Prof Dean Fennell
Mesothelioma Research Group
Robert Kilpatrick Clinical Sciences Building
Leicester Royal Infirmary
Mesothelioma Stratified Therapy (MiST): A stratified multi-arm phase II clinical trial to enable accelerated evaluation of targeted therapies for relapsed malignant mesothelioma.
1. Following standard platinum treatment, does the proposed IMP intervention exhibit a significant disease control rate response in biomarker selected malignant mesothelioma?
2. What are the genomic characteristics of exceptional responders or chemo-refractory tumours in the MiST trial?
East Midlands - Leicester South Research Ethics Committee, 05/07/2018, 18/EM/0118
Interventional non-randomised study
Primary study design
Secondary study design
Non randomised study
Patient information sheet
Not available in web format, please contact: MiST@uhl-tr.nhs.uk to request a participant information sheet
Stage 1 of this study is a molecular pre-screening. 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 is the treatment stage. 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) are as follows:
1. MiST1: Rucaparib for patients with BRCA1/BAP1 negative mesothelioma (600 mg twice daily (BID) every 28 days) for 6 cycles
2. MiST2: Abemaciclib for patients with p16INK4A negative mesothelioma (200 mg orally twice daily (BID) every 28 days) for 6 cycles.
3. MiST3: Pembrolizumab & Bemcentinib. There is no specific biomarker requirement. Bemcentinib will be administered orally once daily every 21 days for 8 cycles. On the first 3 days of administration, the dose will be a loading dose of 400 mg (days 1, 2 and 3); from day 4 onwards, patients will receive a daily dose of 200 mg. Pembrolizumab will be given at a fixed dose of 200 mg via intravenous infusion (IV) on day 1 of each 21 day cycle for 8 cycles.
4. MiST4 Atezolizumab & Bevacizumab for patients with PDL1 expression positive mesothelioma. Atezolizumab will be given at a dose of 1200mg via intravenous infusion (IV) and Bevacizumab will be given at a dose of 15 mg/kg via intravenous infusion (IV). Both drugs will be given on day 1 every 21 days for 8 cycles.
Stage 3 involves molecular profiling, 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 and 4, immune checkpoint, transcriptomic and gut microbiome correlative studies are planned.
MiST3 Pembrolizumab & Bemcentinib
MiST4 Atezolizumab & Bevacizumab
Primary outcome measure
Disease control rate (DCR) after 12 weeks, assessed using modified RECIST 1.1 criteria with CT scan evidence. Scans will be undertaken every 6 weeks and analysis will be timed from study entry using the baseline CT scan results until completion of the treatment cycles, confirmed disease progression or death (whichever occurs first)
Secondary outcome measures
1. Disease control rate (DCR) after 24 weeks, assessed using modified RECIST 1.1 criteria with CT scan evidence. Scans will be undertaken every 6 weeks and analysis will be timed from study entry using the baseline CT scan results until completion of the treatment cycles, confirmed disease progression or death (whichever occurs first)
2. Objective response rate (ORR), assessed using modified RECIST 1.1. criteria with CT scan evidence for 12 months (up to 6 months during treatment and 6 months of follow-up)
3. Safety, assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria for up to 6 months during treatment and 6 months of follow-up
4. Adverse events, recorded in relation to each cycle of treatment and graded according to CTCAE criteria. 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 we cannot guarantee that some patients may participate over 12 months
5. Toxicity, assessed according to CTCAE criteria for up to 6 months during treatment and 6 months of follow-up
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant inclusion criteria
1. Histologically confirmed MM with an available biopsy for research purposes
2. Aged 18 years or older
3. Expected survival of ≥12 weeks or greater
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
5. CT scan of chest and abdomen (and pelvis if applicable) confirming disease progression
6. Received at least one prior line of therapy to include a platinum doublet first-line chemotherapy (within or outside of another clinical trial)
7. Willing to consent for molecular screening of archived tumour block (PIS1 & CF1)
Each individual MiST drug protocol contains the eligibility criteria specific to the treatment allocated to the patient and these are yet to be finalised.
Target number of participants
Participant exclusion criteria
1. Diagnosis of a second malignancy except prostate or cervical cancer in remission, or a diagnosis of basal cell carcinoma of the skin or superficial bladder cancer
2. Uncontrolled CNS disease (asymptomatic brain metastases are allowed if previously treated with radiotherapy >28 days prior to starting the investigational agent)
3. New York Heart Association Class II or greater congestive heart failure
4. Severe hepatic insufficiency or severe renal impairment
5. Requiring long term oxygen therapy.
6. 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
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary, Infirmary Square
Trial participating centre
The Christie NHS Foundation Trust
Trial participating centre
The Royal Marsden NHS Foundation Trust
University of Leicester
Research Governance Office
Leicester General Hospital
British Lung Foundation
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both publically funded and privately funded)
Results and Publications
Publication and dissemination plan
The results of the trial will be published in a high-impact peer reviewed scientific journal around six months after each individual trial treatment protocol has completed.
IPD sharing statement:
The datasets generated during and/or analysed during the current study are/will be available for sharing via controlled access by authorised University of Leicester staff (as delegated by the trial sponsor) and anonymised IPD within the clinical trial dataset will be available for sharing via open access after the trial is published.
Intention to publish date
Participant level data
Available on request
Basic results (scientific)