Investigator [Time frame: Up to approximately 24 months from the enrollment of the last subject]

Secondary outcome measures (7)

• Overall survival [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• PFS per RECIST 1.1 as assessed by blinded independent central review (ICR) [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• Objective Response Rate (ORR) per RECIST v1.1 and assessed by Investigator [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• Change from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire score (EORTC QLQ)-Core 30 (C30) at each post baseline visit [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• Change from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire score (EORTC QLQ)-OV28 at each post baseline visit [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• Change from baseline in EQ-5D-5L score at each post baseline visit [Time frame: Up to approximately 24 months from the enrollment of the last subject]
• Number of Subjects experiencing treatment emergent adverse events (TEAEs) [Time frame: Up to approximately 24 months and 30 days from the enrollment of the last subject]

Eligibility criteria

Inclusion criteria

• Female age ≥ 18 years
• High-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer
• Measurable disease per RECIST Version 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-1
• The subject's tumor tissue must be positive for cyclin E1 protein expression per the Sponsor's clinically validated cyclin E1 IHC investigational, in vitro diagnostic assay
• Prior Therapy:

• Subject must have platinum-resistant disease
• One to 3 prior lines or regimens are allowed (1 to 4 prior lines are permitted, if prior mirvetuximab)
• Prior bevacizumab treatment is required, if eligible per standard of care
• Prior PARP inhibitor treatment is required if BRCA 1/2 mutation or HRD, if eligible per standard of care
• Prior mirvetuximab treatment is required, if eligible per standard of care
• Adequate hematologic and organ function during the screening period

Exclusion criteria

• History of another malignancy in the previous 2 years, unless cured by surgery alone and continuously disease-free. Exceptions include appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, Stage 1 uterine cancer, or other malignancies with an expected curative outcome.
• Subjects with primary platinum-refractory disease.
• Prior therapy with azenosertib or any other WEE1 inhibitor, ATR inhibitor, CHK1/2 inhibitor, or (PKMYT1) inhibitor for PROC.
• A serious illness or medical condition(s) including, but not limited to, the following:

• Clinically or radiographically unstable brain metastases or leptomeningeal disease that requires immediate treatment. Subjects with asymptomatic brain metastases are eligible.
• Acute kidney injury requiring intervention, or presence of indwelling urinary catheter or percutaneous nephrostomy.
• Significant gastrointestinal abnormalities, including an inability to take oral medication, requirement for IV alimentation, active peptic ulcer, chronic diarrhea or vomiting considered to be clinically significant in the judgment of the Investigator, or prior surgical procedures affecting absorption.
• Any evidence of small bowel obstruction as determined by air/fluid levels on computed tomography (CT) scan, recent hospitalization for small bowel obstruction within 3 months before randomization, or recurrent paracentesis or thoracentesis within 6 weeks before randomization.
• Active, uncontrolled infection. Subjects with an infection receiving treatment (antibiotic, antifungal, or antiviral) must have completed such treatment and the infection must be considered controlled/resolved (and afebrile) by the Investigator for at least 7 days before randomization
• Myocardial impairment of any cause resulting in heart failure by New York Heart Association criteria (Class II, III or IV).
• Medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results
• Any of the following treatment interventions within the specified time frame before randomization:

• Hospitalization within 14 days
• Major surgery within 28 days
• Any chemotherapy or targeted tumor therapy within 21 days or 5 half-lives (whichever is shorter)
• Radiation therapy 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 prescription or nonprescription drugs that are prohibited per protocol.
• Inability to discontinue consumption of food and herbal supplements that are prohibited per protocol
• Prior wide-field radiotherapy affecting ≥ 20% of the bone marrow.
• Unresolved toxicity of Grade > 1 attributed to any prior therapies (excluding Grade ≤ 2 neuropathy, alopecia, or skin pigmentation).
• Subjects who are immunocompromised or HIV-positive on highly active anti-retroviral therapy
• Subjects with known active hepatitis B or hepatitis C infection
• Individuals who are judged by the Investigator to be unsuitable as study subjects

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 11 centers

• Site 0107 — Phoenix
• Site 0110 — Antioch
• Site 0115 — San Francisco
• Site 0101 — Torrance
• Site 0111 — Camden
• Site 0108 — Columbus
• Site 0105 — Portland
• Site 0109 — Philadelphia
• … and 3 more centers

France · 9 centers

• Site 3508 — Besançon
• Site 3502 — Brest
• Site 3507 — Dijon
• Site 3504 — Lyon
• Site 3503 — Paris
• Site 3501 — Pierre-Bénite
• Site 3509 — Saint-Herblain
• Site 3505 — Strasbourg
• … and 1 more center

Italy · 7 centers

• Site 3801 — Bologna
• Site 3805 — Milan
• Site 3804 — Milan
• Site 3803 — Milan
• Site 3802 — Naples
• Site 3807 — Prato
• Site 3806 — Rome

South Korea · 6 centers

• Site 1203 — Daegu
• Site 1206 — Goyang-si
• Site 1202 — Seoul
• Site 1205 — Seoul
• Site 1204 — Seoul
• Site 1201 — Seoul

Spain · 6 centers

• Site 4201 — Barcelona
• Site 4205 — Barcelona
• Site 4202 — Madrid
• Site 4206 — Madrid
• Site 4203 — Málaga
• Site 4204 — Vigo

Canada · 4 centers

• Site 0201 — Toronto
• Site 0204 — Montreal
• Site 0203 — Montreal
• Site 0202 — Sherbrooke

Poland · 4 centers

• Site 4006 — Krakow
• Site 4001 — Lodz
• Site 4004 — Poznan
• Site 4003 — Szczecin

Australia · 3 centers

• Site 1101 — Randwick
• Site 1102 — Adelaide
• Site 1103 — Nedlands

Belgium · 2 centers

• Site 3002 — Brussels
• Site 3001 — Leuven

Germany · 2 centers

• Site 3602 — Berlin
• Site 3601 — Dresden

Ireland · 2 centers

• Site 3703 — Cork
• Site 3702 — Dublin

Taiwan · 2 centers

• Site 1301 — Taichung
• Site 1302 — Taipei

Identifiers

NCT: NCT07546500 · ZN-c3-020 · GOG-3147 · ENGOT-ov109

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗