Mesothelioma Stratified Therapy (MiST): A multi-drug phase II trial in malignant mesothelioma

ISRCTN	ISRCTN39816629
DOI	https://doi.org/10.1186/ISRCTN39816629
EudraCT/CTIS number	2017-003353-41
ClinicalTrials.gov number	NCT03654833
Secondary identifying numbers	0627

Submission date: 18/09/2018
Registration date: 01/10/2018
Last edited: 30/08/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-targeted-drugs-for-mesothelioma-mist

Study website

Contact information

Prof Dean Fennell
Scientific

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

ORCID ID	0000-0001-7373-1312

Study information

Study design	Interventional non-randomised study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please contact: MiSTmailbox@leicester.ac.uk to request a participant information sheet.
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.
Study 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(s)	East Midlands - Leicester South Research Ethics Committee, 05/07/2018, 18/EM/0118
Condition	Mesothelioma
Intervention	Current intervention as of 30/08/2022: 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. 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. Closed to recruitment. 2. MiST2: Abemaciclib for patients with p16INK4A negative mesothelioma (200 mg orally twice daily (BID) every 28 days) for 6 cycles. Closed to recruitment. 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. - closed to recruitment. 4. MiST4: Atezolizumab & bevacizumab for patients with PDL1 expression positive mesothelioma. Atezolizumab will be given at a dose of 1200 mg 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. Closed to recruitment. 5. MiST 5: Dostarlimab and niraparib in Patients with platinum-sensitive relapsed mesothelioma. Niraparib will be administered once daily depending on patient’s weight and platelet count. A cycle consists of 21 days and there will be up to 35 cycles in total: 5.1. ≥77 kg and ≥150,000 μL 300 mg (3 X 100 mg capsules) 5.2. <77 kg or <150,000 μL 200 mg (2 X 100 mg capsules) Dostarlimab will be given at a fixed dose of 500 mg via IV infusion on Day 1 of each 21-day cycle for 4 cycles. Followed by 1000 mg via IV infusion on Day 1 of each 42-day cycle for up to 24 months. 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, 4 & 5, immune checkpoint, transcriptomic and gut microbiome correlative studies are planned. _____ Previous 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
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Rucaparib, abemaciclib, pembrolizumab, bemcentinib, atezolizumab, bevacizumab, dostarlimab, niraparib
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 study start date	01/04/2017
Overall study end date	01/10/2023

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	200
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 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	31/01/2023

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University Hospitals of Leicester NHS Trust

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Wythenshawe Hospital

Southmoor Road
Wythenshawe
Manchester
M23 9LT
United Kingdom

Southampton

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Sponsor information

University of Leicester
University/education

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

Website	www.le.ac.uk
"ROR"	https://ror.org/04h699437

Funders

Funder type

Not defined

British Lung Foundation
Private sector organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): BLF
Location: United Kingdom

Results and Publications

Intention to publish date	01/06/2020
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
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 plan	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.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	MiST1	01/06/2021	28/06/2022	Yes	No
Results article	MiST2	01/03/2022	28/06/2022	Yes	No
HRA research summary			28/06/2023	No	No

Editorial Notes

30/08/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/06/2020 to 31/01/2023.
2. The overall trial end date has been changed from 01/01/2021 to 01/10/2023.
3. The intervention has been changed.
4. Dostarlimab and niraparib have been added to the drug names.
5. The participant information sheet instructions have been updated.
6. The target number of participants has been changed from 120 to 200.
7. The Royal Marsden NHS Foundation Trust has been removed from the trial participating centres and The Newcastle upon Tyne Hospitals NHS Foundation Trust, Wythenshawe Hospital and Southampton General Hospital added.
8. The CRUK summary link has been updated.
28/06/2022: Publication references added.
26/06/2020: Cancer Research UK lay summary link added to plain English summary field.