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

University of Leicester

Status and phase: Active, not recruiting; Phase 2

Conditions: Mesothelioma, Malignant

Treatments: Drug: Rucaparib; Drug: Atezolizumab & Bevacizumab; Drug: Abemaciclib; Drug: Dostarlimab and Niraparib; Drug: pembrolizumab & bemcentinib

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03654833

0627

Details and patient eligibility

About

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.

Full 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.

Enrollment: 186 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

186 participants in 5 patient groups

MiST1 Rucaparib

Experimental group

Description:

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

Treatment:

Drug: Rucaparib

MiST2 Abemaciclib

Experimental group

Description:

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

Treatment:

Drug: Abemaciclib

MiST3 Pembrolizumab & Bemcentinib

Experimental group

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.

Treatment:

Drug: pembrolizumab & bemcentinib

MiST4 Atezolizumab & Bevacizumab

Experimental group

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.

Treatment:

Drug: Atezolizumab & Bevacizumab

MiST 5 Dostarlimab and Niraparib

Experimental group

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.

Treatment:

Drug: Dostarlimab and Niraparib