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

Primary Purpose

Mesothelioma, Malignant

Status
Active
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Rucaparib
Abemaciclib
pembrolizumab & bemcentinib
Atezolizumab & Bevacizumab
Dostarlimab and Niraparib
Sponsored by
University of Leicester
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mesothelioma, Malignant focused on measuring Drug: multi-arm, Phase IIa

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University Hospitals of Leicester NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

MiST1 Rucaparib

MiST2 Abemaciclib

MiST3 Pembrolizumab & Bemcentinib

MiST4 Atezolizumab & Bevacizumab

MiST 5 Dostarlimab and Niraparib

Arm Description

BRCA1/BAP1 negative mesothelioma; 600mg twice daily (BID) every 28 days.

p16INK4A negative mesothelioma; 200mg orally twice daily every 28 days.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Objective response rate (ORR) assessed for 12 months
This will be assessed using CT scan evidence according to modified RECIST 1.1 criteria
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.
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.

Full Information

First Posted
August 7, 2018
Last Updated
March 13, 2023
Sponsor
University of Leicester
Collaborators
British Lung Foundation, Clovis Oncology, Inc., Eli Lilly and Company, Merck Sharp & Dohme LLC, BerGenBio ASA, Roche Pharma AG, University Hospitals, Leicester, The Christie NHS Foundation Trust, GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT03654833
Brief Title
Mesothelioma Stratified Therapy (MiST) : A Multi-drug Phase II Trial in Malignant Mesothelioma
Acronym
MiST
Official Title
Mesothelioma Stratified Therapy (MiST): A Stratified Multi-arm Phase IIa Clinical Trial to Enable Accelerated Evaluation of Targeted Therapies for Relapsed Malignant Mesothelioma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 28, 2019 (Actual)
Primary Completion Date
October 31, 2023 (Anticipated)
Study Completion Date
October 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Leicester
Collaborators
British Lung Foundation, Clovis Oncology, Inc., Eli Lilly and Company, Merck Sharp & Dohme LLC, BerGenBio ASA, Roche Pharma AG, University Hospitals, Leicester, The Christie NHS Foundation Trust, GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mesothelioma, Malignant
Keywords
Drug: multi-arm, Phase IIa

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
186 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MiST1 Rucaparib
Arm Type
Experimental
Arm Description
BRCA1/BAP1 negative mesothelioma; 600mg twice daily (BID) every 28 days.
Arm Title
MiST2 Abemaciclib
Arm Type
Experimental
Arm Description
p16INK4A negative mesothelioma; 200mg orally twice daily every 28 days.
Arm Title
MiST3 Pembrolizumab & Bemcentinib
Arm Type
Experimental
Arm Description
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.
Arm Title
MiST4 Atezolizumab & Bevacizumab
Arm Type
Experimental
Arm Description
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.
Arm Title
MiST 5 Dostarlimab and Niraparib
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rucaparib
Other Intervention Name(s)
CO-338
Intervention Description
PARP inhibitor
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Other Intervention Name(s)
LY2835219
Intervention Description
CDK4/6 inhibitor
Intervention Type
Drug
Intervention Name(s)
pembrolizumab & bemcentinib
Other Intervention Name(s)
Keytruda; BGB324
Intervention Description
PD1 checkpoint inhibitor, AXL inhibitor
Intervention Type
Drug
Intervention Name(s)
Atezolizumab & Bevacizumab
Other Intervention Name(s)
MPDL3280A; Avastin
Intervention Description
PDL1 checkpoint inhibitor, VEGF inhibitor
Intervention Type
Drug
Intervention Name(s)
Dostarlimab and Niraparib
Other Intervention Name(s)
Zejula
Intervention Description
IG Antibody, PARP Inhibitor
Primary Outcome Measure Information:
Title
Disease control rate (DCR) at 12 weeks assessed by modified RECIST 1.1, in patients with relapsed mesothelioma.
Description
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.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Disease control rate (DCR) at 24 weeks assessed by modified RECIST 1.1, in patients with relapsed mesothelioma.
Description
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.
Time Frame
24 weeks
Title
Objective response rate (ORR) assessed for 12 months
Description
This will be assessed using CT scan evidence according to modified RECIST 1.1 criteria
Time Frame
Up to 12 months (up to 6 months during treatment and 6 months of follow-up)
Title
Safety assessed according to CTCAE criteria.
Description
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.
Time Frame
12 months (up to 6 months during treatment and 6 months of follow-up)
Title
Toxicity assessed according to CTCAE criteria.
Description
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.
Time Frame
12 months (up to 6 months during treatment and 6 months of follow-up)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dean Fennell, PhD, FRCP
Organizational Affiliation
University of Leicester
Official's Role
Study Director
Facility Information:
Facility Name
University Hospitals of Leicester NHS Trust
City
Leicester
ZIP/Postal Code
LE1 5WW
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35157829
Citation
Fennell DA, King A, Mohammed S, Greystoke A, Anthony S, Poile C, Nusrat N, Scotland M, Bhundia V, Branson A, Brookes C, Darlison L, Dawson AG, Gaba A, Hutka M, Morgan B, Bajaj A, Richards C, Wells-Jordan P, Thomas A; MiST2 study group. Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial. Lancet Oncol. 2022 Mar;23(3):374-381. doi: 10.1016/S1470-2045(22)00062-6. Epub 2022 Feb 11.
Results Reference
derived
PubMed Identifier
33515503
Citation
Fennell DA, King A, Mohammed S, Branson A, Brookes C, Darlison L, Dawson AG, Gaba A, Hutka M, Morgan B, Nicholson A, Richards C, Wells-Jordan P, Murphy GJ, Thomas A; MiST1 study group. Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial. Lancet Respir Med. 2021 Jun;9(6):593-600. doi: 10.1016/S2213-2600(20)30390-8. Epub 2021 Jan 27.
Results Reference
derived

Learn more about this trial

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

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