Study of Volrustomig in Women With High Risk Locally Advanced Cervical Cancer (eVOLVE-Cervical)

Study Overview
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Brief Summary
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This is a phase III, randomized, double-blind, placebo-controlled, multi-center, global study to explore the efficacy and safety of volrustomig in women with high-risk LACC (FIGO 2018 stage IIIC to IVA cervical cancer with lymph node involvement) who have not progressed following platinum-based CCRT.

Detailed Description
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Women with locally advanced cervical cancer will be randomized in a 1:1 ratio to receive treatment with Volrustomig or Placebo.

Official Title
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A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-centre, Global Study of Volrustomig in Women With High Risk Locally Advanced Cervical Cancer Who Have Not Progressed Following Platinum-based, Concurrent Chemoradiation Therapy (eVOLVE-Cervical)

Conditions
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Locally Advanced Cervical Cancer

Intervention / Treatment
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* Biological: Volrustomig
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study, patients should fulfill the following criteria: Female. Aged at least 15 years at the time of screening. Body weight > 35 kg. Histologically documented FIGO 2018 Stage IIIC to IVA cervical adenocarcinoma, cervical squamous carcinoma, or cervical adenosquamous carcinoma, with lymph node involvement. Initial staging procedures performed no more than 42 days prior to the first dose of CCRT. Provision of tumor sample to assess the PD-L1 expression. Must not have progressed following CCRT, participants with persistent disease after definitive CCRT must not be amenable to other available therapies with curative intent. WHO/ECOG performance status of 0 or 1. Adequate organ and bone marrow function. Capable of providing signed informed consent. Exclusion Criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled: Diagnosis of small cell (neuroendocrine) or mucinous adenocarcinoma of cervical cancer. Evidence of metastatic disease. Intent to administer a fertility-sparing treatment regimen. History of organ transplant. Active or prior documented autoimmune or inflammatory disorders. Uncontrolled intercurrent illness. History of another primary malignancy except for a) Malignancy treated with curative intent with no known active disease ≥2 years before the first dose of study intervention; b) Adequately treated nonmelanoma skin cancer or lentigo maligna, or carcinoma in situ without evidence of disease. Unresolved toxicities from previous CCRT except for irreversible toxicity that is not reasonably expected to be exacerbated. Prior history or presence of vesicovaginal, colovaginal, or rectovaginal fistula. History of anaphylaxis to any biologic therapy or vaccine. Current or prior use of immunosuppressive medication within 14 days before the first dose of the study intervention is excluded. The following are exceptions to this criterion: a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection); b) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication or chemotherapy premedication) or a single dose for palliative purpose (eg, pain control). Patients who have undergone a previous hysterectomy, including a supracervical hysterectomy, or will have a hysterectomy as part of their initial cervical cancer therapy. Any prior (besides prior CCRT) or concurrent treatment for cervical cancer. Major surgical procedures within 4 weeks prior to the first dose of the study intervention or still recovering from prior surgery. Exposure to immune mediated therapy prior to the study for any indication. Receipt of live attenuated vaccine within 30 days prior to the first dose of the study intervention. Participants with a known allergy or hypersensitivity to the study intervention, or any excipients of the study intervention.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Volrustomig<br>Volrustomig | Biological: Volrustomig<br>* IV Infusion<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* IV Infusion<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in participants with PD-L1 expression based on the investigator assessment | PFS is defined as the time from date of randomization until RECIST 1.1- defined radiological progression or histopathologically confirmed progression as assessed by the Investigator or death due to any cause, whichever occurs earlier. | The study duration will be approximately 40 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) in participants regardless of PD-L1 expression based on the investigator assessment | PFS is defined as the time from date of randomization until RECIST 1.1-defined radiological progression or histopathologically confirmed progression as assessed by the Investigator or death due to any cause, whichever occurs earlier. | The study duration will be approximately 40 months | 
| Overall Survival (OS) in participants regardless of PD-L1 expression. | OS defined as time from randomization until the date of death due to any cause. | The study duration will be approximately 6 years. | 
| Overall Survival (OS) in participants with PD-L1 expression | OS defined as time from randomization until the date of death due to any cause. | The study duration will be approximately 6 years. | 
| Objective Response Rate (ORR) in participants with PD-L1 expression/regardless of PD-L1 expression. | ORR is defined as the proportion of participants who have a CR or PR, as determined by Investigator per RECIST 1.1 | The study duration will be approximately 40 months | 
| Duration of Response (DoR) in participants with a CR or PR in the PD-L1 expression analysis set/FAS. | DoR in participants with a CR or PR: Time from date of first detection of CR or PR until the date of RECIST 1.1-defined radiological progression or histopathologically confirmed progression. | The study duration will be approximately 40 months | 
| Time to First Subsequent Therapy or death (TFST) in the PD-L1 expression analysis set/FAS | TFST: The time from randomization until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death due to any cause. | The study duration will be approximately 40 months | 
| Time to second progression or death (PFS2) in the PD-L1 expression analysis set/FAS. | PFS2: The time from randomization to the earliest of the progression event (following the initial Investigator-assessed progression), after first subsequent therapy, or death. The date of second progression will be recorded by the Investigator in the eCRF and defined according to local standard clinical practice. | The study duration will be approximately 6 years. | 
| PFS by BICR in the PD-L1 expression analysis set/FAS. | Endpoints based on the PFS by BICR assessment according to RECIST 1.1. | The study duration will be approximately 40 months | 
| The incidence of local progression, and distant disease progression as the first documented progression event in the PD-L1 expression analysis set/FAS. | Incidence of Local Progression, and Distant Disease Progression: Number and percentage of participants who develop local progression, distant disease recurrence. | The study duration will be approximately 40 months | 
| PK of Volrustomig | Concentration of Volrustomig in serum. | The study duration will be approximately 40 months. | 
| The immunogenicity of volrustomig. | Incidence of ADAs against volrustomig in serum. | The study duration will be approximately 40 months | 
| Incidence of adverse events of Volrustomig compared to placebo; | An AE is definded as the development of any untoward medical occurrence (other than progression of the malignancy under evaluation) in a patient or clinical study participant administered a medicinal product, and which does not necessarily have a causal relationship with this treatment. | The study duration will be approximately 40 months. | 
| Participant-reported disease-related symptoms | Change from baseline as measured by the European Organization for Research and Treatment of Cancer IL318 (EORTC IL318, Symptom Experience subscale of the EORTC Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24)). The score of scale for EORTC IL318 is from 1-4. | The study duration will be approximately 40 months. | 
| Participant-reported physical functioning | Change from baseline of physical functioning as measured by the Patient Reported Outcomes Measurement Information System - Short Form - Physical Functioning 8c (PROMIS SF-PF 8c). The score of scale for PROMIS SF-PF 8c is from 1-5. | The study duration will be approximately 40 months. | 
| Participant-reported global health status/Quality of Life. | Change from baseline of Global Health Status/ Quality of Life (GHS/QoL) as measured by the European Organization for Research and Treatment of Cancer IL172 (EORTC IL172). The score of scale for EORTC IL172 is from 1-7. | The study duration will be approximately 40 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally Advanced Cervical Cancer;, Adolescent and Young Adult;, Volrustomig