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

Conditions

Mesothelioma, Malignant

Keywords

Drug: multi-arm, Phase IIa

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.

Zhang M, Bzura A, Baitei EY, Zhou Z, Spicer JB, Poile C, Rogel J, Branson A, King A, Barber S, Kamata T, Dzialo J, Harber J, Greystoke A, Nusrat N, Faulkner D, Sun Q, Nolan L, Hahne JC, Scotland M, Walter H, Darlison L, Morgan B, Bajaj A, Brookes C, Hollox EJ, Lubawska D, Jama M, Griffiths G, Nakas A, Kutywayo K, Luo JL, Klampatsa A, Cooper A, Halder K, Wells-Jordan P, Zhou H, Dudbridge F, Thomas A, Richards CJ, Pritchard C, Yang H, Barer M, Fennell DA.

2024-08-2119 citations

10.1038/s41467-024-49842-5

Niraparib and dostarlimab efficacy in patients with platinum-sensitive relapsed mesothelioma: MIST5, a phase IIa clinical trial.

Dean A. Fennell, Amy Branson, Amy King, Charlotte Poile, Shaun Barber et al. (15 authors)

Journal of Clinical Oncology2024-06-01

10.1200/jco.2024.42.16_suppl.8017

Reflecting real-world patients with mesothelioma in research: an interim report of baseline characteristics from the ASSESS-meso cohort

Ruairi James Harwood Conway, Natalie Smith, William A. Cooper, Geraldine Lynch, Sampada Patole et al. (10 authors)

ERJ Open Research2023-11-017 citations

10.1183/23120541.00467-2023

Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres

Dean A. Fennell, Daniel E. Griffiths, Zina Eminton, Abigail Morgan-Fox, Kayleigh Hill et al. (19 authors)

BMJ Open2023-11-014 citations

10.1136/bmjopen-2023-073120

Bemcentinib and pembrolizumab in patients with relapsed mesothelioma: MIST3, a phase IIa trial with cellular and molecular correlates of efficacy.

Matthew Krebs, Amy Branson, Shaun Barber, Charlotte Poile, Amy King et al. (17 authors)

Journal of Clinical Oncology2023-06-016 citations

10.1200/jco.2023.41.16_suppl.8511

A gut microbiota rheostat to forecast response to PDL1-VEGF blockade in mesothelioma.

Dean A. Fennell, Aleksandra Bzura, Amy Branson, Amy King, Jan Rogel et al. (20 authors)

Journal of Clinical Oncology2023-06-011 citations

10.1200/jco.2023.41.16_suppl.e20534

28P Epithelial mesenchymal transition confers resistance to dual PDL1-VEGF inhibition in relapsed mesothelioma

Essa Y. Baitei, M. Zhang, C. Poile, J-L. Luo, J. Dzialo et al. (15 authors)

Immuno-Oncology Technology2022-12-01

10.1016/j.iotech.2022.100133

Atezolizumab and bevacizumab in patients with relapsed mesothelioma: MIST4—a phase IIa trial with cellular and molecular correlates of efficacy.

Dean A. Fennell, Amy King, Amy Branson, Shaun Barber, Alastair Greystoke et al. (16 authors)

Journal of Clinical Oncology2022-06-011 citations

10.1200/jco.2022.40.16_suppl.8560

Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial.

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.

2022-02-1149 citations

10.1016/s1470-2045(22)00062-6

A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.

Dean A. Fennell, Amy King, Seid Mohammed, Amy Branson, Alastair Greystoke et al. (19 authors)

Journal of Clinical Oncology2021-05-207 citations

10.1200/jco.2021.39.15_suppl.8558

Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial.

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.

2021-01-2775 citations

10.1016/s2213-2600(20)30390-8

MiST1: A phase IIa trial of rucaparib in patients harbouring BAP1/BRCA1 deficient relapsed malignant mesothelioma.

Dean A. Fennell, Liz Darlison, Peter Wells-Jordan, C. J. Richards, Aarti Gaba et al. (18 authors)

Journal of Clinical Oncology2020-05-205 citations

10.1200/jco.2020.38.15_suppl.9057

Interventions

DRUGRucaparib

PARP inhibitor

DRUGAbemaciclib

CDK4/6 inhibitor

DRUGpembrolizumab & bemcentinib

PD1 checkpoint inhibitor, AXL inhibitor

DRUGAtezolizumab & Bevacizumab

PDL1 checkpoint inhibitor, VEGF inhibitor

DRUGDostarlimab and Niraparib

IG Antibody, PARP Inhibitor

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
Disease Control Rate (DCR) at 12 Weeks Assessed by Modified RECIST 1.1, in Patients With Relapsed Mesothelioma.	12 weeks	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. Complete response (CR): disappearance of all target and non-target lesions with no evidence of tumour elsewhere Partial response (PR): reduction of at least 30% in the sum of all measurements with no evidence of significant disease progression in non-target lesions or new lesions Progressive disease (PD): 1: increase of at least 20% in the sum of all measurements compared with the previous best response, 2: appearance of one or more significant (overall 20% increase in tumour diameters) new lesions, 3: significant increase in target lesions Stable disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD

Secondary

Measure	Time frame	Description
Disease Control Rate (DCR) at 24 Weeks Assessed by Modified RECIST 1.1, in Patients With Relapsed Mesothelioma.	24 weeks	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. Complete response (CR): disappearance of all target and non-target lesions with no evidence of tumour elsewhere Partial response (PR): reduction of at least 30% in the sum of all measurements with no evidence of significant disease progression in non-target lesions or new lesions Progressive disease (PD): 1: increase of at least 20% in the sum of all measurements compared with the previous best response, 2: appearance of one or more significant (overall 20% increase in tumour diameters) new lesions, 3: significant increase in target lesions Stable disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD
Objective Response Rate (ORR) at 24 Weeks Assessed by Modified RECIST 1.1, in Patients With Relapsed Mesothelioma.	24 weeks	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. Complete response (CR): disappearance of all target and non-target lesions with no evidence of tumour elsewhere Partial response (PR): reduction of at least 30% in the sum of all measurements with no evidence of significant disease progression in non-target lesions or new lesions Progressive disease (PD): 1: increase of at least 20% in the sum of all measurements compared with the previous best response, 2: appearance of one or more significant (overall 20% increase in tumour diameters) new lesions, 3: significant increase in target lesions Stable disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD

Countries

United Kingdom

Contacts

STUDY_DIRECTORDean Fennell, PhD, FRCP

University of Leicester

Participant flow

Pre-assignment details

The MiST Master protocol states "Trial Design of the MiST study is in three stages: Stage 1-molecular pre-screening: The MiST Master protocol describes the identification of patients, biomarker testing and analysis. Stage 2- Treatment: The MiST treatment protocol will be specific to the treatment allocated to the patient Stage 3-Genomic Profiling": The Screening target for the pre-screening stage was 186 patients. After screening the number recruited for the treatment stage was 130 patients.

Baseline characteristics

Characteristic	—
Age, Continuous	69.5 years
ECOG status One	20 Participants
ECOG status Zero	4 Participants
First line therapy Bevacizumab alone	0 Participants
First line therapy Bevacizumab and Pemetrexed and/or Carboplatin	5 Participants
First line therapy Missing	9 Participants
First line therapy Other	0 Participants
First line therapy Pemetrexed alone	1 Participants
First line therapy Pemetrexed and Cisplatin/Carboplatin	0 Participants
First line therapy Pemetrexed and/or Carboplatin	0 Participants
First line therapy Pemetrexed and/or Cisplatin	8 Participants
First line therapy Pemetrexed & Carboplatin	0 Participants
First line therapy Pemetrexed/Carboplatin	7 Participants
First line therapy Pemetrexed & Cisplatin	0 Participants
First line therapy Pemetrexed/Cisplatin	0 Participants
First line therapy Pemetrexed & Cisplatin & Bevacizumab	1 Participants
First line therapy Radiotherapy	0 Participants
History of asbestos No	0 Participants
History of asbestos Unknown	9 Participants
History of asbestos Yes	89 Participants
Mesothelioma subtype Biphasic	5 Participants
Mesothelioma subtype Epithelioid	21 Participants
Mesothelioma subtype NOS	1 Participants
Mesothelioma subtype Sarcomatoid	2 Participants
M-stage M0	97 Participants
M-stage M1	4 Participants
M-stage Missing	0 Participants
M-stage Unobtainable	5 Participants
N-stage Missing	1 Participants
N-stage N0	59 Participants
N-stage N1	7 Participants
N-stage N2	7 Participants
N-stage N3	2 Participants
N-stage Unobtainable	3 Participants
Number of prior courses of systemic anticancer therapy Five	1 Participants
Number of prior courses of systemic anticancer therapy Four	1 Participants
Number of prior courses of systemic anticancer therapy One	12 Participants
Number of prior courses of systemic anticancer therapy Three	17 Participants
Number of prior courses of systemic anticancer therapy Two	7 Participants
P16 Negative	0 Participants
P16 Not applicable	0 Participants
P16 Positive	6 Participants
Primary Tumour site Abdominal	1 Participants
Primary Tumour site Missing	0 Participants
Primary Tumour site Pelvis	1 Participants
Primary Tumour site Thoracic	24 Participants
Race and Ethnicity Not Collected	0 Participants
Second line therapy ADI-Peg 20/placebo	1 Participants
Second line therapy Bevacizumab	0 Participants
Second line therapy Carboplatin and taxel	0 Participants
Second line therapy Gemcitabine & AZD6738	1 Participants
Second line therapy Missing	20 Participants
Second line therapy Nivolumab/Placebo	0 Participants
Second line therapy Other	8 Participants
Second line therapy Pembrolizumab + Defactinid	0 Participants
Second line therapy Pemetrexed and/or Carboplatin	0 Participants
Second line therapy Pemetrexed and/or Cisplatin	0 Participants
Second line therapy Pemetrexed & Carboplatin	0 Participants
Second line therapy Pemetrexed/Carboplatin	0 Participants
Second line therapy Pemetrexed/Carboplatin and Bevacizumab	0 Participants
Second line therapy Pemetrexed & Cisplatin	0 Participants
Second line therapy Pemetrexed/Cisplatin	2 Participants
Second line therapy Pemetrexed & Cisplatin & Bevacizumab	0 Participants
Second line therapy Radiotherapy	1 Participants
Second line therapy RSO-1	1 Participants
Second line therapy Rucaparib	2 Participants
Second line therapy Vinorelbine	0 Participants
Second line therapy Vinorelbine & carboplatin	0 Participants
Sex: Female, Male Female	4 Participants
Sex: Female, Male Male	22 Participants
Smoking status Ex-smoker	9 Participants
Smoking status Non-smoker	66 Participants
Smoking status Smoker	2 Participants
T-stage Missing	1 Participants
T-stage T1	6 Participants
T-stage T2	21 Participants
T-stage T3	37 Participants
T-stage T4	9 Participants
T-stage TX	3 Participants
T-stage Unobtainable	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	12 / 26	12 / 26	16 / 26	7 / 26	15 / 26
other Total, other adverse events	24 / 26	22 / 26	24 / 26	23 / 26	22 / 26
serious Total, serious adverse events	9 / 26	6 / 26	10 / 26	11 / 26	9 / 26

Outcome results

None listed