Condition category
Cancer
Date applied
18/09/2018
Date assigned
01/10/2018
Last edited
01/10/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Malignant mesothelioma is a lethal cancer caused by asbestos. Effective therapy is lacking and there is a pressing unmet need for this. Personalising therapy has led to dramatic advances in the treatment of several cancers. With increasing knowledge of the genetic differences between patients with mesothelioma, the opportunity to select patients most likely to benefit from specific drugs is becoming a reality.
Mesothelioma Stratified Therapy (MiST) has been conceived as the first ever research platform for testing new therapies for patients with mesothelioma who have been identified as having specific subtypes most likely to respond to new, targeted therapies. The aim of MiST is to accelerate the development of effective therapy for mesothelioma in order to improve the limited survival associated with this cancer.

Who can participate?
Adults who have mesothelioma that has come back after chemotherapy treatment, and who are willing to provide a sample of tissue and blood for the trial, have satisfactory blood test results and are able to take care of themselves

What does the study involve?
The MiST study is in three stages.
Stage 1 is called molecular pre-screening, where participants will have their tumour tested for predictive biomarkers, which are molecules that act as indicators of the disease and will be used to determine what treatment they will be most likely to benefit from. The results of this will then be used to classify participants into one of four molecularly-defined treatment arms. Participants will therefore be offered a specific study based on the results of their biomarkers.
Stage 2 is then treatment, which is based on the results of stage 1. Participants will be given different drug treatments depending on the biomarkers they do and do not have. Treatment will continue for the duration of the study or until there is evidence that the mesothelioma has grown, the patient or doctor decides to stop it due to side effects, or the patient dies.
Stage 3 is called genomic analysis, where DNA (and/or RNA) is extracted from patient biopsies from stage 1. This will create a profile that can be used to look for biomarkers of the response to the treatment.

What are the possible benefits and risks of participating?
The potential benefits of participating are potential disease control, control of symptoms and longer survival. The potential risks of participating in this study are a lack of efficacy and potential toxicity. Side effects will differ depending on what treatment arm the patients will receive. The study doctor will advise on the specific side effects relating to the treatment.

Where is the study run from?
1. University Hospitals of Leicester NHS Trust (UK) (lead centre)
2. The Christie NHS Foundation Trust (UK)
3. The Royal Marsden NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
April 2017 to January 2021

Who is funding the study?
The British Lung Foundation (UK)

Who is the main contact?
Amy King (manager of the Mesothelioma Research Programme)
MiST@uhl-tr.nhs.uk

Trial website

www.mesothelioma-research-leicester.com/mist/

Contact information

Type

Scientific

Primary contact

Prof Dean Fennell

ORCID ID

http://orcid.org/0000-0001-7373-1312

Contact details

Mesothelioma Research Group
Level 4
Robert Kilpatrick Clinical Sciences Building
Leicester Royal Infirmary
Leicester
LE2 7LG
United Kingdom

Additional identifiers

EudraCT number

2017-003353-41

ClinicalTrials.gov number

NCT03654833

Protocol/serial number

0627

Study information

Scientific title

Mesothelioma Stratified Therapy (MiST): A stratified multi-arm phase II clinical trial to enable accelerated evaluation of targeted therapies for relapsed malignant mesothelioma.

Acronym

MiST

Study hypothesis

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?

Ethics approval

East Midlands - Leicester South Research Ethics Committee, 05/07/2018, 18/EM/0118

Study design

Interventional non-randomised study

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please contact: MiST@uhl-tr.nhs.uk to request a participant information sheet

Condition

Mesothelioma

Intervention

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.

Intervention type

Drug

Phase

Phase II

Drug names

MiST1 Rucaparib
MiST2 Abemaciclib
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

01/04/2017

Overall trial end date

01/01/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Pre-screening:
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.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

120

Participant exclusion criteria

Pre-screening:
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

01/01/2019

Recruitment end date

01/06/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary, Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
Wilmslow Road
Manchester
M20 4BX
United Kingdom

Trial participating centre

The Royal Marsden NHS Foundation Trust
Fulham Road
LONDON
SW3 6JJ
United Kingdom

Sponsor information

Organisation

University of Leicester

Sponsor details

Research Governance Office
Academic Departments
Leicester General Hospital
Leicester
LE5 4PW
United Kingdom

Sponsor type

University/education

Website

www.le.ac.uk

Funders

Funder type

Not defined

Funder name

British Lung Foundation

Alternative name(s)

BLF

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United Kingdom

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

01/06/2020

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes