Mesothelioma Stratified Therapy (MiST) : A Multi-drug Phase II Trial in Malignant Mesothelioma

Study Overview
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Brief Summary
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MiST is a British Lung Foundation funded, University of Leicester Study, a multi-arm stratified therapy based clinical trial for patients with relapsed mesothelioma. The goal of MiST is to enable acceleration of novel, effective personalised therapy as a basis for improving survival outcomes for patients with mesothelioma.

Detailed Description
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Stage 1 - molecular pre-screening: The MiST Master protocol describes the identification of patients, biomarker testing and analysis. Patients with relapsed mesothelioma will be offered to consent for molecular panel testing of their diagnostic tumour block for predictive biomarkers. The results of this assessment will be used to classify patients into one of several possible molecularly defined treatment arms. Patients will therefore be offered a specific study treatment determined by their molecular profile. Patients, who exhibit positive testing in more than one biomarker, will potentially be eligible to subsequently be treated on a different treatment protocol upon disease progression or treatment failure. Stage 2 - Treatment: The MiST treatment protocol will be specific to the treatment allocated to the patient - based on the results of their biomarker testing in stage 1. Specific agent(s) will be detailed separately in each of the separate treatment protocols. Stage 3 - Molecular Profiling : In order to understand the genomic basis of drug response in the MiST trial, archival tumour tissue from all patients enrolled will be interrogated using molecular inversion probe- based microarray analysis of the somatic copy number aberrations. Optional re-biopsy of patients who progress on treatment, followed confirmed radiological response, will be offered, to investigate genomic interrogation of tumours at the time of acquired resistance. For arms 3, 4 and 5 immune checkpoint, transcriptomic and gut microbiome correlative studies are planned.

Official Title
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Mesothelioma Stratified Therapy (MiST): A Stratified Multi-arm Phase IIa Clinical Trial to Enable Accelerated Evaluation of Targeted Therapies for Relapsed Malignant Mesothelioma

Conditions
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Mesothelioma, Malignant

Intervention / Treatment
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* Drug: Rucaparib
* Drug: Abemaciclib
* Drug: pembrolizumab & bemcentinib
* Drug: Atezolizumab & Bevacizumab
* Drug: Dostarlimab and Niraparib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA FOR PRE-SCREENING Histologically confirmed MM with an available biopsy for research purposes Male or female patients aged ≥18 years. Expected survival of ≥12 weeks or greater ECOG PS 0-1 CT scan chest, abdomen (and pelvis if applicable) confirming disease progression. Patients must have received at least one prior line of therapy to include a platinum doublet first-line chemotherapy (within or outside of another clinical trial) Willing to consent for molecular screening of archived tumour block (PIS1 & CF1) EXCLUSION CRITERIA FOR PRE-SCREENING Patients with a diagnosis of a second malignancy except prostate or cervical cancer in remission, patients with a diagnosis of basal cell carcinoma of the skin or superficial bladder cancer. Uncontrolled CNS disease. Asymptomatic brain metastases are allowed if previously treated with radiotherapy >28 days prior to starting the investigational agent. New York Heart Association Class II or greater congestive heart failure. Patients with severe hepatic insufficiency or severe renal impairment. Patients requiring long term oxygen therapy. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial. Each individual MiST drug protocol contains the eligibility criteria specific to the treatment allocated to the patient.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MiST1 Rucaparib<br>BRCA1/BAP1 negative mesothelioma; 600mg twice daily (BID) every 28 days. | Drug: Rucaparib<br>* PARP inhibitor<br>* Other names: CO-338;|
| Experimental: MiST2 Abemaciclib<br>p16INK4A negative mesothelioma; 200mg orally twice daily every 28 days. | Drug: Abemaciclib<br>* CDK4/6 inhibitor<br>* Other names: LY2835219;|
| Experimental: MiST3 Pembrolizumab & Bemcentinib<br>No specific biomarker requirement: Pembrolizumab 200mg IV infusion on Day 1 only: Bemcentinib loading dose of 400mg on days 1-3, on day 4 on-wards 200mg daily every 21-days. | Drug: pembrolizumab & bemcentinib<br>* PD1 checkpoint inhibitor, AXL inhibitor<br>* Other names: Keytruda; BGB324;|
| Experimental: MiST4 Atezolizumab & Bevacizumab<br>PDL1 expression positive mesothelioma: Atezolizumab 1200 milligrams via intravenous nfusion; Bevacizumab 15 milligrams per kilogram via IV infusion both on Days 1 every 21-days. | Drug: Atezolizumab & Bevacizumab<br>* PDL1 checkpoint inhibitor, VEGF inhibitor<br>* Other names: MPDL3280A; Avastin;|
| Experimental: MiST 5 Dostarlimab and Niraparib<br>Platinum sensitive mesothelioma: Niraparib 200-300mg daily every 21 days; Dostarlimab 500mg on day 1 of each 21 day cycle for 4 cycles, then 1000mg on day 1 of each 42 day cycle. | Drug: Dostarlimab and Niraparib<br>* IG Antibody, PARP Inhibitor<br>* Other names: Zejula;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) at 12 weeks assessed by modified RECIST 1.1, in patients with relapsed mesothelioma. | This will be assessed using CT scan evidence according to modified RECIST 1.1 criteria reporting. Scans will be undertaken every 6 weeks. Analysis will be timed from study entry using the baseline CT scan results until completion of treatment cycles, confirmed disease progression or death - whichever comes first. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) at 24 weeks assessed by modified RECIST 1.1, in patients with relapsed mesothelioma. | This will be assessed using CT scan evidence according to modified RECIST 1.1 criteria reporting. Scans will be undertaken every 6 weeks. Analysis will be timed from study entry using the baseline CT scan results until completion of treatment cycles, confirmed disease progression or death - whichever comes first. | 24 weeks | 
| Objective response rate (ORR) assessed for 12 months | This will be assessed using CT scan evidence according to modified RECIST 1.1 criteria | Up to 12 months (up to 6 months during treatment and 6 months of follow-up) | 
| Safety assessed according to CTCAE criteria. | Adverse events will be recorded in relation to each cycle of treatment and graded according to Common Terminology Criteria for Adverse Events (CTCAE). The incidence of each adverse event (all grades and grade 3/4) will be reported as a per-patient-cycle rate and as a per-patient rate. Investigators expect patients to participate in the study for a maximum of 6 months of Treatment and 6 months of follow-up, however cannot guarantee that some patients may participate over 12 months. | 12 months (up to 6 months during treatment and 6 months of follow-up) | 
| Toxicity assessed according to CTCAE criteria. | Adverse events will be recorded in relation to each cycle of treatment and graded according to Common Terminology Criteria for Adverse Events (CTCAE). The incidence of each adverse event (all grades and grade 3/4) will be reported as a per-patient-cycle rate and as a per-patient rate. Investigators expect patients to participate in the study for a maximum of 6 months of Treatment and 6 months of follow-up, however cannot guarantee that some patients may participate over 12 months. | 12 months (up to 6 months during treatment and 6 months of follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug: multi-arm, Phase IIa