MEDI5752 in Combination With Carboplatin Plus Pemetrexed in Unresectable Pleural Mesothelioma

Study Overview
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Brief Summary
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This is a phase III, randomized, open-label, multicenter, global study to determine the efficacy and safety of Volrustomig (MEDI5752) + Carboplatin + Pemetrexed vs the investigator's choice of platinum + Pemetrexed or Nivolumab + Ipilimumab in participants with unresectable pleural mesothelioma.

Detailed Description
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Adult patients with histologically proven diagnosis of pleural mesothelioma with advanced unresectable disease are eligible to be enrolled. Patients will be randomized 1:1 to receive Volrustomig (MEDI5752) + Carboplatin + Pemetrexed or the investigator's choice of platinum+Pemetrexed or Nivolumab+Ipilimumab, based on their histology.

Official Title
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A Phase III, Randomized, Open-Label, Multicenter, Global Study of Volrustomig (MEDI5752) in Combination With Carboplatin Plus Pemetrexed Versus Platinum Plus Pemetrexed or Nivolumab Plus Ipilimumab in Participants With Unresectable Pleural Mesothelioma (eVOLVE-Meso)

Conditions
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Unresectable Pleural Mesothelioma

Intervention / Treatment
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* Drug: Volrustomig
* Drug: Pemetrexed
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participant must be ≥ 18 years at the time of screening Histologically proven diagnosis of pleural mesothelioma with known histology (epithelioid vs. non-epithelioid) Advanced unresectable disease that cannot be treated with curative surgery (with or without chemotherapy) WHO/ECOG performance status of 0 or 1 with no deterioration (that is, ECOG PS>1) over the previous 2 weeks prior to day of first dosing Has measurable disease per modified RECIST1.1 Has adequate bone marrow reserve and organ function at baseline Key Exclusion Criteria: As judged by the investigator, any condition that would interfere with evaluation of the investigational product or interpretation of participant safety or study results. Active or prior documented autoimmune or inflammatory disorders History of another primary malignancy with exceptions. Uncontrolled intercurrent illness Tuberculosis, hepatitis B (HBV) or hepatitis C (HCV), human immunodeficiency virus (HIV) infection that is not well controlled Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment Untreated or progressive CNS metastatic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Interventional Model Description: This is a randomized, open-label, Phase III trial in participants with untreated unresectable pleural mesothelioma. Approximately 600 participants across histology subtypes will be randomized in a 1:1 ratio to receive volrustomig in combination with carboplatin plus pemetrexed or the investigator's choice of nivolumab plus ipilimumab or platinum plus pemetrexed chemotherapy for participants with epithelioid histology, and nivolumab plus ipilumab for participants with non-epithelioid histology.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Volrustomig + Carboplatin + pemetrexed<br>Volrustomig in combination with carboplatin plus pemetrexed | Drug: Volrustomig<br>* MEDI5752: Administered as IV infusion<br>* Other names: MEDI5752;Drug: Pemetrexed<br>* Alimta: Administered as IV infusion<br>* Other names: Alimta;Drug: Carboplatin<br>* Paraplatin: Administered as IV infusion<br>* Other names: Paraplatin;|
| Active Comparator: Investigator's choice of standard care<br>The investigator's choice of nivolumab plus ipilimumab or platinum plus pemetrexed chemotherapy for participants with epithelioid histology, and nivolumab plus ipilumab for participants with non-epithelioid histology. | Drug: Pemetrexed<br>* Alimta: Administered as IV infusion<br>* Other names: Alimta;Drug: Carboplatin<br>* Paraplatin: Administered as IV infusion<br>* Other names: Paraplatin;Drug: Cisplatin<br>* Platinol: Administered as IV infusion<br>* Other names: Platinol;Drug: Nivolumab<br>* Opdivo: Administered as IV infusion<br>* Other names: Opdivo;Drug: Ipilimumab<br>* Yervoy: Administered as IV infusion<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in experimental arm relative to comparator arm | OS is defined as the time from randomization until the date of death due to any cause. | up to approximately 52 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from randomization until the date of death due to any cause. | up to approximately 52 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from randomization until progression per mRECIST 1.1 and/or RECIST 1.1 as assessed by the investigator at local site, or death due to any cause. | up to approximately 52 months | 
| Landmark OS | Landmarks of OS12, OS18, OS24, and OS36. | 12, 18, 24, 36 months | 
| Landmark PFS | Landmarks of PFS6, PFS12, PFS18, and PFS24 | 6, 12, 18, 24 months | 
| Overall Response Rate (ORR) | Proportion of participants who have a confirmed Complete Response or confirmed Partial Response, as determined by the investigator at local site per mRECIST 1.1 and/or RECIST 1.1. | up to approximately 52 months | 
| Duration of Response (DoR) | DoR defined as the time from the date of first documented response until date of documented progression per mRECIST 1.1 and/or RECIST 1.1 as assessed by the investigator at local site or death due to any cause. | up to approximately 52 months | 
| PFS2 | PFS2 defined as the time from randomization to the earliest of the progression event (following the initial investigator-assessed progression), after first subsequent therapy, or death. | up to approximately 52 months | 
| Patient-reported physical functioning | TTD in physical functioning as measured by PROMIS (Patient Reported Outcomes Measurement Information System) Physical Function Short Form 8c. There are 8 questions each from a scale of 1 (unable to do) to a scale of 5 (With a little difficulty). The higher the scores the better the patient-reported physical functioning is. | up to approximately 52 months. | 
| Disease-related symptoms using EORTC IL305 (Q1) | Change from baseline in disease-related symptoms as measured by individual symptom items from the EORTC (European Organisation For Research And Treatment Of Cancer) IL305 (Item Library 305) (Q1). It is scored from a 1 (not at all) to a 4 (very much). The higher the score the higher the disease-related symptoms. | Up to approximately 52 months. | 
| Disease-related symptoms using PRO-CTCAE (Q1, 5, 6, 9) | Change from baseline in disease-related symptoms as measured by individual symptom items from the PRO-CTCAE (Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events) (Q1, 5, 6, 9). PRO-CTCAE responses are scored from 0 to 4 (or 0/1 for absent/present). The higher the score the higher the disease-related symptoms. | Up to approximately 52 months | 
| Patient-reported role functioning using EORTC QLQ-C30 RF subscale (IL305 Q2 3) | Change from baseline in functioning will be assessed by the following measure: Role functioning: EORTC (European Organisation For Research And Treatment Of Cancer) QLQ (Quality of Life Questionnaire) -C30 RF (Role Functioning) subscale (IL305 Q2 3) (Item Library 305). The questions are from a scale of 1 (not at all) to 4 (very much). The lower the score the higher the patient-reported role functioning is. | up to approximately 52 months | 
| Patient-reported HRQoL (Health-related Quality of Life) using EORTC QLQ-C30 HRQoL subscale (IL305 Q7-8) | Change from baseline in functioning will be assessed by the following measure: HRQoL: EORTC (European Organisation For Research And Treatment Of Cancer) QLQ (Quality of Life Questionnaire) -C30 HRQoL subscale (IL305 Q7-8) (Item Library 305). The questions are from a scale of 1 (very poor) to 7 (excellent). The higher the score the higher the HRQoL. | Up to approximately 52 months | 
| Immunogenicity of volrustomig | Incidence of Anti-Drug Antibodies against volrustomig. | up to approximately 52 months | 
| Incidence of Adverse Events (AEs) AEs graded by CTCAE version 5.0 | Incidence of Adverse Events (AEs) AEs graded by CTCAE (Common Terminology Criteria for Adverse Events) version 5.0. Grade refers to the severity of the AE. The CTCAE displays grade 1 (mild) through 5 (death related to AE). Grade 2 (moderate), Grade 3 (Severe) and Grade 4 (Life-threatening consequences). | Up to approximately 52 months | 
| Area under the curve (AUC) | The concentration of MEDI5752 in serum will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered. | Up to approximately 52 months | 
| Maximum plasma concentration of the drug (Cmax) | The concentration of MEDI5752 in serum will be determined (Cmax will be derived). | Up to approximately 52 months | 
| The time taken to reach the maximum concentration (Tmax) | The concentration of MEDI5752 in serum will be determined (Tmax will be derived). | Up to approximately 52 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesothelioma, Pleural Mesothelioma, Unresectable Pleural Mesothelioma, Advanced pleural mesothelioma